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Treatment of Recurrent Corneal Erosion and Corneal Edema with Topical Osmotic Colloidal Solution
Treatment of Recurrent Corneal Erosion and Corneal Edema with
Topical Osmotic
Colloidal Solution GARY N. FOULKS, MD
Abstract: Ten patients with recurrent corneal erosion unresponsive to conventional therapy were treated with a topical colloidal solution to obtain epithelial dehydration and lubrication. Nine of the ten patients responded with improved vision and resolution of symptoms. All erosions healed and focal epithelial abnormalities were decreased or reversed. Similar treatment of ten patients with corneal edema due to endothelial decompensation did not significantly reduce symptoms or improve vision , but such a solution may have significant dehydrating effect when edema results solely from epithelial abnormalities. Pachometric studies of the cornea demonstrated no significant change in stromal thickness during therapy. Colloidal hyperosmotic solutions are well tolerated and appear effective in treating recurrent corneal erosion. [Key words : colloidal solutions, corneal edema, corneal erosion.] Ophthalmology 88:801-803, 1981
Recurrent corneal erosion and corneal edema are frustrating disorders for both patient and physician. As corneal disease they are relatively common and occasionally difficult to treat. Pain and decreased vision are often significant in limiting the patient's ability to function. Various treatment regimens are available for both conditions, but there are failures on medical and surgical therapy. This paper discusses the clinical evaluation of a topical solution of high molecular weight polysaccharide in concentration equal to or slightly hyperosmolar to corneal stroma and also disCusses the theory of its effectiveness. From the Department of Ophthalmology. Duke University Eye Center, Durham , North Carolina. Supported in part by a grant from the North Carolina Lions Association. Reprint requests to Gary N. Foulks, MD, Duke University Eye Center, PO Box 3802, Durham, NC 27706.
0161-6420/81/0800/0801/$00.65 © American Academy of Ophthalmology
MATERIALS AND METHODS The study was organized in three phases . Phase I included ten patients with recurrent corneal erosion (Table 1). All patients represented treatment failures to conventional therapy for recurrent erosion (Table 2). Eight patients had anterior membrane dystrophy, one had prior abrasive trauma, and one had epithelial dystrophy (Stocker-Holt). Therapy was begun with instillation of one drop of topical colloidal dextran polysaccharide solution* (pH 7.0, 280-310 mOsm), five per day and prior to sleep. Treatment was continued for at least two months with an average duration of three months. Patients were evaluated by the same examiner • The solution evaluated contains high molecular weight dextran and is manufactured by Holies Laboratories, Cohasset, Massachusetts, as DehydrexilM> (US and overseas patents pending). The author has no proprietary interest in the development nor marketing of this preparation and no financial interest in Holies Laboratories.
801
OPHTHALMOLOGY· AUGUST 1981 • VOLUME 88 • NUMBER 8
Table 1. Patient Profile Phase Average No. Patients Age (Yr) Male/Female
10
II
III
10 11
40
49 50
3/7
2/8 3/8
RESULTS Diagnosis
Anterior membrane dystrophy Trauma Epithelial dystrophy
8
Bullous keratopathy with aphakia Fuchs' dystrophy
6
Bullous keratopathy with aphakia Fuchs' dystrophy
0
1 1 4
5
Table 2. Prior Unsuccessful Therapy for Corneal Erosion in Ten Patients Numbers Receiving Treatment Patching Artificial tear 5% NaCI
SCl
Antibiotic/steroid Debridement
10 10 10
6 6 1
All 10 patients were treatment failures with these methods.
for visual acuity, symptoms and slit-lamp evidence of recurrence during a 12-month period. Pachometry measurements were made with the Haag-Streit pachometer according to Mishima and Hedbys with control of fixation.! Phase II included ten patients with corneal edema due to endothelial decompensation (Table 1). All patients had previously required topical hypertonic sodium chloride drops or ointment. Six patients had bullous keratopathy associated with aphakia and four patients had Fuchs' dystrophy. Treatment with topical colloidal polysaccharide solution was begun at one drop five times per day and continued for at least one month. Patients were monitored for visual acuity, symptoms, slit-lamp appearance, and by serial pac home try as 'described above. Phase III included 11 patients with corneal edema secondary to endothelial dysfunction due to bullous keratopathy associated with aphakia or Fuchs' dystrophy (Table 1). Visual acuity and corneal pachometry were compared before and after instillation of topical solution given one drop every five minutes for three doses. Patients received colloidal solution on one visit and sodium chloride 5% solution on a different day. Four patients received one drop of topical anhydrous glycerin for comparison. All patients participating in the study provided informed consent after receiving a full explanation of the nature of the study. 802
Phase I. Nine of the ten patients noted resolution of symptoms of foreign body sensation and visual blurring on topical colloidal therapy, while all ten patients demonstrated improved visual acuity. A decrease in the microcystic epithelial and focal edema occurred in all patients, but no significant change in corneal stromal thickness appeared. After follow-up from 5 to 12 months (average 8 months) following cessation of therapy, only two of nine successful patients experienced recurrence of symptoms, and these resolved on resumption of treatment. No intolerance or adverse reactions to the medication were noted (Table 3). Phase II. During the one- to two-month follow-up on topical therapy with the colloidal solution only one of ten patients with corneal edema described improvement in symptoms. While three patients observed improvement of vision by one-line Snellen acuity, only one patient preferred the colloidal preparation over 5% sodium chloride. No significant pachometric changes were detected in the edematous corneas (Table 3). Phase III. Comparison of the effect of rapid sequence topical instillation of colloidal solution with 5% sodium chloride revealed no significant difference in visual improvement or pachometric readings. Topical glycerin instillation did result in corneal thinning significantly greater than either colloidal or sodium chloride solutions (P > 0.01) (Table 4).
DISCUSSION Recurrent corneal erosion resulting from trauma, corneal dystrophy, diabetes, or herpetic keratitis is a relatively common problem seen by most ophthalmologists. Initial therapy of patching and lubrication may be effective, but recurrences appear even with instillation of hypertonic sodium chloride or ointment lubrication at night. While good results are the rule with bandage soft contact lenses,2 patient tolerance to these lenses varies, particularly in diabetics and postherpetic patients. Possible infection and expense of lost lenses add difficulties to this form of treatment. Topical therapy with a safe, effective, well-tolerated, and inexpensive medication is desirable, and the mildly hypertonic dextran polysaccharide solution evaluated in this study shows promise as such therapy. Table 3. Results of Therapy Phase I (Erosion) Ten Patients Improved symptoms 9 Improved VA 10 Recurrence of symptoms 2 Pachometric change No significant change
Phase II (Edema) Ten Patients 1
3
No significant change
FOULKS • CORNEAL EROSIONS AND COLLOIDAL SOLUTION
Table 4. Pachometric change-Rapid Sequence Instillation Solution Patients Corneal thinning (mm)
Colloid
Sodium Chloride 5%
Glycerin
11
11
4
0.01 ± 0.01 (P > 0.1)
0.04 ± 0.01 (P < 0.01)
0.01 ± 0.01 (P>0 .1)
Previous studies have shown hypertonic colloidal solutions to be effective dehydrating agents in the face of abnormal epithelial permeability, and indeed, colloidal solutions are superior to electrolyte solutions in such situations. 3 Epithelial permeability is abnormal in recurrent erosive states since frank surface defects and accumulation of fluorescein in microcystic spaces can be seen. One theory of the mechanism of recurrent erosion is that such areas offocal edema and microcyst formation prevent adequate deposition of basement membrane or intercellular attachments and allow disruption of the surface by lid motion or minor trauma.4 It is well established that topically applied solutions remain in contact with the preocular surface for only a few minutes. It is also known, however, that macromolecules adsorbed at the preocular surface can linger on for over an hour, thus affecting tear mm stability.5 If the dehydrating effect of topically applied macromolecule solutions were solely due to a bulk osmotic effect only, a net dehydration could not be expected since the osmotic gradient is small and the solution is in contact with the cornea a short time. The only way the observed epithelial dehydrating effect can be explained is to assume that the polymer adsorbed at the cornea surface creates an osmotic gradient at the interface, which can move water out of the cornea. 6 As long as the excreted water is continuously removed, eg, by blinking, this boundary osmotic pump will continue to work. In such a case the adsorptive and surface properties of the colloid are also important, in addition to molecular size and concentration. There are indications that the type of hydrophilic polymer included in the colloidal formulation is important. We speculate that the differences lie in the structure of the adsorbed polymer layers at the cellular and tissue interfaces. Certain polymers adsorbed at cell surfaces are able to affect cell behavior, especially interaction and adhesion. 7 The lubricating effect of a colloidal solution would also be helpful in protecting the epithelial surface during the eight-week period required for secure attachment to underlying basement membrane. 8 Adsorbed hydrophilic polymers would hold a thin layer of aqueous solution adjacent to the epithelial surface that would act as an effective lubricant due to its low shear
strength. Such a protective lubricating effect has been demonstrated in a previous study on normal corneas and would be expected for diseased cornea as well. 9 Corneal edema secondary to endothelial dysfunction does not respond well clinically to the topical colloidal solution tested. The slightly hyperosmolar concentration does not provide sufficient osmotic gradient to overcome the imbibition of fluid by the corneal stroma and epithelium . It is not surprising that such an effect would not be pronounced when an osmolality of 5% sodium chloride, which is 400 times greater than the colloidal osmolality of the polysaccharide solution , was not very effective. Indeed, significant thinning of these corneas required the application of anhydrous glycerin. The definitive treatment of significant corneal edema continues to be surgical. 10
ACKNOWLEDGMENT The author gratefully acknowledges the assistance of Frank J . Holly, PhD, inventor of DEHYDREX@), Associate Professor of Ophthalmology and Biochemistry, Texas Tech University Health Sciences Center, and that of Holies Laboratories, Inc., Cohasset, Massachusetts, for providing the formulations.
REFERENCES 1. Mishima S. Corneal thickness . Surv Ophthalmol 1968; 13: 57-96. 2. Mobilia EF, Foster CS. The management of recurrent corneal erosions with ultra-thin lenses. Contact Intraocul Lens Med J 1978; 4:25-9. 3. Lamberts OW, Foulks GN, Holly FJ. Effect of colloidal isosmotic solutions on edema and epithelialization of denuded rabbit cornea in vivo. ARVO Abstracts. Invest Ophthalmol Vis Sci April 1978; Suppl :277. 4. Kenyon KR. Recurrent corneal erosion : pathogenesis and therapy. Int Ophthalmol Clinic 1979; 19(2): 169-195. 5. Lemp MA, Goldberg M, Roddy MR. The effect of tear substitutes on tear film break-up time. Invest Ophthalmol 1975; 14:255-58. 6. Lamberts OW, Foulks GN, Holly FJ . Effect of colloidal as mastic solutions on the hydration of de-epithelialized cornea in the rabbit. Arch Ophthalmol (in press). 7. Holly FJ. Biophysical aspects of epithelial adhesion to stroma. Invest Ophthalmol Vis Sci 1978; 17:552-7. 8. Khoudadoust AA, Silverstein AM, Kenyon KR. Dowling JE. Adhesion of regenerating corneal epithelium: the role of basement membrane. Am J Ophthalmol 1968; 65:339 - 48. 9. Do YH, Lamberts OW, Holly FJ. Prevention of epithelial trauma during tonography. ARVO Abstracts. Invest Ophthalmol Vis Sci April 1979; Suppl: 146. 10. Lamberts OW. Topical hyperosmotic agents and secretory stimulants. Int Ophthalmol Clin 1980; 20(3) : 163-9.
803
Topical Osmotic
Colloidal Solution GARY N. FOULKS, MD
Abstract: Ten patients with recurrent corneal erosion unresponsive to conventional therapy were treated with a topical colloidal solution to obtain epithelial dehydration and lubrication. Nine of the ten patients responded with improved vision and resolution of symptoms. All erosions healed and focal epithelial abnormalities were decreased or reversed. Similar treatment of ten patients with corneal edema due to endothelial decompensation did not significantly reduce symptoms or improve vision , but such a solution may have significant dehydrating effect when edema results solely from epithelial abnormalities. Pachometric studies of the cornea demonstrated no significant change in stromal thickness during therapy. Colloidal hyperosmotic solutions are well tolerated and appear effective in treating recurrent corneal erosion. [Key words : colloidal solutions, corneal edema, corneal erosion.] Ophthalmology 88:801-803, 1981
Recurrent corneal erosion and corneal edema are frustrating disorders for both patient and physician. As corneal disease they are relatively common and occasionally difficult to treat. Pain and decreased vision are often significant in limiting the patient's ability to function. Various treatment regimens are available for both conditions, but there are failures on medical and surgical therapy. This paper discusses the clinical evaluation of a topical solution of high molecular weight polysaccharide in concentration equal to or slightly hyperosmolar to corneal stroma and also disCusses the theory of its effectiveness. From the Department of Ophthalmology. Duke University Eye Center, Durham , North Carolina. Supported in part by a grant from the North Carolina Lions Association. Reprint requests to Gary N. Foulks, MD, Duke University Eye Center, PO Box 3802, Durham, NC 27706.
0161-6420/81/0800/0801/$00.65 © American Academy of Ophthalmology
MATERIALS AND METHODS The study was organized in three phases . Phase I included ten patients with recurrent corneal erosion (Table 1). All patients represented treatment failures to conventional therapy for recurrent erosion (Table 2). Eight patients had anterior membrane dystrophy, one had prior abrasive trauma, and one had epithelial dystrophy (Stocker-Holt). Therapy was begun with instillation of one drop of topical colloidal dextran polysaccharide solution* (pH 7.0, 280-310 mOsm), five per day and prior to sleep. Treatment was continued for at least two months with an average duration of three months. Patients were evaluated by the same examiner • The solution evaluated contains high molecular weight dextran and is manufactured by Holies Laboratories, Cohasset, Massachusetts, as DehydrexilM> (US and overseas patents pending). The author has no proprietary interest in the development nor marketing of this preparation and no financial interest in Holies Laboratories.
801
OPHTHALMOLOGY· AUGUST 1981 • VOLUME 88 • NUMBER 8
Table 1. Patient Profile Phase Average No. Patients Age (Yr) Male/Female
10
II
III
10 11
40
49 50
3/7
2/8 3/8
RESULTS Diagnosis
Anterior membrane dystrophy Trauma Epithelial dystrophy
8
Bullous keratopathy with aphakia Fuchs' dystrophy
6
Bullous keratopathy with aphakia Fuchs' dystrophy
0
1 1 4
5
Table 2. Prior Unsuccessful Therapy for Corneal Erosion in Ten Patients Numbers Receiving Treatment Patching Artificial tear 5% NaCI
SCl
Antibiotic/steroid Debridement
10 10 10
6 6 1
All 10 patients were treatment failures with these methods.
for visual acuity, symptoms and slit-lamp evidence of recurrence during a 12-month period. Pachometry measurements were made with the Haag-Streit pachometer according to Mishima and Hedbys with control of fixation.! Phase II included ten patients with corneal edema due to endothelial decompensation (Table 1). All patients had previously required topical hypertonic sodium chloride drops or ointment. Six patients had bullous keratopathy associated with aphakia and four patients had Fuchs' dystrophy. Treatment with topical colloidal polysaccharide solution was begun at one drop five times per day and continued for at least one month. Patients were monitored for visual acuity, symptoms, slit-lamp appearance, and by serial pac home try as 'described above. Phase III included 11 patients with corneal edema secondary to endothelial dysfunction due to bullous keratopathy associated with aphakia or Fuchs' dystrophy (Table 1). Visual acuity and corneal pachometry were compared before and after instillation of topical solution given one drop every five minutes for three doses. Patients received colloidal solution on one visit and sodium chloride 5% solution on a different day. Four patients received one drop of topical anhydrous glycerin for comparison. All patients participating in the study provided informed consent after receiving a full explanation of the nature of the study. 802
Phase I. Nine of the ten patients noted resolution of symptoms of foreign body sensation and visual blurring on topical colloidal therapy, while all ten patients demonstrated improved visual acuity. A decrease in the microcystic epithelial and focal edema occurred in all patients, but no significant change in corneal stromal thickness appeared. After follow-up from 5 to 12 months (average 8 months) following cessation of therapy, only two of nine successful patients experienced recurrence of symptoms, and these resolved on resumption of treatment. No intolerance or adverse reactions to the medication were noted (Table 3). Phase II. During the one- to two-month follow-up on topical therapy with the colloidal solution only one of ten patients with corneal edema described improvement in symptoms. While three patients observed improvement of vision by one-line Snellen acuity, only one patient preferred the colloidal preparation over 5% sodium chloride. No significant pachometric changes were detected in the edematous corneas (Table 3). Phase III. Comparison of the effect of rapid sequence topical instillation of colloidal solution with 5% sodium chloride revealed no significant difference in visual improvement or pachometric readings. Topical glycerin instillation did result in corneal thinning significantly greater than either colloidal or sodium chloride solutions (P > 0.01) (Table 4).
DISCUSSION Recurrent corneal erosion resulting from trauma, corneal dystrophy, diabetes, or herpetic keratitis is a relatively common problem seen by most ophthalmologists. Initial therapy of patching and lubrication may be effective, but recurrences appear even with instillation of hypertonic sodium chloride or ointment lubrication at night. While good results are the rule with bandage soft contact lenses,2 patient tolerance to these lenses varies, particularly in diabetics and postherpetic patients. Possible infection and expense of lost lenses add difficulties to this form of treatment. Topical therapy with a safe, effective, well-tolerated, and inexpensive medication is desirable, and the mildly hypertonic dextran polysaccharide solution evaluated in this study shows promise as such therapy. Table 3. Results of Therapy Phase I (Erosion) Ten Patients Improved symptoms 9 Improved VA 10 Recurrence of symptoms 2 Pachometric change No significant change
Phase II (Edema) Ten Patients 1
3
No significant change
FOULKS • CORNEAL EROSIONS AND COLLOIDAL SOLUTION
Table 4. Pachometric change-Rapid Sequence Instillation Solution Patients Corneal thinning (mm)
Colloid
Sodium Chloride 5%
Glycerin
11
11
4
0.01 ± 0.01 (P > 0.1)
0.04 ± 0.01 (P < 0.01)
0.01 ± 0.01 (P>0 .1)
Previous studies have shown hypertonic colloidal solutions to be effective dehydrating agents in the face of abnormal epithelial permeability, and indeed, colloidal solutions are superior to electrolyte solutions in such situations. 3 Epithelial permeability is abnormal in recurrent erosive states since frank surface defects and accumulation of fluorescein in microcystic spaces can be seen. One theory of the mechanism of recurrent erosion is that such areas offocal edema and microcyst formation prevent adequate deposition of basement membrane or intercellular attachments and allow disruption of the surface by lid motion or minor trauma.4 It is well established that topically applied solutions remain in contact with the preocular surface for only a few minutes. It is also known, however, that macromolecules adsorbed at the preocular surface can linger on for over an hour, thus affecting tear mm stability.5 If the dehydrating effect of topically applied macromolecule solutions were solely due to a bulk osmotic effect only, a net dehydration could not be expected since the osmotic gradient is small and the solution is in contact with the cornea a short time. The only way the observed epithelial dehydrating effect can be explained is to assume that the polymer adsorbed at the cornea surface creates an osmotic gradient at the interface, which can move water out of the cornea. 6 As long as the excreted water is continuously removed, eg, by blinking, this boundary osmotic pump will continue to work. In such a case the adsorptive and surface properties of the colloid are also important, in addition to molecular size and concentration. There are indications that the type of hydrophilic polymer included in the colloidal formulation is important. We speculate that the differences lie in the structure of the adsorbed polymer layers at the cellular and tissue interfaces. Certain polymers adsorbed at cell surfaces are able to affect cell behavior, especially interaction and adhesion. 7 The lubricating effect of a colloidal solution would also be helpful in protecting the epithelial surface during the eight-week period required for secure attachment to underlying basement membrane. 8 Adsorbed hydrophilic polymers would hold a thin layer of aqueous solution adjacent to the epithelial surface that would act as an effective lubricant due to its low shear
strength. Such a protective lubricating effect has been demonstrated in a previous study on normal corneas and would be expected for diseased cornea as well. 9 Corneal edema secondary to endothelial dysfunction does not respond well clinically to the topical colloidal solution tested. The slightly hyperosmolar concentration does not provide sufficient osmotic gradient to overcome the imbibition of fluid by the corneal stroma and epithelium . It is not surprising that such an effect would not be pronounced when an osmolality of 5% sodium chloride, which is 400 times greater than the colloidal osmolality of the polysaccharide solution , was not very effective. Indeed, significant thinning of these corneas required the application of anhydrous glycerin. The definitive treatment of significant corneal edema continues to be surgical. 10
ACKNOWLEDGMENT The author gratefully acknowledges the assistance of Frank J . Holly, PhD, inventor of DEHYDREX@), Associate Professor of Ophthalmology and Biochemistry, Texas Tech University Health Sciences Center, and that of Holies Laboratories, Inc., Cohasset, Massachusetts, for providing the formulations.
REFERENCES 1. Mishima S. Corneal thickness . Surv Ophthalmol 1968; 13: 57-96. 2. Mobilia EF, Foster CS. The management of recurrent corneal erosions with ultra-thin lenses. Contact Intraocul Lens Med J 1978; 4:25-9. 3. Lamberts OW, Foulks GN, Holly FJ. Effect of colloidal isosmotic solutions on edema and epithelialization of denuded rabbit cornea in vivo. ARVO Abstracts. Invest Ophthalmol Vis Sci April 1978; Suppl :277. 4. Kenyon KR. Recurrent corneal erosion : pathogenesis and therapy. Int Ophthalmol Clinic 1979; 19(2): 169-195. 5. Lemp MA, Goldberg M, Roddy MR. The effect of tear substitutes on tear film break-up time. Invest Ophthalmol 1975; 14:255-58. 6. Lamberts OW, Foulks GN, Holly FJ . Effect of colloidal as mastic solutions on the hydration of de-epithelialized cornea in the rabbit. Arch Ophthalmol (in press). 7. Holly FJ. Biophysical aspects of epithelial adhesion to stroma. Invest Ophthalmol Vis Sci 1978; 17:552-7. 8. Khoudadoust AA, Silverstein AM, Kenyon KR. Dowling JE. Adhesion of regenerating corneal epithelium: the role of basement membrane. Am J Ophthalmol 1968; 65:339 - 48. 9. Do YH, Lamberts OW, Holly FJ. Prevention of epithelial trauma during tonography. ARVO Abstracts. Invest Ophthalmol Vis Sci April 1979; Suppl: 146. 10. Lamberts OW. Topical hyperosmotic agents and secretory stimulants. Int Ophthalmol Clin 1980; 20(3) : 163-9.
803