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Corneal Mucus Plaques
CORNEAL MUCUS PLAQUES F R E D E R I C K T . F R A U N F E L D E R , M.D. Little Rock,
Arkansas
AND P E T E R W R I G H T , F . R . C . S . , AND R A M E S H C . T R I P A T H I , F . R . C . S . London,
In a recent series of patients with keratoconjunctivitis sicca, 100% had abnormal Schirmer's tests, 8 7 % had excess ocular tear film mucus, and 8 5 % had a thinned tear film with a decreased marginal tear strip. In addition, 8 0 % showed corneal and conjunctival staining with rose bengal, 7 5 % had conjunctival staphylococcal infections or a blepharitis, and 5 5 % had filamentary keratitis. Mucus plaques of various thicknesses, sizes, and shapes firmly attached to the corneal epithelium, are an additional feature that may occur with keratoconjunctivitis sicca. We have named this entity corneal mucus plaques. 1
1
M A T E R I A L AND M E T H O D S
Sixty-six patients observed during a long-term keratoconjunctivitis sicca study at the Dry E y e and Mucus Clinic at Moorfields E y e Hospital were also examined for corneal mucus plaques. These patients were observed from one to ten years and had extensive ophthalmic and medical examinations. Laboratory tests included ocular cultures, complete blood cell counts, x-ray films of involved joints, sedimentation rates, and tests for specific associated disease. An immunologic battery was done on each patient which included tests for immunoglobulins, 2
From the Institute of Ophthalmology, Department of Clinical Ophthalmology and Pathology, University of London, Moorfields Eye Hospital, London, England. Reprint requests to Frederick T . Fraunfelder, M.D., Department of Ophthalmology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72201.
England
immunofluorescence tests for tissuespecific antibodies, and latex tests for rheumatoid factor. One additional case of extensive corneal mucus plaques (Case 17) came from the Ophthalmology Department of the University of Arkansas for Medical Sciences. Patients were categorized as to age, sex, symptoms, associated ocular or systemic disease, frequency of corneal mucus plaques, and evaluation of the tears and mucus. Various corneal mucus plaques were stained with either fluorescein, rose bengal, Alcian blue, lissamine green, or eosin. Superficial biopsy of corneal epithelium with adherent plaques was performed under topical anesthesia and the sections were immediately fixed in 1% osmium tetroxide in veronal acetate buffer. T h e tissue was dehydrated in ascending grades of ethanol and embedded in Araldite. Semithin sections were stained with toluidine blue and examined by light microscopy. Ultrathin sections were stained with uranyl acetate and lead citrate and analyzed in a Joel 100C electron microscope. RESULTS
Of the 6 6 patients in the Moorfields keratoconjunctivitis sicca series, 16 (24%) had corneal mucus plaques. O f these 16 patients and the one from the University of Arkansas, four were men and 13 were women ranging in age from 2 7 to 7 5 years. Of the 17 patients, 15 had filamentary keratitis and 14 had staphylococcal blepharitis. Eleven of the 17 had rheumatoid arthritis, two had Raynaud's disease, one had benign reticulosis, and one had 191
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AMERICAN JOURNAL OF OPHTHALMOLOGY
lupus erythematosus. Therefore, 15 of the 17 patients had a major systemic disease when the corneal mucus plaques were discovered. In addition to these systemic diseases, at least 11 of the 17 also had Sjogren's syndrome, two had psoriasis, one each had ulcerative colitis, erythema nodosum, or a combination of Raynaud's disease and rheumatoid arthritis. Eightyeight percent (15 of 17 patients) were older than 50 years, had bilateral corneal mucus plaques, and had two or more episodes of corneal mucus plaque formation. Symptoms due to corneal mucus plaques varied and, except when severe, often were indistinguishable from the patient's keratoconjunctivitis sicca symptomatology. All 17 patients had keratoconjunctivitis sicca with decreased Schirmer's tests, decreased tear films, decreased marginal tear strips, and increased mucus. Sixteen had positive rheumatoid latex fixation tests, and in one the test was not performed. Other than abnormal results for a specific disease process, laboratory tests generally showed mild hypergammaglobulinemia with slight elevation of IgA and IgM. Sedimentation rates were intermittently elevated, and a few patients had slight leukopenia, mild eosinophilia, or proteinuria. Clinical description—Corneal mucus plaques varied in size, shape, a n d pattern. T h e earliest forms were usually semitranslucent, white to gray, slightly elevated, and usually in the horizontal median. Some plaques became thickened, more elevated, opaque, and involved half the total surface of the cornea (Fig. 1). Plaques became elevated well above the tear film and had a dry surface. While corneal mucus plaques adhered to the corneal epithelium, they were easily removed with superficial corneal scraping. Once a plaque adhered to the cornea, it stayed for a few days or weeks; while recurrences occurred, they seldom occurred in the same location. Multiple
FEBRUARY, 1977
plaques were common and frequently bilateral. Corneal mucus plaques were more prevalent when filaments were present but were occasionally seen in the absence of filamentary keratitis. Fluorescein stained these mucus plaques faintly, while we obtained vivid staining with rose bengal. Alcian blue, lissamine green, and eosin also stained these corneal mucus adhérences. Pathology—Corneal mucus plaques were a mixture of mucus, epithelial cells, and proteinaceous and lipoidal material (Fig. 2). Variable amounts and shapes of mucus were present between the widened intercellular spaces of adjoining epithelial cells and in the cytoplasmic gaps of degenerate cells. An electron-dense unit membrane usually surrounded individual mucus deposits. T h e mucus appeared as a moderately electron-dense homogeneous amorphous material containing electronlucent, round spicular configurations and electron-dense granules. T h e epithelial cells were in various stages of degeneration including nucleated or nonnucleated, fragmented, and totally necrotic cells. While the epithelial cells and the mucus deposits were the main components of corneal mucus plaques, these were enmeshed in a proteinaceous material that, by electron microscopy, appeared as flocculent deposits of moderate or low electron density (Fig. 3). Treatment—Corneal mucus plaques were prevented by the topical ocular application of 1 0 % acetylcysteine, one to four times daily. Existing plaques were often rapidly loosened and dissolved by acetylcysteine. When acetylcysteine was discontinued, the plaques occasionally recurred within 2 4 hours; in other cases, only one attack of corneal mucus plaques occurred. Plaques occurred even if a patient was receiving 1 0 % acetylcysteine, but usually the mucus adhérences were smaller or remained on the cornea for shorter lengths of time than if the patient
Fig. 1 (Fraunfelder, Wright, and Tripathi). An extensive area of multiple corneal mucus plaques occurred in a 52-yearold white woman with keratitis sicca and severe rheumatoid arthritis.
Fig. 4 (Fraunfelder, Wright, and Tripathi). Topical fluorescein outlines the ridges typically seen in corneal mucus plaques during cysteine therapy in a 27-year-old white woman with keratitis sicca, lupus erythematosus, and multiple attacks of corneal mucus plaques.
195
CORNEAL MUCUS PLAQUES
VOL. 83, NO. 2
' Fig. 2 (Fraunfelder, Wright, and Tripathi). Light photomicrograph of corneal mucus plaques in section showing mucus material, epithelial cells, and debris (1-u. thick Araldite section; toluidine blue, x 1,150).
was not receiving therapy. Corneal mucus plaques that occurred during topical acetylcysteine therapy had a more irregular surface than those that occurred while the patient was not on therapy (Fig. 4). B e cause of variation i n i r e o j i e n c y and severity of corneal mucus plaques, the use of topical acetylcysteine was individualized. We also treated dry eye by controlling associated local staphylococcal infections and with artificial tears. DISCUSSION
Corneal mucus plaques are primarily seen in patients with keratoconjunctivitis sicca, but we have also seen several cases
of plaques in patients with herpes zoster keratitis with similar clinical and histologic features. Thick, tenacious mucus firmly adhered to the cornea in a patient with normal tear studies and without systemic disease. Mucus-like threads attached to the cornea occurred in 5 % of the cases with keratitis sicca. Possibly, corneal mucus plaques have been confused with filamentary keratitis; however, they are easily differentiated by clinical appearance, differences in mechanical removal, response to acetylcysteine, or histology. While no systemic illness was found in some patients with corneal mucus 3
4
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY, 1977
Fig. 3 (Fraunfelder, Wright, and Tripathi). Survey electron micrograph of part of corneal mucus plaque showing mucus material (M) with numerous spicular and round configurations and electron-dense granules, recognizable profiles of relatively intact epithelial cells (E), epithelial cells in various stages of degeneration (D), and debris. The whole corneal mucus plaque is enmeshed in a granuloamorphous proteinaceous material (uranyl acetate and lead citrate, x2,600).
VOL. 83, NO. 2
CORNEAL MUCUS PLAQUES
plaques, in our series, the incidence o f systemic disease, primarily rheumatoid arthritis or other collagen diseases, was, higher than that found in keratoconjunctivitis sicca or Sjogren's syndrome. Multiple causes and factors may be involved in the formation o f corneal mucus plaques. In most instances, an abnormality of the exposed surface o f fhe superficial corneal epithelial cells probably occurs initially. T h i s abnormality may be due to abnormal tear secretions, exposure, denervation, or l o c a l or systemic pathology. While an epithelial cell abnormality is a probable factor, epithelial cell defects are the rule, not the exception, in keratoconjunctivitis sicca; so additional factors are necessary. Increased mucus viscosity due to dehydration o f its glycoprotein in an already relatively dehydrated environment occurred in nearly all cases of keratitis sicca, and this may be a contributing factor. A change in the composition o f the mucus itself probably occurs, such as an increase in sialomucin which increases viscosity. Local infection causes mucus of high viscosity in the respiratory tract by destroying mucoprotein and mucopolysaccharides with bacterial enzymes. High viscosity due to bronchial infections has been reversed by antibiotic thera p y and may be valuable in preventing corneal mucus plaques. Staphylococcal blepharitis was associated with most of our cases and may have the potential to increase the viscosity o f ocular mucus. 3
5
197
mucus plaques in place. While these attachments are much weaker than filaments, they may be surprisingly firm if they cover a large area (Fig. 1). SUMMARY
Corneal mucus plaques adhered to the anterior corneal surface in 17 of 6 7 advanced cases of keratoconjunctivitis sicca. T h e plaques were translucent to opaque and varied" in s i z e a n d shape, from multiple isolated islands to bizarre patterns involving more than half the corneal surface. Ultrastructurally, they consisted of mucus mixed with desquamated degenerating epithelial cells and proteinaceous and lipoidal material. T h e condition may b e symptomatic but can b e controlled and prevented in most cases by topical ocular application o f 1 0 % acetylcysteine. ACKNOWLEDGMENT
Calvin Hanna, Ph.D., provided Figure 1.
6
7
Corneal mucus plaques are probably an entity in w h i c h the usual desquamated epithelial cell is enmeshed with high viscosity mucus and proteinaceous material. While the normal turnover rate for corneal epithelial cells is seven to ten days, these plaques may remain in the same location for weeks. Mucus attaches deep between loosened intercellular spaces and through cytojllasmic perforation of degenerated cells to hold the corneal 8
REFERENCES
1. Wright, P.: Diagnosis and management of dry eyes. Trans. Ophthalmol. Soc. U. K. 91:119, 1971. 2. Trimble, R., and Wright, P.: A 5-year review of keratoconjunctivitis sicca. Br. J . Ophthalmol. In press. 3. Shaw, E . L., and Gasset, A. R.: Management of an unusual care of keratitis mucosa with hydrophilic contact lenses and N-acetylcysteine. Ann. Ophthalmol. 6:1054, 1974. 4. Williamson, J . , Doig. W. M., Forrester, J . V., Tham, M. H., Wilson, T., Whaley, K., and Dick, W. C : Management of the dry eye in Sjogren's syndrome. Br. J . Ophthalmol. 58:798, 1974. 5. DeHaas, E . B. H.: The pathogenesis of keratoconjunctivitis sicca. Ophthalmologica 147:118, 1964. 6. Reid, L.: Disturbances in the pattern of secretion of bronchial mucous glands. In Porter, R., and O'Connor, M. (eds.): Cystic Fibrosis. Ciba Foundation Study Group, No. 32. Boston, Little Brown and Co., 1968. 7. Bürgi, H.: Die Viskosität des purulenten und sterilen Sputums bei chronischer Asthmabronchitis. Med. Thorac. 21:156, 1964. 8. Hanna, C , Bicknell, D. S., and O'Brien, J . E.: Cell turnover in the adult human eye. Arch. Ophthalmol. 65:695, 1961.
Arkansas
AND P E T E R W R I G H T , F . R . C . S . , AND R A M E S H C . T R I P A T H I , F . R . C . S . London,
In a recent series of patients with keratoconjunctivitis sicca, 100% had abnormal Schirmer's tests, 8 7 % had excess ocular tear film mucus, and 8 5 % had a thinned tear film with a decreased marginal tear strip. In addition, 8 0 % showed corneal and conjunctival staining with rose bengal, 7 5 % had conjunctival staphylococcal infections or a blepharitis, and 5 5 % had filamentary keratitis. Mucus plaques of various thicknesses, sizes, and shapes firmly attached to the corneal epithelium, are an additional feature that may occur with keratoconjunctivitis sicca. We have named this entity corneal mucus plaques. 1
1
M A T E R I A L AND M E T H O D S
Sixty-six patients observed during a long-term keratoconjunctivitis sicca study at the Dry E y e and Mucus Clinic at Moorfields E y e Hospital were also examined for corneal mucus plaques. These patients were observed from one to ten years and had extensive ophthalmic and medical examinations. Laboratory tests included ocular cultures, complete blood cell counts, x-ray films of involved joints, sedimentation rates, and tests for specific associated disease. An immunologic battery was done on each patient which included tests for immunoglobulins, 2
From the Institute of Ophthalmology, Department of Clinical Ophthalmology and Pathology, University of London, Moorfields Eye Hospital, London, England. Reprint requests to Frederick T . Fraunfelder, M.D., Department of Ophthalmology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72201.
England
immunofluorescence tests for tissuespecific antibodies, and latex tests for rheumatoid factor. One additional case of extensive corneal mucus plaques (Case 17) came from the Ophthalmology Department of the University of Arkansas for Medical Sciences. Patients were categorized as to age, sex, symptoms, associated ocular or systemic disease, frequency of corneal mucus plaques, and evaluation of the tears and mucus. Various corneal mucus plaques were stained with either fluorescein, rose bengal, Alcian blue, lissamine green, or eosin. Superficial biopsy of corneal epithelium with adherent plaques was performed under topical anesthesia and the sections were immediately fixed in 1% osmium tetroxide in veronal acetate buffer. T h e tissue was dehydrated in ascending grades of ethanol and embedded in Araldite. Semithin sections were stained with toluidine blue and examined by light microscopy. Ultrathin sections were stained with uranyl acetate and lead citrate and analyzed in a Joel 100C electron microscope. RESULTS
Of the 6 6 patients in the Moorfields keratoconjunctivitis sicca series, 16 (24%) had corneal mucus plaques. O f these 16 patients and the one from the University of Arkansas, four were men and 13 were women ranging in age from 2 7 to 7 5 years. Of the 17 patients, 15 had filamentary keratitis and 14 had staphylococcal blepharitis. Eleven of the 17 had rheumatoid arthritis, two had Raynaud's disease, one had benign reticulosis, and one had 191
192
AMERICAN JOURNAL OF OPHTHALMOLOGY
lupus erythematosus. Therefore, 15 of the 17 patients had a major systemic disease when the corneal mucus plaques were discovered. In addition to these systemic diseases, at least 11 of the 17 also had Sjogren's syndrome, two had psoriasis, one each had ulcerative colitis, erythema nodosum, or a combination of Raynaud's disease and rheumatoid arthritis. Eightyeight percent (15 of 17 patients) were older than 50 years, had bilateral corneal mucus plaques, and had two or more episodes of corneal mucus plaque formation. Symptoms due to corneal mucus plaques varied and, except when severe, often were indistinguishable from the patient's keratoconjunctivitis sicca symptomatology. All 17 patients had keratoconjunctivitis sicca with decreased Schirmer's tests, decreased tear films, decreased marginal tear strips, and increased mucus. Sixteen had positive rheumatoid latex fixation tests, and in one the test was not performed. Other than abnormal results for a specific disease process, laboratory tests generally showed mild hypergammaglobulinemia with slight elevation of IgA and IgM. Sedimentation rates were intermittently elevated, and a few patients had slight leukopenia, mild eosinophilia, or proteinuria. Clinical description—Corneal mucus plaques varied in size, shape, a n d pattern. T h e earliest forms were usually semitranslucent, white to gray, slightly elevated, and usually in the horizontal median. Some plaques became thickened, more elevated, opaque, and involved half the total surface of the cornea (Fig. 1). Plaques became elevated well above the tear film and had a dry surface. While corneal mucus plaques adhered to the corneal epithelium, they were easily removed with superficial corneal scraping. Once a plaque adhered to the cornea, it stayed for a few days or weeks; while recurrences occurred, they seldom occurred in the same location. Multiple
FEBRUARY, 1977
plaques were common and frequently bilateral. Corneal mucus plaques were more prevalent when filaments were present but were occasionally seen in the absence of filamentary keratitis. Fluorescein stained these mucus plaques faintly, while we obtained vivid staining with rose bengal. Alcian blue, lissamine green, and eosin also stained these corneal mucus adhérences. Pathology—Corneal mucus plaques were a mixture of mucus, epithelial cells, and proteinaceous and lipoidal material (Fig. 2). Variable amounts and shapes of mucus were present between the widened intercellular spaces of adjoining epithelial cells and in the cytoplasmic gaps of degenerate cells. An electron-dense unit membrane usually surrounded individual mucus deposits. T h e mucus appeared as a moderately electron-dense homogeneous amorphous material containing electronlucent, round spicular configurations and electron-dense granules. T h e epithelial cells were in various stages of degeneration including nucleated or nonnucleated, fragmented, and totally necrotic cells. While the epithelial cells and the mucus deposits were the main components of corneal mucus plaques, these were enmeshed in a proteinaceous material that, by electron microscopy, appeared as flocculent deposits of moderate or low electron density (Fig. 3). Treatment—Corneal mucus plaques were prevented by the topical ocular application of 1 0 % acetylcysteine, one to four times daily. Existing plaques were often rapidly loosened and dissolved by acetylcysteine. When acetylcysteine was discontinued, the plaques occasionally recurred within 2 4 hours; in other cases, only one attack of corneal mucus plaques occurred. Plaques occurred even if a patient was receiving 1 0 % acetylcysteine, but usually the mucus adhérences were smaller or remained on the cornea for shorter lengths of time than if the patient
Fig. 1 (Fraunfelder, Wright, and Tripathi). An extensive area of multiple corneal mucus plaques occurred in a 52-yearold white woman with keratitis sicca and severe rheumatoid arthritis.
Fig. 4 (Fraunfelder, Wright, and Tripathi). Topical fluorescein outlines the ridges typically seen in corneal mucus plaques during cysteine therapy in a 27-year-old white woman with keratitis sicca, lupus erythematosus, and multiple attacks of corneal mucus plaques.
195
CORNEAL MUCUS PLAQUES
VOL. 83, NO. 2
' Fig. 2 (Fraunfelder, Wright, and Tripathi). Light photomicrograph of corneal mucus plaques in section showing mucus material, epithelial cells, and debris (1-u. thick Araldite section; toluidine blue, x 1,150).
was not receiving therapy. Corneal mucus plaques that occurred during topical acetylcysteine therapy had a more irregular surface than those that occurred while the patient was not on therapy (Fig. 4). B e cause of variation i n i r e o j i e n c y and severity of corneal mucus plaques, the use of topical acetylcysteine was individualized. We also treated dry eye by controlling associated local staphylococcal infections and with artificial tears. DISCUSSION
Corneal mucus plaques are primarily seen in patients with keratoconjunctivitis sicca, but we have also seen several cases
of plaques in patients with herpes zoster keratitis with similar clinical and histologic features. Thick, tenacious mucus firmly adhered to the cornea in a patient with normal tear studies and without systemic disease. Mucus-like threads attached to the cornea occurred in 5 % of the cases with keratitis sicca. Possibly, corneal mucus plaques have been confused with filamentary keratitis; however, they are easily differentiated by clinical appearance, differences in mechanical removal, response to acetylcysteine, or histology. While no systemic illness was found in some patients with corneal mucus 3
4
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY, 1977
Fig. 3 (Fraunfelder, Wright, and Tripathi). Survey electron micrograph of part of corneal mucus plaque showing mucus material (M) with numerous spicular and round configurations and electron-dense granules, recognizable profiles of relatively intact epithelial cells (E), epithelial cells in various stages of degeneration (D), and debris. The whole corneal mucus plaque is enmeshed in a granuloamorphous proteinaceous material (uranyl acetate and lead citrate, x2,600).
VOL. 83, NO. 2
CORNEAL MUCUS PLAQUES
plaques, in our series, the incidence o f systemic disease, primarily rheumatoid arthritis or other collagen diseases, was, higher than that found in keratoconjunctivitis sicca or Sjogren's syndrome. Multiple causes and factors may be involved in the formation o f corneal mucus plaques. In most instances, an abnormality of the exposed surface o f fhe superficial corneal epithelial cells probably occurs initially. T h i s abnormality may be due to abnormal tear secretions, exposure, denervation, or l o c a l or systemic pathology. While an epithelial cell abnormality is a probable factor, epithelial cell defects are the rule, not the exception, in keratoconjunctivitis sicca; so additional factors are necessary. Increased mucus viscosity due to dehydration o f its glycoprotein in an already relatively dehydrated environment occurred in nearly all cases of keratitis sicca, and this may be a contributing factor. A change in the composition o f the mucus itself probably occurs, such as an increase in sialomucin which increases viscosity. Local infection causes mucus of high viscosity in the respiratory tract by destroying mucoprotein and mucopolysaccharides with bacterial enzymes. High viscosity due to bronchial infections has been reversed by antibiotic thera p y and may be valuable in preventing corneal mucus plaques. Staphylococcal blepharitis was associated with most of our cases and may have the potential to increase the viscosity o f ocular mucus. 3
5
197
mucus plaques in place. While these attachments are much weaker than filaments, they may be surprisingly firm if they cover a large area (Fig. 1). SUMMARY
Corneal mucus plaques adhered to the anterior corneal surface in 17 of 6 7 advanced cases of keratoconjunctivitis sicca. T h e plaques were translucent to opaque and varied" in s i z e a n d shape, from multiple isolated islands to bizarre patterns involving more than half the corneal surface. Ultrastructurally, they consisted of mucus mixed with desquamated degenerating epithelial cells and proteinaceous and lipoidal material. T h e condition may b e symptomatic but can b e controlled and prevented in most cases by topical ocular application o f 1 0 % acetylcysteine. ACKNOWLEDGMENT
Calvin Hanna, Ph.D., provided Figure 1.
6
7
Corneal mucus plaques are probably an entity in w h i c h the usual desquamated epithelial cell is enmeshed with high viscosity mucus and proteinaceous material. While the normal turnover rate for corneal epithelial cells is seven to ten days, these plaques may remain in the same location for weeks. Mucus attaches deep between loosened intercellular spaces and through cytojllasmic perforation of degenerated cells to hold the corneal 8
REFERENCES
1. Wright, P.: Diagnosis and management of dry eyes. Trans. Ophthalmol. Soc. U. K. 91:119, 1971. 2. Trimble, R., and Wright, P.: A 5-year review of keratoconjunctivitis sicca. Br. J . Ophthalmol. In press. 3. Shaw, E . L., and Gasset, A. R.: Management of an unusual care of keratitis mucosa with hydrophilic contact lenses and N-acetylcysteine. Ann. Ophthalmol. 6:1054, 1974. 4. Williamson, J . , Doig. W. M., Forrester, J . V., Tham, M. H., Wilson, T., Whaley, K., and Dick, W. C : Management of the dry eye in Sjogren's syndrome. Br. J . Ophthalmol. 58:798, 1974. 5. DeHaas, E . B. H.: The pathogenesis of keratoconjunctivitis sicca. Ophthalmologica 147:118, 1964. 6. Reid, L.: Disturbances in the pattern of secretion of bronchial mucous glands. In Porter, R., and O'Connor, M. (eds.): Cystic Fibrosis. Ciba Foundation Study Group, No. 32. Boston, Little Brown and Co., 1968. 7. Bürgi, H.: Die Viskosität des purulenten und sterilen Sputums bei chronischer Asthmabronchitis. Med. Thorac. 21:156, 1964. 8. Hanna, C , Bicknell, D. S., and O'Brien, J . E.: Cell turnover in the adult human eye. Arch. Ophthalmol. 65:695, 1961.