- Email: [email protected]
Unusual Keratitis from a Household Remedy
UNUSUAL KERATITIS FROM A HOUSEHOLD REMEDY ANDREW A. DAHL, M.D., A: ) W. MORTON GRANT,
Boston, M
During a nine-month period, we have seen seven patients with a rather uniform clinical picture of keratoconjunctivitis which ap pears to have been caused by a new form of Vick's VapoRub, marketed on a trial basis in Boston and Detroit. This new product has also proved injurious to the eyes of rabbits, whereas regular Vick's VapoRub has been innocuous. Although the new product has been with drawn from the market, publication of our observations seems worthwhile for several reasons. Of the several hundred thousand tubes that were distributed, many may re main in the hands of consumers, providing a potential cause of keratitis. In addition, de scription of the recognizable distinguishing characteristics of this keratitis should facili tate its diagnosis. The experience with this product provides additional evidence that preparations for the skin can readily con taminate the eyes without producing any warning discomfort unless, of course, a com ponent is present which immediately causes irritation. Mathalone and Easty 1 and Brodkin and Bleiberg2 have recently reported a similar type of keratitis resulting from the use of Exolan cream in the treatment of psoriasis. A-200 Pyrinate, a pediculocide ap plied to the hair, has also caused severe tran sitory keratitis through accidental contami nation of the eyes, as described by Reinecke and Kinder,3 and continues to be a cause of eye injuries, particularly in children. We feel that attention should be called to the possibility that components of the gel From the Howe Laboratory of Ophthalmology, Harvard Medical School, and Massachusetts Eye and Ear Infirmary. This study was supported by USPHS Grant NB 05691 and Research Grant NB 00218 from the National Institute of Neurological Diseases and Blindness. Reprint requests to W. Morton Grant, M.D., Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts 02114.
M.D.
sachusetts
base of greaseless VapoRub which are inju rious to the cornea may be used in other preparations for application to the skin, or possibly to the eyes, with similar results. Popp 4 described an almost identical clinical picture in 17 patients who used a sulfonamide eye ointment containing a polyethyleneglycol ether in its base ; this too produced no warning discomfort. Because the compo sition of VapoRub gel has not been revealed, it is impossible to determine the harmful components. Pharmaceutical manufacturers and ophthalmologists can, however, be gen erally alerted to this potential complication. Vick's VapoRub has been used exten sively for many years as a popular selftreatment for symptoms of upper respira tory congestion and sometimes for minor headache ; there have been no reported cases of eye disturbance. A new form of Vick's VapoRub, which recently became available, principally in Boston and Detroit, is a greaseless gel preparation packaged in a plastic squeeze tube. It is easily distin guished from the regular form which is dis pensed in a jar and has a greasy petrolatum base. The new product has been labeled with a list of the same "active ingredients" as the old preparation (camphor, menthol, spirits of turpentine, thymol, eucalyptus oil, cedar leaf oil, myristica oil) and gives similar di rections for the product's use (apply to chest, neck and back). Although facial appli cation is not mentioned, many people, through their own initiative and preference, have been accustomed to applying the regu lar VapoRub to their face and nose. The seven patients in whom an unusual type of keratitis was recognized had fre quently used the old form of Vick's Vapo Rub for eight to 30 years without complica tions. Each had recently purchased a tube of the new greaseless gel preparation. Six of the seven patients had used the new form
UNUSUAL KERATITIS
VOL. 68, NO. 5
for the first time a few hours prior to the onset of their ocular difficulties. The seventh patient could not remember which form of the medication he had used on that occasion. Each of the seven patients applied the new medication much as they had applied the regular one over the preceding years. Six patients denied that the material had entered their eyes; one patient (Case 2) thought she might have accidentally introduced some into her eyes, but was not sure. One patient ( Case 3) had not used the medication herself but had applied it by hand to her son's chest prior to the onset of her ocular symptoms. The seven patients developed symptoms four to 12 hours after the use of Vick's VapoRub. In all cases blurring of vision was the initial symptom. All but one (Case 5) had a pain-free period followed by onset of ocu lar discomfort two to 24 hours later. One pa tient (Case 1) was without pain at the time of her initial examination; at that time hypesthesia of the cornea was detected by test with a cotton wisp. All patients had subnor mal visual acuity, conjunctival hyperemia and corneal edema with irregularity of the epithelium. Some had patchy loss of corneal epithelium, edema of the stroma and folds in Descemet's membrane, but only two patients had flare in the anterior chamber. None showed cells in the aqueous humor. Indications that a toxic factor was respon sible, leading to investigations along this line, included the absence of all ordinary in dications of bacterial or viral infection, uveitis, glaucoma, exposure to ultraviolet light, wearing of contact lenses or physical trauma such as that which might cause corneal edema, epithelial defects and discomfort. Questioning revealed the common factor of exposure to the new VapoRub preparation. CASE REPORTS CASE 1
A 26-year-old woman had used regular Vick's VapoRub on and around her nose in the treatment of nasal congestion for at least 10 years. She then used a new greaseless gel form of VapoRub for the first time, applying it to the surface of her nose
859
prior to retiring. She awoke in the morning with blurring of her vision in both eyes, but with no dis comfort. When seen in our emergency room three hours later, her visual acuity was : R.E., 20/50 ; L.E., 20/160. Examination revealed: slight conjunc tival hyperemia, but markedly subnormal corneal sensitivity to testing with a wisp of cotton ; a great deal of corneal epithelial irregularity and clouding in the right eye ; and almost complete denudation of the corneal epithelium with a trace of stromal edema in the left eye (fig. 1). Both anterior cham bers were clear. Intraocular pressure was normal to palpation. The patient was treated with mydriatic, antibiotic and eyepads. Four hours later, severe dis comfort and tearing began in both eyes, gradually increasing and reaching a maximum the next day, when corneal sensation was found to have returned to normal, although the corneal epithelium in both eyes still showed defects and irregularities. Folds in Descemet's membrane were still present in the left eye. The anterior chambers continued to have no cells or flare. Under the same treatment the eyes gradually became more comfortable; three and one-half days after the initial exposure vision was : R.E., 20/20 ; L.E., 20/27. The corneas appeared nor mal at that time except for a small amount of subepithelial haze in the left eye. CASE 2
For 30 years this 54-year-old woman had fre quently applied regular Vick's VapoRub to her face for the relief of headache and cold symptoms; this had never produced any eye irritation. Four hours after applying the new greaseless gel VapoRub to her forehead for relief of headache she noticed bi lateral blurred vision, which persisted without pain until she was awakened the next morning by ocular foreign body-type discomfort and lacrimation. Her visual acuity was: R.E., 20/80; L.E., 20/120. The eyelids were edematous and the conjunctivas were diffusely hyperemia Both corneas showed superfi cial irregularities, edema and small areas of loss of epithelium. The anterior chambers were clear. The patient was treated with mydriatic, topical antibiotic and eyepads. She became essentially free of pain 12 hours later, although slight blurring of vision per sisted for three days. After four days vision in both eyes was 20/30+ and the conjunctivas showed minimal hyperemia. The corneas were lustrous. CASE 3
A 31-year-old woman, who had used regular Vick's VapoRub for at least eight years without trouble, applied the greaseless gel form for the first time to her son's chest and back with her fingers to relieve his nasal congestion. The following morning she awoke with tearing and blurred vision in the right eye; two hours later she noted the onset of discomfort in that eye. In our emergency room four hours later, visual acuity was: R.E., 20/120; L.E., 20/40. The affected right eye had moderate eyelid edema, conjunctival hyperemia, extensive haze, irregularity and edema of the corneal epithe lium, stromal edema and numerous folds in Desce-
860
P"
AMERICAN JOURNAL OF OPHTHALMOLOGY
*^η0
N O V E M B E R , 1969
τ < .»s^ÉÉML.
'*%
%-m; i·
Fig. 1 (Dahl and Grant). Left eye of the patient in Case 1, day of onset of symptoms, showing corneal irregularity due to loss of epithelium and slight stromal edema after applying greaseless gel medication on and around the nose the previous evening. met's membrane. Corneal haze prevented adequate evaluation of the character of the aqueous humor. The intraocular pressure was 8.0 mm H g in both eyes. The right eye was treated with mydriatic, an tibiotic and eyepad. The next day the patient still complained of severe blurring of vision and discom fort; the cornea of the right eye had lost a large area of epithelium. T h e patient became asymptom atic two days later. Six days following exposure to VapoRub the cornea of the right eye was normal. CASE 4
A 33-year-old woman, who had used regular Vick's VapoRub for at least 10 years without trou ble, applied the new greaseless form for the first time to the outside of her nose for nasal congestion. Upon awakening the following morning vision was blurred in the right eye. She was without discom fort until much later in the day. When she came to our emergency room visual acuity w a s : R.E., 20/120; L.E., 25/25. The right eye had moderate conjunctival hyperemia, diffuse haze in the corneal epithelium and areas of loss of epithelium ; the an terior chamber was clear, however. After treatment with mydriatic, topical antibiotic and eyepad for 24 hours, the eye became comfortable ; vision returned to normal within 48 hours of the exposure to Vapo Rub.
CASE 5
A 35-year-old woman, who had used regular Vick's VapoRub for at least 10 years for relief of headache, applied the new greaseless form for the first time to her forehead in the usual manner. Upon awakening the following morning she noted blurring of vision and foreign-body sensation in both eyes. The discomfort persisted and later that day became worse, accompanied by lacrimation and photophobia. When she came to our emergency room that evening, visual acuity w a s : R.E., 20/50; L.E., 20/40. Both eyes had moderate conjunctival hyperemia, edema and haze of the corneal epithe lium and moderate flare without cells in the aqueous humor. After treatment for two days with mydriatic, topical antibiotic and eye dressings the eyes became asymptomatic, the corneas became clear and visual acuity improved to 20/20 in both eyes. CASE 6
A 50-year-old woman, who had applied regular Vick's VapoRub to her temples for relief of head ache for at least 20 years, used the new greaseless form for the first time in a similar manner. The next morning she noticed blurred vision in the right eye without discomfort; four hours later she expe rienced mild pain in the right eye. The pain and
VOL. 68, NO. S
UNUSUAL KERATITIS
blurring were still present the following day when she was seen in our emergency room. Visual acuity was: R.E., 20/200; L.E., 20/30. The affected eye had moderate edema of the eyelids, conspicuous conjunctival hyperemia and a large defect in the corneal epithelium centrally with surrounding epi thelial haze. The anterior chamber was clear. After treatment with topical antibiotic and corticosteroid for 36 hours the patient was asymptomatic and vi sual acuity had returned to normal. CASE 7
A 60-year-old man had used regular Vick's VapoRub for over 20 years for symptomatic relief of colds. He had recently purchased the new greaseless preparation but he could not recall which form he applied to his forehead on the evening prior to the onset of his visual difficulties. He awoke with blur ring of vision in both eyes which persisted. The fol lowing day he first noted discomfort in both eyes but he did not seek medical attention until two days later. When seen in our emergency room, the pa tient's vision was: R.E., counting fingers at IS feet ; L.E., counting fingers at four feet. He had blepharospasm and conjunctival hyperemia. Both corneas showed severe surface irregularity and haze with patches of loss of epithelium, moderate stromal edema and many folds in Descemet's mem brane. Very slight flare was seen in the aqueous humor of both eyes. Both lenses had posterior subcapsular cataracts. After treatment for two days with mydriatic, antibiotic and double eyepads, the patient still had irregularity and cloudiness of the corneal epithelium, but by 11 days after his use of Vick's VapoRub his corneas had become clear and visual acuity had improved to 20/100 in the right eye and counting fingers at six feet in the left eye. This was consistent with the amount of cataract present, probably the same as before the episode of keratitis. EXPERIMENTAL
STUDIES
In order to examine and compare the ef fects of both forms of VapoRub on the eye, we tested them on rabbits. After local anes thesia was induced with a drop of 0.5% pro paracaine hydrochloride solution on both eyes of two albino rabbits, the regular Vapo Rub was applied to both right eyes and the new greaseless gel preparation was applied to the left eyes. We placed an amount about the size of a split pea on the upper limbus with a glass rod and allowed it to spread spontaneously and by motion of the eyelids. The right eyes, exposed to the regular Vapo Rub, showed no injury at any time and no disturbance was detectable by slitlamp biomicroscopy. No immediate effect was seen in
861
the left eyes, which had been exposed to the greaseless gel, but 17 hours later they showed hyperemia and chemosis and were photophobic. The corneal epithelium in these eyes was irregular, hazy and absent from some areas. Testing with a cotton wisp showed the corneas of both left eyes to be hypesthetic. In 10 days these corneas healed and returned to normal. The same type of reaction, although less severe, was induced in three additional rabbits tested with the greaseless gel preparation without prelimi nary anesthetic. The eyes usually healed in three to four days. In order to separate vehicle and volatile constituents, a sample of the greaseless gel was subjected to vacuum with a rotary oil pump at warm room temperature for several hours; the content of volatile components was reduced to the degree that the residue retained only slight aroma compared to the strong smell of the original. This residue was tested on rabbit eyes after application of 0.5% proparacaine hydrochloride in the same manner as in the first experiments and caused the same type of injury to the corneal epithelium as did the original gel material, suggesting that the injurious component was not readily volatile, as were the listed "active ingredients." We explored the effects of the readily vol atile components of the gel-type VapoRub which had caused keratitis when applied di rectly to the rabbits' eyes by coating the in side of a cylindrical glass jar ( 12-inch diam eter, 18-inch length) with the gel prepara tion directly from the tube. We positioned a rabbit in a holder inside the jar so that its eyes were approximately five inches from the nearest coated surface. The rabbit could not actually touch the coating with any part of its head or body. Although no anesthetic was used, the rabbit showed no discomfort and did not close its eyes. However, the con junctivas soon appeared hyperemic and con siderable watery fluid dripped from nose and mouth. After four hours' exposure, and three additional hours on the next day with a
862
AMERICAN JOURNAL OF OPHTHALMOLOGY
fresh coating in the jar, no abnormality of corneas or conjunctivas was detectable ex cept for the mild and inconsequential conjunctival hyperemia seen during exposure. Tests on the eyes of one human volunteer showed no injury from 0.1 ml of 0.3% greaseless gel in saline solution. However, application of 1.6 mg of the undissolved gel caused foreign-body type discomfort and slight veiling of vision, such as that pro duced by mild epithelial edema, for 24 hours, with hyperemia and mucoid discharge. Re covery was complete in 36 hours. Household items which might be splashed in the eye, such as cleaners, detergents and similar substances, are currently required to be screened for possible adverse ocular ef fects under the Hazardous Substances Act. In order to fulfill the legal requirements, a modification of the Draize test is employed in which one eye of each of nine albino rab bits is used, the fellow eye serving as a con trol. The compound in question is placed in the conjunctival fornix in a fixed amount and the anterior segment is observed at in tervals for a period of four days using ap propriate magnification and illumination by competent observers. The amount of damage is noted and if there is any significant con junctival hyperemia, corneal epithelial loss or sign of anterior chamber inflammation, the substance is required to carry a warning of the possibility of eye damage on its label. Cosmetics are also regularly tested for eye irritancy. However, no testing or labeling procedures appear to be required for prepa rations that are considered to be drugs, al though they may be used in the vicinity of the eyes and may accidentally contaminate the eye. It would be of great value if manu facturers of such drug products would con duct testing procedures similar to those which are now required of the companies which produce household items such as cleaners and detergents. Although there is no question that the human eye may react dif ferently to a substance than the eye of an
NOVEMBER, 1969
experimental animal, the use of rabbits or similar animals in testing procedures should certainly screen out a large number of com pounds which are potentially toxic to the human eye, provided that the examination is performed by experienced observers using adequate illumination and magnification. Suitable labeling could then forewarn the consumer to avoid contaminating his eyes with the potentially injurious medicaments intended for his skin or hair. SUMMARY
Several hours after spreading a new greaseless gel trial form of a proprietary cold remedy (Vick's VapoRub) on the skin, principally on the nose and temples, seven patients developed hazy vision and moderate ocular discomfort, with edema of the cornea and loss of patches of corneal epithelium. The ocular symptoms generally lasted two or three days. These patients had never encoun tered adverse effects from a standard form of VapoRub which has a petrolatum base but which contains the same fragrant volatile medicaments. Rabbit and human eye tests provided supporting evidence that, while the standard petrolatum preparation was innocu ous, the new greaseless gel had injurious ac tion on the cornea and that this was caused by the greaseless gel base, not by the volatile constituents. Similar injuries to the eyes of patients are being induced by other medi cated skin and hair preparations, particularly Exolan cream and A-200 Pyrinate shampoo. More premarketing animal eye testing and warning labels are indicated. REFERENCES
1. Mathalone, M. B. R. and Easty, D. L. : Acute keratitis in psoriatic patients using triacetoxyanthracene. Lancet 2:195, 1967. 2. Brodkin, R. H. and Bleiberg, J. : Ophthalmologic side effects of a new topical psoriatic medica tion. Arch. Derm. 98 :S2S, 1968. 3. Reinecke, R. D. and Kinder, R. S. L. : Corneal toxicity of the pediculocide A-200 Pyrinate. Arch. Ophth. 68:36, 1962. 4. Popp, G: Korneaerosionen durch Polyäthylenglykoläther. Klin. Mbl. Augenh. 126:176, 19SS.
Boston, M
During a nine-month period, we have seen seven patients with a rather uniform clinical picture of keratoconjunctivitis which ap pears to have been caused by a new form of Vick's VapoRub, marketed on a trial basis in Boston and Detroit. This new product has also proved injurious to the eyes of rabbits, whereas regular Vick's VapoRub has been innocuous. Although the new product has been with drawn from the market, publication of our observations seems worthwhile for several reasons. Of the several hundred thousand tubes that were distributed, many may re main in the hands of consumers, providing a potential cause of keratitis. In addition, de scription of the recognizable distinguishing characteristics of this keratitis should facili tate its diagnosis. The experience with this product provides additional evidence that preparations for the skin can readily con taminate the eyes without producing any warning discomfort unless, of course, a com ponent is present which immediately causes irritation. Mathalone and Easty 1 and Brodkin and Bleiberg2 have recently reported a similar type of keratitis resulting from the use of Exolan cream in the treatment of psoriasis. A-200 Pyrinate, a pediculocide ap plied to the hair, has also caused severe tran sitory keratitis through accidental contami nation of the eyes, as described by Reinecke and Kinder,3 and continues to be a cause of eye injuries, particularly in children. We feel that attention should be called to the possibility that components of the gel From the Howe Laboratory of Ophthalmology, Harvard Medical School, and Massachusetts Eye and Ear Infirmary. This study was supported by USPHS Grant NB 05691 and Research Grant NB 00218 from the National Institute of Neurological Diseases and Blindness. Reprint requests to W. Morton Grant, M.D., Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts 02114.
M.D.
sachusetts
base of greaseless VapoRub which are inju rious to the cornea may be used in other preparations for application to the skin, or possibly to the eyes, with similar results. Popp 4 described an almost identical clinical picture in 17 patients who used a sulfonamide eye ointment containing a polyethyleneglycol ether in its base ; this too produced no warning discomfort. Because the compo sition of VapoRub gel has not been revealed, it is impossible to determine the harmful components. Pharmaceutical manufacturers and ophthalmologists can, however, be gen erally alerted to this potential complication. Vick's VapoRub has been used exten sively for many years as a popular selftreatment for symptoms of upper respira tory congestion and sometimes for minor headache ; there have been no reported cases of eye disturbance. A new form of Vick's VapoRub, which recently became available, principally in Boston and Detroit, is a greaseless gel preparation packaged in a plastic squeeze tube. It is easily distin guished from the regular form which is dis pensed in a jar and has a greasy petrolatum base. The new product has been labeled with a list of the same "active ingredients" as the old preparation (camphor, menthol, spirits of turpentine, thymol, eucalyptus oil, cedar leaf oil, myristica oil) and gives similar di rections for the product's use (apply to chest, neck and back). Although facial appli cation is not mentioned, many people, through their own initiative and preference, have been accustomed to applying the regu lar VapoRub to their face and nose. The seven patients in whom an unusual type of keratitis was recognized had fre quently used the old form of Vick's Vapo Rub for eight to 30 years without complica tions. Each had recently purchased a tube of the new greaseless gel preparation. Six of the seven patients had used the new form
UNUSUAL KERATITIS
VOL. 68, NO. 5
for the first time a few hours prior to the onset of their ocular difficulties. The seventh patient could not remember which form of the medication he had used on that occasion. Each of the seven patients applied the new medication much as they had applied the regular one over the preceding years. Six patients denied that the material had entered their eyes; one patient (Case 2) thought she might have accidentally introduced some into her eyes, but was not sure. One patient ( Case 3) had not used the medication herself but had applied it by hand to her son's chest prior to the onset of her ocular symptoms. The seven patients developed symptoms four to 12 hours after the use of Vick's VapoRub. In all cases blurring of vision was the initial symptom. All but one (Case 5) had a pain-free period followed by onset of ocu lar discomfort two to 24 hours later. One pa tient (Case 1) was without pain at the time of her initial examination; at that time hypesthesia of the cornea was detected by test with a cotton wisp. All patients had subnor mal visual acuity, conjunctival hyperemia and corneal edema with irregularity of the epithelium. Some had patchy loss of corneal epithelium, edema of the stroma and folds in Descemet's membrane, but only two patients had flare in the anterior chamber. None showed cells in the aqueous humor. Indications that a toxic factor was respon sible, leading to investigations along this line, included the absence of all ordinary in dications of bacterial or viral infection, uveitis, glaucoma, exposure to ultraviolet light, wearing of contact lenses or physical trauma such as that which might cause corneal edema, epithelial defects and discomfort. Questioning revealed the common factor of exposure to the new VapoRub preparation. CASE REPORTS CASE 1
A 26-year-old woman had used regular Vick's VapoRub on and around her nose in the treatment of nasal congestion for at least 10 years. She then used a new greaseless gel form of VapoRub for the first time, applying it to the surface of her nose
859
prior to retiring. She awoke in the morning with blurring of her vision in both eyes, but with no dis comfort. When seen in our emergency room three hours later, her visual acuity was : R.E., 20/50 ; L.E., 20/160. Examination revealed: slight conjunc tival hyperemia, but markedly subnormal corneal sensitivity to testing with a wisp of cotton ; a great deal of corneal epithelial irregularity and clouding in the right eye ; and almost complete denudation of the corneal epithelium with a trace of stromal edema in the left eye (fig. 1). Both anterior cham bers were clear. Intraocular pressure was normal to palpation. The patient was treated with mydriatic, antibiotic and eyepads. Four hours later, severe dis comfort and tearing began in both eyes, gradually increasing and reaching a maximum the next day, when corneal sensation was found to have returned to normal, although the corneal epithelium in both eyes still showed defects and irregularities. Folds in Descemet's membrane were still present in the left eye. The anterior chambers continued to have no cells or flare. Under the same treatment the eyes gradually became more comfortable; three and one-half days after the initial exposure vision was : R.E., 20/20 ; L.E., 20/27. The corneas appeared nor mal at that time except for a small amount of subepithelial haze in the left eye. CASE 2
For 30 years this 54-year-old woman had fre quently applied regular Vick's VapoRub to her face for the relief of headache and cold symptoms; this had never produced any eye irritation. Four hours after applying the new greaseless gel VapoRub to her forehead for relief of headache she noticed bi lateral blurred vision, which persisted without pain until she was awakened the next morning by ocular foreign body-type discomfort and lacrimation. Her visual acuity was: R.E., 20/80; L.E., 20/120. The eyelids were edematous and the conjunctivas were diffusely hyperemia Both corneas showed superfi cial irregularities, edema and small areas of loss of epithelium. The anterior chambers were clear. The patient was treated with mydriatic, topical antibiotic and eyepads. She became essentially free of pain 12 hours later, although slight blurring of vision per sisted for three days. After four days vision in both eyes was 20/30+ and the conjunctivas showed minimal hyperemia. The corneas were lustrous. CASE 3
A 31-year-old woman, who had used regular Vick's VapoRub for at least eight years without trouble, applied the greaseless gel form for the first time to her son's chest and back with her fingers to relieve his nasal congestion. The following morning she awoke with tearing and blurred vision in the right eye; two hours later she noted the onset of discomfort in that eye. In our emergency room four hours later, visual acuity was: R.E., 20/120; L.E., 20/40. The affected right eye had moderate eyelid edema, conjunctival hyperemia, extensive haze, irregularity and edema of the corneal epithe lium, stromal edema and numerous folds in Desce-
860
P"
AMERICAN JOURNAL OF OPHTHALMOLOGY
*^η0
N O V E M B E R , 1969
τ < .»s^ÉÉML.
'*%
%-m; i·
Fig. 1 (Dahl and Grant). Left eye of the patient in Case 1, day of onset of symptoms, showing corneal irregularity due to loss of epithelium and slight stromal edema after applying greaseless gel medication on and around the nose the previous evening. met's membrane. Corneal haze prevented adequate evaluation of the character of the aqueous humor. The intraocular pressure was 8.0 mm H g in both eyes. The right eye was treated with mydriatic, an tibiotic and eyepad. The next day the patient still complained of severe blurring of vision and discom fort; the cornea of the right eye had lost a large area of epithelium. T h e patient became asymptom atic two days later. Six days following exposure to VapoRub the cornea of the right eye was normal. CASE 4
A 33-year-old woman, who had used regular Vick's VapoRub for at least 10 years without trou ble, applied the new greaseless form for the first time to the outside of her nose for nasal congestion. Upon awakening the following morning vision was blurred in the right eye. She was without discom fort until much later in the day. When she came to our emergency room visual acuity w a s : R.E., 20/120; L.E., 25/25. The right eye had moderate conjunctival hyperemia, diffuse haze in the corneal epithelium and areas of loss of epithelium ; the an terior chamber was clear, however. After treatment with mydriatic, topical antibiotic and eyepad for 24 hours, the eye became comfortable ; vision returned to normal within 48 hours of the exposure to Vapo Rub.
CASE 5
A 35-year-old woman, who had used regular Vick's VapoRub for at least 10 years for relief of headache, applied the new greaseless form for the first time to her forehead in the usual manner. Upon awakening the following morning she noted blurring of vision and foreign-body sensation in both eyes. The discomfort persisted and later that day became worse, accompanied by lacrimation and photophobia. When she came to our emergency room that evening, visual acuity w a s : R.E., 20/50; L.E., 20/40. Both eyes had moderate conjunctival hyperemia, edema and haze of the corneal epithe lium and moderate flare without cells in the aqueous humor. After treatment for two days with mydriatic, topical antibiotic and eye dressings the eyes became asymptomatic, the corneas became clear and visual acuity improved to 20/20 in both eyes. CASE 6
A 50-year-old woman, who had applied regular Vick's VapoRub to her temples for relief of head ache for at least 20 years, used the new greaseless form for the first time in a similar manner. The next morning she noticed blurred vision in the right eye without discomfort; four hours later she expe rienced mild pain in the right eye. The pain and
VOL. 68, NO. S
UNUSUAL KERATITIS
blurring were still present the following day when she was seen in our emergency room. Visual acuity was: R.E., 20/200; L.E., 20/30. The affected eye had moderate edema of the eyelids, conspicuous conjunctival hyperemia and a large defect in the corneal epithelium centrally with surrounding epi thelial haze. The anterior chamber was clear. After treatment with topical antibiotic and corticosteroid for 36 hours the patient was asymptomatic and vi sual acuity had returned to normal. CASE 7
A 60-year-old man had used regular Vick's VapoRub for over 20 years for symptomatic relief of colds. He had recently purchased the new greaseless preparation but he could not recall which form he applied to his forehead on the evening prior to the onset of his visual difficulties. He awoke with blur ring of vision in both eyes which persisted. The fol lowing day he first noted discomfort in both eyes but he did not seek medical attention until two days later. When seen in our emergency room, the pa tient's vision was: R.E., counting fingers at IS feet ; L.E., counting fingers at four feet. He had blepharospasm and conjunctival hyperemia. Both corneas showed severe surface irregularity and haze with patches of loss of epithelium, moderate stromal edema and many folds in Descemet's mem brane. Very slight flare was seen in the aqueous humor of both eyes. Both lenses had posterior subcapsular cataracts. After treatment for two days with mydriatic, antibiotic and double eyepads, the patient still had irregularity and cloudiness of the corneal epithelium, but by 11 days after his use of Vick's VapoRub his corneas had become clear and visual acuity had improved to 20/100 in the right eye and counting fingers at six feet in the left eye. This was consistent with the amount of cataract present, probably the same as before the episode of keratitis. EXPERIMENTAL
STUDIES
In order to examine and compare the ef fects of both forms of VapoRub on the eye, we tested them on rabbits. After local anes thesia was induced with a drop of 0.5% pro paracaine hydrochloride solution on both eyes of two albino rabbits, the regular Vapo Rub was applied to both right eyes and the new greaseless gel preparation was applied to the left eyes. We placed an amount about the size of a split pea on the upper limbus with a glass rod and allowed it to spread spontaneously and by motion of the eyelids. The right eyes, exposed to the regular Vapo Rub, showed no injury at any time and no disturbance was detectable by slitlamp biomicroscopy. No immediate effect was seen in
861
the left eyes, which had been exposed to the greaseless gel, but 17 hours later they showed hyperemia and chemosis and were photophobic. The corneal epithelium in these eyes was irregular, hazy and absent from some areas. Testing with a cotton wisp showed the corneas of both left eyes to be hypesthetic. In 10 days these corneas healed and returned to normal. The same type of reaction, although less severe, was induced in three additional rabbits tested with the greaseless gel preparation without prelimi nary anesthetic. The eyes usually healed in three to four days. In order to separate vehicle and volatile constituents, a sample of the greaseless gel was subjected to vacuum with a rotary oil pump at warm room temperature for several hours; the content of volatile components was reduced to the degree that the residue retained only slight aroma compared to the strong smell of the original. This residue was tested on rabbit eyes after application of 0.5% proparacaine hydrochloride in the same manner as in the first experiments and caused the same type of injury to the corneal epithelium as did the original gel material, suggesting that the injurious component was not readily volatile, as were the listed "active ingredients." We explored the effects of the readily vol atile components of the gel-type VapoRub which had caused keratitis when applied di rectly to the rabbits' eyes by coating the in side of a cylindrical glass jar ( 12-inch diam eter, 18-inch length) with the gel prepara tion directly from the tube. We positioned a rabbit in a holder inside the jar so that its eyes were approximately five inches from the nearest coated surface. The rabbit could not actually touch the coating with any part of its head or body. Although no anesthetic was used, the rabbit showed no discomfort and did not close its eyes. However, the con junctivas soon appeared hyperemic and con siderable watery fluid dripped from nose and mouth. After four hours' exposure, and three additional hours on the next day with a
862
AMERICAN JOURNAL OF OPHTHALMOLOGY
fresh coating in the jar, no abnormality of corneas or conjunctivas was detectable ex cept for the mild and inconsequential conjunctival hyperemia seen during exposure. Tests on the eyes of one human volunteer showed no injury from 0.1 ml of 0.3% greaseless gel in saline solution. However, application of 1.6 mg of the undissolved gel caused foreign-body type discomfort and slight veiling of vision, such as that pro duced by mild epithelial edema, for 24 hours, with hyperemia and mucoid discharge. Re covery was complete in 36 hours. Household items which might be splashed in the eye, such as cleaners, detergents and similar substances, are currently required to be screened for possible adverse ocular ef fects under the Hazardous Substances Act. In order to fulfill the legal requirements, a modification of the Draize test is employed in which one eye of each of nine albino rab bits is used, the fellow eye serving as a con trol. The compound in question is placed in the conjunctival fornix in a fixed amount and the anterior segment is observed at in tervals for a period of four days using ap propriate magnification and illumination by competent observers. The amount of damage is noted and if there is any significant con junctival hyperemia, corneal epithelial loss or sign of anterior chamber inflammation, the substance is required to carry a warning of the possibility of eye damage on its label. Cosmetics are also regularly tested for eye irritancy. However, no testing or labeling procedures appear to be required for prepa rations that are considered to be drugs, al though they may be used in the vicinity of the eyes and may accidentally contaminate the eye. It would be of great value if manu facturers of such drug products would con duct testing procedures similar to those which are now required of the companies which produce household items such as cleaners and detergents. Although there is no question that the human eye may react dif ferently to a substance than the eye of an
NOVEMBER, 1969
experimental animal, the use of rabbits or similar animals in testing procedures should certainly screen out a large number of com pounds which are potentially toxic to the human eye, provided that the examination is performed by experienced observers using adequate illumination and magnification. Suitable labeling could then forewarn the consumer to avoid contaminating his eyes with the potentially injurious medicaments intended for his skin or hair. SUMMARY
Several hours after spreading a new greaseless gel trial form of a proprietary cold remedy (Vick's VapoRub) on the skin, principally on the nose and temples, seven patients developed hazy vision and moderate ocular discomfort, with edema of the cornea and loss of patches of corneal epithelium. The ocular symptoms generally lasted two or three days. These patients had never encoun tered adverse effects from a standard form of VapoRub which has a petrolatum base but which contains the same fragrant volatile medicaments. Rabbit and human eye tests provided supporting evidence that, while the standard petrolatum preparation was innocu ous, the new greaseless gel had injurious ac tion on the cornea and that this was caused by the greaseless gel base, not by the volatile constituents. Similar injuries to the eyes of patients are being induced by other medi cated skin and hair preparations, particularly Exolan cream and A-200 Pyrinate shampoo. More premarketing animal eye testing and warning labels are indicated. REFERENCES
1. Mathalone, M. B. R. and Easty, D. L. : Acute keratitis in psoriatic patients using triacetoxyanthracene. Lancet 2:195, 1967. 2. Brodkin, R. H. and Bleiberg, J. : Ophthalmologic side effects of a new topical psoriatic medica tion. Arch. Derm. 98 :S2S, 1968. 3. Reinecke, R. D. and Kinder, R. S. L. : Corneal toxicity of the pediculocide A-200 Pyrinate. Arch. Ophth. 68:36, 1962. 4. Popp, G: Korneaerosionen durch Polyäthylenglykoläther. Klin. Mbl. Augenh. 126:176, 19SS.