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The Effect of 6-Mercaptopurine (6-Mp) on Corneal Heterografts in Dogs*
MODIFICATION OF CORNEAL IMMUNE RESPONSE in vitro production of antibody in corneal limbal lymphoid foci. J. 117:197,1963. 13. Thompson, R., and Olson, production in the rabbit cornea. 65 :633-651,19S0.
delayed phase Exper. Med., H. : Antibody J. Immunol.,
14. Leibowitz. H. M., Parks, J. J., and Maume-
71S
nee, A. E. : Manifestation of localized hypersensitivity in a previously sensitized tissue. Arch. Ophth., 68:66, 1962. IS. Leibowitz, H. M., and Elliott, J. H.: Antimetabolite suppression of corneal hypersensitivity. Arch. Ophth., 73:94, 1965.
T H E E F F E C T O F 6-MERCAPTOPURINE (6-MP) ON CORNEAL HETEROGRAFTS IN DOGS* MARIO LANZIERI^ M.D., ANTONIO G. SECCHI^ M.D., CORRADO BALACCO GABRIELI, M.D.
AND
Bari, Italy
The reactions which produce the rejection of heterografts, as well as homografts, in animals are caused, in most cases, by intol erance phenomena induced by the antigenic power of the grafted tissues and conditioned by the resulting formation of immunoglobulins.1 Recent studies by D'Ermo, Lanzieri and Secchi2 have confirmed the fact that corneal heterografts and homografts in animals caused the formation of specific anticorneal immunoglobulins, at the highest rate between the 14th and the 28th day after operation. These immunoglobulins might be responsi ble for phenomena of an immune nature re sulting from the graft. Thus a reduction in the immune response might be brought about by inhibition of the formation of im munoglobulins. It is possible to induce such inhibition by means of chemical and physical interference acting at different levels. Among the drugs tested for chemical ac tion, some purine derivatives such as 6-mercaptopurine (6-MP), thioguanine, B.W. 57-322 (6( l-methyl-4-nitro-5-imidazolyl) thyopurine), B.W. 57-323 (2-amino-6(lmethyl-4-nitro-5-imidazolyl) thyopurine), are effective by means of an action which, in gen* From the Department of Ophthalmology, University of Bari. t Present address : Clinica Oculistica Universitario, Padova, Italy.
eral, is said to be antimetabolic. Schwartz, Eisner and Dameshek3 observed that 6-mercaptopurine (6-MP) has a direct chemical action on immunoglobulin-forming tissues, likely by interference in the synthesis of the nucleic acids. Calne4 showed that 6-MP prolonged the functional survival of kidney homotransplantation in the dog. Meeker, Condie, Weiner, Good and Varco,5·6 McLaren, 7 Rubin and Lewis 8 and others have pointed out that 6-MP delayed the rejection of skin homotransplantation. Recently Cobb and Basu9 performed similar experiments in rabbits which had undergone an interlamellar corneal heterograft. Neovascularization and opacification in animals treated with 6-MP were observed to occur about seven days later than in con trol animals. The delay was associated with a clear diminution of the lymphocytes and eosinophilic polymorphonuclear leukocytes at the level of the grafted discs. We found it interesting to study the ac tion of 6-MP in the immune reaction fol lowing heterologous full-thickness keratoplasty, a situation in which the antigenic stimulus and the immune response are still more marked. MATERIALS AND METHOD
Sixteen dogs, weighing between 7 and 10 kg, were treated with 6-MP (Mercaptopur-
716
M. LANZIERI, A. G. SECCHI, AND C. B. GABRIELI
ine, Simes, Milan) by mouth at a 18 mg/kg weight dose every third day. Higher doses were fatally toxic. Before treatment with 6-MP was begun and weekly afterward for 60 days, leukocyte counts were performed. Thirty days after the beginning treatment the animals underwent full-thickness heterografts, receiving corneal discs from freshly killed calves. The surgical procedures were carried out with general anesthesia (Kemithal sodium, Imperial Chemical Ind. Ltd., 40-50 mg/kg body weight intravenously) and thoroughly aseptic conditions. Begin ning three days before the operation the an imals received tetracycline (Criseociclina, Farmitalia, Milan, 15-20 mg/kg/day), anti biotic ointments (Strepto-Penicil, Tubi Lux, Naples) and 2% pilocarpine combined with 0.5% eserine. Treatment was continued 1520 days after operation, but miotic drugs were replaced by 1% atropine sulfate. The treatment with 6-MP, at a 18 mg/kg body weight dose every third day, was continued for 30 days after operation. Every third day an examination was car ried out on all operated dogs to check the appearance of the eye. A group of 12 dogs of the same size, which had never been treated with 6-MP, were used as controls ; a partial corneal heterograft at full-thickness was performed on them, following the same method as for the treated animals. The antibiotic treatment prior to and after the operation was exact ly the same as already described and these animals, too, underwent weekly blood cell counts. RESULTS
The 12 control dogs never treated with 6-MP showed the postoperative course typi cal of full-thickness corneal heterografts. During the first few days the grafted disc re mained nearly transparent, although with a spreading edema and a perikeratic reaction. After the seventh to eighth day, the reaction of the host cornea and the grafted disc in creased, with an intense edema and neovas
cularization. The disc was often completely ectasic and always richly vascularized. The reaction was marked for about two weeks and then gradually regressed. A dense opacification of the disc continued to in crease. In two dogs there was a complete rejection of the graft about the 15th day after operation. In the dogs which were treated with 6-MP, the first six to seven days postoperatively were characterized by a slight edema of the host cornea and grafted disc and by a moderate perikeratic reaction. During the second week, the reaction increased, al though it was less severe than in the control animals. Neovascularization was limited to a few fine vessels, mainly at the level of the stitches. The graft, even though showing a spreading but moderate edema, always re mained in place, sometimes being a little prominent on the surface of the host cornea. Two of the 16 dogs died of natural causes between the 10th and 15th postoperative day. A progressive, permanent opacification of the graft began 15-20 days after the transplantation. Only in a few cases did the disc remain relatively and partially trans parent. In no cases were rejections of the graft seen. Two more dogs died of natural causes around the 45th day after operation. Table 1 shows the results in the two groups of animals and the importance of the reaction and the transparency of the graft. The transparency of the disc was estimated according to the method described by Muel ler and Smith.10 Treatment with 6-MP caused a reduction of the number of circulating leukocytes, ranging from 30% to 50% of the initial val ues. Two months after the graft, all treated and control animals were killed and the eyes enu cleated ; histologie preparations were made of all the corneas. There was no difference be tween the treated and control animals. The histologie picture was typical of corneal grafts which suffered from clouding and
EFFECT OF 6-MP ON CORNEAL GRAFTS
717
TABLE 1 SUMMARY OF STUDY
Days after Graft No. Dogs
8
15
Treated 16
Control 12
Treated 14
16
12
6
Control 12
Reaction
+++ ++ + +-
1
7 1
0
3 9 2
X = 2.734 P>0.05
Control 10
5 9
Treated 12
Control 10
12
3 7
2 7 1
4 6 4
X2 = 9.998 0.05>P>0.02
Transparency of Graft 9 7
Treated 14
9
X2 = 24 P<0.001
++ +
54
30
1 9 2
1 4 9
10
!
X = 2.016 P>0.05
X = 4.S11 P>0.05
X2 = 4.164 P>0.05
4 8
10 2
X = 4.048 P>0.05
2
Rejection
Severity of the ocular reaction was graded from (absence) to + + + (very strong reaction). Transparency of the graft was evaluated as follows: + + , grafted disc fully transparent; + , grafted disc transparent enough to allow observations of the iris structure; 0, grafted disc quite cloudy. Statistical analysis of the results was performed by the X2 method corrected for low values.
neovascularization. No significant histologie difference was observed. DISCUSSION
Our findings differed slightly from those of Cobb and Basu. These authors showed that treatment with 6-MP caused one week's delay in the opacification of heterologous corneal discs grafted interlamellarly in the thickness of rabbit corneas. We found that, after the 20th day, the local reaction and the transparency of the graft followed the same course in treated and control dogs, while dur ing the first three weeks, the reactive phe nomena were less marked in the treated ani mals. We think that the essential differences in the operative techniques used (grafts at full-thickness in our experiments) may ex plain the partial differences in the clinical and histologie results. We think it interesting to stress that treatment with 6-MP, an inhibitor of the
globulin synthesis and, thus, of the immune reaction, did not bring about preservation of the transparency of the corneal grafts. These data would seem to indicate that other processes (most likely, trophic altera tions of the tissues ; Venco,11 D'Ermo, 12 Delogu and Vecchione 1 '), in addition to immune factors, whose presence cannot be doubted, gather to provoke the reactive phenomena which cause the opacification of corneal grafts. SUMMARY
The effect of 6-MP, a metabolic antago nist to immunoglobulin formation, on the reaction following penetrating corneal heterografts in dogs was studied. It was shown that the treatment with the drug ( 18 mg/kg body weight every third day) induced a diminution of the reaction only within the first 20 days after grafting; later the reaction was almost the same in both ex perimental and control groups of animals;
718
M. LANZIERI, A. G. SECCHI, AND C. B. GABRIELI
two months after the transplantation both groups of dogs showed almost complete opacification of the grafted disc. Clinica Oculistica dell Universita. REFERENCES
1. Billingham, R. E., Brent, L., and Medawar, P. B. : Quantitative studies on Tissue Trans plantation. I I : The Origin, strength and duration of actively and adoptively acquired immunity. Proc. Roy. Soc. B., 143 :S8, 1954. 2. D'Ermo, F., Lanzieri, M., and Secchi, A. G. : Anticorneal antibodies in rabbits after homologous and heterologous corneal grafts. Unpublished paper. 3. Schwartz, R., Eisner, A., and Dameshek, W. : The effect of 6-mercaptopurine on primary and secondary immune response. J. 'Clin. Invest., 38:1394, 1959. 4. Calne, R. Y. : The rejection of renal homografts: Inhibition in dogs by 6-MP. Lancet, 1:417, 1960. 5. Meeker, W., Condie, R., Weiner, D., Varco, R. L., and Good, R. A. : Prolongation of skin homograft survival in rabbits by 6-MP. Proc. Soc. Exper. Biol. & Med., 102:459, 1959. 6. Meeker, W., Condie, R., Good, R. A., and
Varco, R. L. : Alteration of the homograft re sponse by antimetabolites. Ann. N.Y. Acad. Sei., 87 :203, 1960. 7. McLaren, A. : Induction of tolerance to skin homografts in mice treated with 6-mercaptopurine. Transpl. Bull., 28:479, 1961. 8. Rubin, B. A., and Lewis, R. W. : Sustained tol erance of Homotransplantation induced with 6-MP Proc. Am. A. Cancer Res., 3 :264, 1961. 9. Cobb, G. M., and Basu, P. K.: Effect of 6-MP on the immune response in inter-lamellar corneal heterografts. Transpl., 1:232, 1964. 10. Mueller, F. O., and Smith, A. U. : Some ex periments on grafting frozen corneal tissue in rabbits. Exper. Eye Res.. 2 :237, 1963. 11. Venco, L. : Considerazioni sulla cosidetta "Malattia del lembo" nella cheratoplastica. Rass. Oftal., 18 :65, 1949. 12. D'Ermo, F. : Problemi immunitari nell'omotrapianto do cornea. Atti del Simposio sulla Che ratoplastica. Problemi attuali di Biologia e Clinica. Ed. Soc. Oftal. Lombarda, Milano, 1963, p. 120. 13. Delogu, A. and Vecchione, L. : Lo stato attuale delle conoscenze sui problemi concernenti l'attecchimento e la trasparenza del trapianto corneale, alia luce delle piu' recenti esperienze. Giorn. It. Oftal., 18 :21, 1964.
DISTICHIASIS AND T R I C H I A S I S : ORIGIN AND MANAGEMENT* HAROLD G. SCHEIE, M.D.,
AND DANIEL M. ALBERT,
M.D.
Philadelphia, Pennsylvania
This paper suggests the use of the oper ating microscope for removal of aberrant lashes and discusses briefly the nature of distichiasis and trichiasis. Each condition may cause severe irritation and corneal ul cération with diminution of vision. Distichiasis is considered to be a congeni tal anomaly in which lashes grow from an abnormal position along the posterior bor der of the lid margin, apparently from the openings of the meibomian glands. It has been suggested that the meibomian glands in the normal eyelid actually are modified seba ceous glands which represent a row of lash es no longer present in man. In patients with distichiasis, the meibomian glands become modified and take on hair-bearing function,1 probably an atavistic phenome non. * From the Department of Ophthalmology, Hospital of the University of Pennsylvania, Phil adelphia General Hospital, Veterans Administra tion Hospital and Children's Hospital of Phila delphia.
We believe that the condition can also be acquired. In several of our patients with long-standing inflammation and hyperemia of the lids and conjunctiva, especially in as sociation with late changes of Stevens-John son syndrome, slitlamp examination demon strated cilia arising from the meibomian glands at various sites along the inner as pect of the lid margin. New aberrant lashes can subsequently develop and add to pre-ex isting difficulties. The lashes usually appear stunted and nonpigmented. They may also be extremely fine and lie crumpled on the epithelial surface. This latter type may easi ly be overlooked unless slitlamp microscopy is used. Our opinion is supported by some pre vious observations. Rählmann 2 described new hair follicles developing along the inner margin of the lid in patients with trichiasis. He believed, however, that these developed by the downgrowth of the surface epitheli um.
delayed phase Exper. Med., H. : Antibody J. Immunol.,
14. Leibowitz. H. M., Parks, J. J., and Maume-
71S
nee, A. E. : Manifestation of localized hypersensitivity in a previously sensitized tissue. Arch. Ophth., 68:66, 1962. IS. Leibowitz, H. M., and Elliott, J. H.: Antimetabolite suppression of corneal hypersensitivity. Arch. Ophth., 73:94, 1965.
T H E E F F E C T O F 6-MERCAPTOPURINE (6-MP) ON CORNEAL HETEROGRAFTS IN DOGS* MARIO LANZIERI^ M.D., ANTONIO G. SECCHI^ M.D., CORRADO BALACCO GABRIELI, M.D.
AND
Bari, Italy
The reactions which produce the rejection of heterografts, as well as homografts, in animals are caused, in most cases, by intol erance phenomena induced by the antigenic power of the grafted tissues and conditioned by the resulting formation of immunoglobulins.1 Recent studies by D'Ermo, Lanzieri and Secchi2 have confirmed the fact that corneal heterografts and homografts in animals caused the formation of specific anticorneal immunoglobulins, at the highest rate between the 14th and the 28th day after operation. These immunoglobulins might be responsi ble for phenomena of an immune nature re sulting from the graft. Thus a reduction in the immune response might be brought about by inhibition of the formation of im munoglobulins. It is possible to induce such inhibition by means of chemical and physical interference acting at different levels. Among the drugs tested for chemical ac tion, some purine derivatives such as 6-mercaptopurine (6-MP), thioguanine, B.W. 57-322 (6( l-methyl-4-nitro-5-imidazolyl) thyopurine), B.W. 57-323 (2-amino-6(lmethyl-4-nitro-5-imidazolyl) thyopurine), are effective by means of an action which, in gen* From the Department of Ophthalmology, University of Bari. t Present address : Clinica Oculistica Universitario, Padova, Italy.
eral, is said to be antimetabolic. Schwartz, Eisner and Dameshek3 observed that 6-mercaptopurine (6-MP) has a direct chemical action on immunoglobulin-forming tissues, likely by interference in the synthesis of the nucleic acids. Calne4 showed that 6-MP prolonged the functional survival of kidney homotransplantation in the dog. Meeker, Condie, Weiner, Good and Varco,5·6 McLaren, 7 Rubin and Lewis 8 and others have pointed out that 6-MP delayed the rejection of skin homotransplantation. Recently Cobb and Basu9 performed similar experiments in rabbits which had undergone an interlamellar corneal heterograft. Neovascularization and opacification in animals treated with 6-MP were observed to occur about seven days later than in con trol animals. The delay was associated with a clear diminution of the lymphocytes and eosinophilic polymorphonuclear leukocytes at the level of the grafted discs. We found it interesting to study the ac tion of 6-MP in the immune reaction fol lowing heterologous full-thickness keratoplasty, a situation in which the antigenic stimulus and the immune response are still more marked. MATERIALS AND METHOD
Sixteen dogs, weighing between 7 and 10 kg, were treated with 6-MP (Mercaptopur-
716
M. LANZIERI, A. G. SECCHI, AND C. B. GABRIELI
ine, Simes, Milan) by mouth at a 18 mg/kg weight dose every third day. Higher doses were fatally toxic. Before treatment with 6-MP was begun and weekly afterward for 60 days, leukocyte counts were performed. Thirty days after the beginning treatment the animals underwent full-thickness heterografts, receiving corneal discs from freshly killed calves. The surgical procedures were carried out with general anesthesia (Kemithal sodium, Imperial Chemical Ind. Ltd., 40-50 mg/kg body weight intravenously) and thoroughly aseptic conditions. Begin ning three days before the operation the an imals received tetracycline (Criseociclina, Farmitalia, Milan, 15-20 mg/kg/day), anti biotic ointments (Strepto-Penicil, Tubi Lux, Naples) and 2% pilocarpine combined with 0.5% eserine. Treatment was continued 1520 days after operation, but miotic drugs were replaced by 1% atropine sulfate. The treatment with 6-MP, at a 18 mg/kg body weight dose every third day, was continued for 30 days after operation. Every third day an examination was car ried out on all operated dogs to check the appearance of the eye. A group of 12 dogs of the same size, which had never been treated with 6-MP, were used as controls ; a partial corneal heterograft at full-thickness was performed on them, following the same method as for the treated animals. The antibiotic treatment prior to and after the operation was exact ly the same as already described and these animals, too, underwent weekly blood cell counts. RESULTS
The 12 control dogs never treated with 6-MP showed the postoperative course typi cal of full-thickness corneal heterografts. During the first few days the grafted disc re mained nearly transparent, although with a spreading edema and a perikeratic reaction. After the seventh to eighth day, the reaction of the host cornea and the grafted disc in creased, with an intense edema and neovas
cularization. The disc was often completely ectasic and always richly vascularized. The reaction was marked for about two weeks and then gradually regressed. A dense opacification of the disc continued to in crease. In two dogs there was a complete rejection of the graft about the 15th day after operation. In the dogs which were treated with 6-MP, the first six to seven days postoperatively were characterized by a slight edema of the host cornea and grafted disc and by a moderate perikeratic reaction. During the second week, the reaction increased, al though it was less severe than in the control animals. Neovascularization was limited to a few fine vessels, mainly at the level of the stitches. The graft, even though showing a spreading but moderate edema, always re mained in place, sometimes being a little prominent on the surface of the host cornea. Two of the 16 dogs died of natural causes between the 10th and 15th postoperative day. A progressive, permanent opacification of the graft began 15-20 days after the transplantation. Only in a few cases did the disc remain relatively and partially trans parent. In no cases were rejections of the graft seen. Two more dogs died of natural causes around the 45th day after operation. Table 1 shows the results in the two groups of animals and the importance of the reaction and the transparency of the graft. The transparency of the disc was estimated according to the method described by Muel ler and Smith.10 Treatment with 6-MP caused a reduction of the number of circulating leukocytes, ranging from 30% to 50% of the initial val ues. Two months after the graft, all treated and control animals were killed and the eyes enu cleated ; histologie preparations were made of all the corneas. There was no difference be tween the treated and control animals. The histologie picture was typical of corneal grafts which suffered from clouding and
EFFECT OF 6-MP ON CORNEAL GRAFTS
717
TABLE 1 SUMMARY OF STUDY
Days after Graft No. Dogs
8
15
Treated 16
Control 12
Treated 14
16
12
6
Control 12
Reaction
+++ ++ + +-
1
7 1
0
3 9 2
X = 2.734 P>0.05
Control 10
5 9
Treated 12
Control 10
12
3 7
2 7 1
4 6 4
X2 = 9.998 0.05>P>0.02
Transparency of Graft 9 7
Treated 14
9
X2 = 24 P<0.001
++ +
54
30
1 9 2
1 4 9
10
!
X = 2.016 P>0.05
X = 4.S11 P>0.05
X2 = 4.164 P>0.05
4 8
10 2
X = 4.048 P>0.05
2
Rejection
Severity of the ocular reaction was graded from (absence) to + + + (very strong reaction). Transparency of the graft was evaluated as follows: + + , grafted disc fully transparent; + , grafted disc transparent enough to allow observations of the iris structure; 0, grafted disc quite cloudy. Statistical analysis of the results was performed by the X2 method corrected for low values.
neovascularization. No significant histologie difference was observed. DISCUSSION
Our findings differed slightly from those of Cobb and Basu. These authors showed that treatment with 6-MP caused one week's delay in the opacification of heterologous corneal discs grafted interlamellarly in the thickness of rabbit corneas. We found that, after the 20th day, the local reaction and the transparency of the graft followed the same course in treated and control dogs, while dur ing the first three weeks, the reactive phe nomena were less marked in the treated ani mals. We think that the essential differences in the operative techniques used (grafts at full-thickness in our experiments) may ex plain the partial differences in the clinical and histologie results. We think it interesting to stress that treatment with 6-MP, an inhibitor of the
globulin synthesis and, thus, of the immune reaction, did not bring about preservation of the transparency of the corneal grafts. These data would seem to indicate that other processes (most likely, trophic altera tions of the tissues ; Venco,11 D'Ermo, 12 Delogu and Vecchione 1 '), in addition to immune factors, whose presence cannot be doubted, gather to provoke the reactive phenomena which cause the opacification of corneal grafts. SUMMARY
The effect of 6-MP, a metabolic antago nist to immunoglobulin formation, on the reaction following penetrating corneal heterografts in dogs was studied. It was shown that the treatment with the drug ( 18 mg/kg body weight every third day) induced a diminution of the reaction only within the first 20 days after grafting; later the reaction was almost the same in both ex perimental and control groups of animals;
718
M. LANZIERI, A. G. SECCHI, AND C. B. GABRIELI
two months after the transplantation both groups of dogs showed almost complete opacification of the grafted disc. Clinica Oculistica dell Universita. REFERENCES
1. Billingham, R. E., Brent, L., and Medawar, P. B. : Quantitative studies on Tissue Trans plantation. I I : The Origin, strength and duration of actively and adoptively acquired immunity. Proc. Roy. Soc. B., 143 :S8, 1954. 2. D'Ermo, F., Lanzieri, M., and Secchi, A. G. : Anticorneal antibodies in rabbits after homologous and heterologous corneal grafts. Unpublished paper. 3. Schwartz, R., Eisner, A., and Dameshek, W. : The effect of 6-mercaptopurine on primary and secondary immune response. J. 'Clin. Invest., 38:1394, 1959. 4. Calne, R. Y. : The rejection of renal homografts: Inhibition in dogs by 6-MP. Lancet, 1:417, 1960. 5. Meeker, W., Condie, R., Weiner, D., Varco, R. L., and Good, R. A. : Prolongation of skin homograft survival in rabbits by 6-MP. Proc. Soc. Exper. Biol. & Med., 102:459, 1959. 6. Meeker, W., Condie, R., Good, R. A., and
Varco, R. L. : Alteration of the homograft re sponse by antimetabolites. Ann. N.Y. Acad. Sei., 87 :203, 1960. 7. McLaren, A. : Induction of tolerance to skin homografts in mice treated with 6-mercaptopurine. Transpl. Bull., 28:479, 1961. 8. Rubin, B. A., and Lewis, R. W. : Sustained tol erance of Homotransplantation induced with 6-MP Proc. Am. A. Cancer Res., 3 :264, 1961. 9. Cobb, G. M., and Basu, P. K.: Effect of 6-MP on the immune response in inter-lamellar corneal heterografts. Transpl., 1:232, 1964. 10. Mueller, F. O., and Smith, A. U. : Some ex periments on grafting frozen corneal tissue in rabbits. Exper. Eye Res.. 2 :237, 1963. 11. Venco, L. : Considerazioni sulla cosidetta "Malattia del lembo" nella cheratoplastica. Rass. Oftal., 18 :65, 1949. 12. D'Ermo, F. : Problemi immunitari nell'omotrapianto do cornea. Atti del Simposio sulla Che ratoplastica. Problemi attuali di Biologia e Clinica. Ed. Soc. Oftal. Lombarda, Milano, 1963, p. 120. 13. Delogu, A. and Vecchione, L. : Lo stato attuale delle conoscenze sui problemi concernenti l'attecchimento e la trasparenza del trapianto corneale, alia luce delle piu' recenti esperienze. Giorn. It. Oftal., 18 :21, 1964.
DISTICHIASIS AND T R I C H I A S I S : ORIGIN AND MANAGEMENT* HAROLD G. SCHEIE, M.D.,
AND DANIEL M. ALBERT,
M.D.
Philadelphia, Pennsylvania
This paper suggests the use of the oper ating microscope for removal of aberrant lashes and discusses briefly the nature of distichiasis and trichiasis. Each condition may cause severe irritation and corneal ul cération with diminution of vision. Distichiasis is considered to be a congeni tal anomaly in which lashes grow from an abnormal position along the posterior bor der of the lid margin, apparently from the openings of the meibomian glands. It has been suggested that the meibomian glands in the normal eyelid actually are modified seba ceous glands which represent a row of lash es no longer present in man. In patients with distichiasis, the meibomian glands become modified and take on hair-bearing function,1 probably an atavistic phenome non. * From the Department of Ophthalmology, Hospital of the University of Pennsylvania, Phil adelphia General Hospital, Veterans Administra tion Hospital and Children's Hospital of Phila delphia.
We believe that the condition can also be acquired. In several of our patients with long-standing inflammation and hyperemia of the lids and conjunctiva, especially in as sociation with late changes of Stevens-John son syndrome, slitlamp examination demon strated cilia arising from the meibomian glands at various sites along the inner as pect of the lid margin. New aberrant lashes can subsequently develop and add to pre-ex isting difficulties. The lashes usually appear stunted and nonpigmented. They may also be extremely fine and lie crumpled on the epithelial surface. This latter type may easi ly be overlooked unless slitlamp microscopy is used. Our opinion is supported by some pre vious observations. Rählmann 2 described new hair follicles developing along the inner margin of the lid in patients with trichiasis. He believed, however, that these developed by the downgrowth of the surface epitheli um.