A Review of Limbal Stem Cell Deficiency
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Abstract
Limbal stem cell deficiency (LSCD) can be secondary to multiple etiologies including contact lens wear, chemical or thermal trauma, and systemic disease, any of which can result in the reduction of the number of stem cells or their decreased functionality. Primary LSCD is seen with a variety of congenital anterior segment disorders. Often LSCD can be stabilized and timely diagnosis is the key. The use of topical corticosteroids and artificial tear lubricants, along with treatment of any underlying conditions, and discontinuation of contact lenses are important initial treatment strategies. Advance treatments include amniotic membranes, limbal stem cell transplantation and keratoprostheses.
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References
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2. Thoft RA, Wiley LA, Sundarraj N. The multipotential cells of the limbus. Eye 1989;3:109.
3. Thoft RA, Friend J. Biochemical transformation of regenerating ocular surface epithelium. Invest Ophthalmol Vis Sci 1977;16(1):14–20.
4. Shapiro MS, Friend J, Thoft RA. Corneal re-epithelialization from the conjunctiva. Invest Ophthalmol Vis Sci 1981;21(1 Pt 1):135–42.
5. Sun TT, Lavker RM. Corneal epithelial stem cells: past, present, and future. The journal of investigative dermatology Symposium proceedings 2004;9(3):202–7.
6. Tseng SCG. Concept and application of limbal stem cells. Eye 1989;3:141.
7. Jawaheer L, Anijeet D, Ramaesh K. Diagnostic criteria for limbal stem cell deficiency-a systematic literature review. Surv Ophthalmol 2017;62(4):522–32.
8. Le Q, Yang Y, Deng SX, Xu J. Correlation between the existence of the palisades of Vogt and limbal epithelial thickness in limbal stem cell deficiency. Clin Exp Ophthalmol 2017;45(3):224–31.
9. Bobba S, Di Girolamo N, Mills R, et al. Nature and incidence of severe limbal stem cell deficiency in Australia and New Zealand. Clin Exp Ophthalmol 2017;45(2):174–81.
10. Schwartz GS, Holland EJ. Iatrogenic limbal stem cell deficiency. Cornea 1998;17(1):31–7.
11. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol 2000;44(5):415–25.
12. Zaidi FH, Bloom PA, Corbett MC. Limbal stem cell deficiency: a clinical chameleon. Eye (Lond) 2003;17(7):837–9.
13. Holland EJ. Management of limbal stem cell deficiency: a historical perspective, past, present, and future. Cornea 2015;34 Suppl 10:S9–15.
14. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci 1990;31(7):1301–14.
15. Huang AJ, Tseng SC. Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci 1991;32(1):96–105.
16. Hogan MJ AJ, Weddell JE. Histology of the human eye. 1971:112-26.
17. Le Q, Xu J, Deng SX. The diagnosis of limbal stem cell deficiency. Ocul Surf 2018;16(1):58–69.
18. Vazirani J, Nair D, Shanbhag S, Wurity S, Ranjan A, Sangwan V. Limbal stem cell deficiency-demography and underlying causes. Am J Ophthalmol 2018;188:99–103.
19. Donisi PM, Rama P, Fasolo A, Ponzin D. Analysis of limbal stem cell deficiency by corneal impression cytology. Cornea 2003;22(6):533–8.
20. Kim KH, Kim WS. Corneal limbal stem cell deficiency associated with the anticancer drug S-1. Optom Vis Sci 2015;92(4 Suppl 1):S10–3.
21. Kim BY, Riaz KM, Bakhtiari P, et al. Medically reversible limbal stem cell disease: clinical features and management strategies. Ophthalmology 2014;121(10):2053–8.
22. Martin R. Corneal conjunctivalisation in long-standing contact lens wearers. Clin Exp Optom 2007;90(1):26–30.
23. Jeng BH, Halfpenny CP, Meisler DM, Stock EL. Management of focal limbal stem cell deficiency associated with soft contact lens wear. Cornea 2011;30(1):18–23.
24. Nguyen DQ, Srinivasan S, Hiscott P, Kaye SB. Thimerosal-induced limbal stem cell failure: report of a case and review of the literature. Eye Contact Lens 2007;33(4):196–8.
25. Termote K, Schendel S, Moloney G, Holland SP, Lange AP. Focal limbal stem cell deficiency associated with soft contact lens wear. Can J Ophthalmol J. 2017;52(6):552–8.
26. Holden BA, Stephenson A, Stretton S, et al. Superior epithelial arcuate lesions with soft contact lens wear. Optom Vis Sci 2001;78(1):9–12.
27. Rossen J, Amram A, Milani B, et al. Contact lens-induced limbal stem cell deficiency. Ocular Surface 2016;14(4):419–34.
28. Holland EJ, Schwartz GS. Iatrogenic limbal stem cell deficiency. Trans Am Ophthalmol Soc 1997;95:95–107; discussion -10.
29. Chan CC, Holland EJ. Severe limbal stem cell deficiency from contact lens wear: patient clinical features. Am J Ophthalmol 2013;155(3):544–9 e2.
30. Ksander BR, Kolovou PE, Wilson BJ, et al. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 2014;511(7509):353–7.
31. Dua HS. The conjunctiva in corneal epithelial wound healing. Br J Ophthalmol 1998;82(12):1407–11.
32. Kim KH, Mian SI. Diagnosis of corneal LSCD. Curr Opin Ophthalmol 2017;28(4):355–62.
33. Bron AJ, Mengher LS. The ocular surface in keratoconjunctivitis sicca. Eye (Lond). 1989;3 ( Pt 4):428–37.
34. Araujo AL, Ricardo JR, Sakai VN, et al. Impression cytology and in vivo confocal microscopy in corneas with total LSCD. Arq Bras Oftalmol 2013;76(5):305–8.
35. Sacchetti M, Lambiase A, Cortes M, et al. Clinical and cytological findings in limbal stem cell deficiency. Graefes Arch Clin Exp Ophthalmol 2005;243(9):870–6.
36. Lathrop KL, Gupta D, Kagemann L, Schuman JS, Sundarraj N. Optical coherence tomography as a rapid, accurate, noncontact method of visualizing the palisades of Vogt. Invest Ophthalmol Vis Sci 2012;53(3):1381–7.
37. Espandar L, Steele JF, Lathrop KL. Optical coherence tomography imaging of the palisades of Vogt to assist clinical evaluation and surgical planning in a case of limbal stem-cell deficiency. Eye Contact Lens 2017;43(5):e19–e21.
38. Banayan N, Georgeon C, Grieve K, Borderie VM. Spectral domain optical coherence tomography in limbal stem cell deficiency. A Case Control Study Am J Ophthalmol 2018.
39. Chan EH, Chen L, Yu F, Deng SX. Epithelial thinning in limbal stem cell deficiency. Am J Ophthalmol 2015;160(4):669–77 e4.
40. Chidambaranathan GP, Mathews S, Panigrahi AK, et al. In vivo confocal microscopic analysis of limbal stroma in patients with limbal stem cell deficiency. Cornea 2015;34(11):1478–86.
41. Pellegrini G, Rama P, Di Rocco A, et al. Concise review: hurdles in a successful example of limbal stem cell-based regenerative medicine. Stem Cells 2014;32(1):26–34.
42. Cheung AY, Sarnicola E, Govil A, Holland EJ. Combined conjunctival limbal autografts and living-related conjunctival limbal allografts for severe unilateral ocular surface failure. Cornea 2017;36(12):1570–5.
43. Shoughy SS, Jaroudi MO, Tabbara KF. Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Clin Ophthalmol (Auckland, NZ) 2016;10:643–7.
44. Chahal HS, Estrada M, Sindt CW, et al. Scleral contact lenses in an academic oculoplastics clinic: epidemiology and emerging considerations. Ophthal Plastic Reconstr Surg 2017.
45. Paolin A, Cogliati E, Trojan D, et al. Amniotic membranes in ophthalmology: long term data on transplantation outcomes. Cell Tissue Banking 2016;17(1):51–8.
46. Sabater AL, Perez VL. Amniotic membrane use for management of corneal limbal stem cell deficiency. Curr Opin Ophthalmol 2017;28(4):363–9.
47. Kheirkhah A, Johnson DA, Paranjpe DR, et al. Temporary sutureless amniotic membrane patch for acute alkaline burns. Arch Ophthalmol 2008;126(8):1059–66.
48. Kolomeyer AM, Do BK, Tu Y, Chu DS. Placement of ProKera in the management of ocular manifestations of acute Stevens-Johnson syndrome in an outpatient. Eye Contact Lens 2013;39(3):e7–11.
49. Baradaran-Rafii A, Asl NS, Ebrahimi M, et al. The role of amniotic membrane extract eye drop (AMEED) in in vivo cultivation of limbal stem cells. Ocul Surf 2018;16(1):146–53.
50. Daya SM. Conjunctival-limbal autograft. Curr Opin Ophthalmol 2017;28(4):370–6.
51. He H, Yiu SC. Stem cell-based therapy for treating limbal stem cells deficiency: A review of different strategies. Saudi J Ophthalmol 2014;28(3):188–94.
52. Atallah MR, Palioura S, Perez VL, Amescua G. Limbal stem cell transplantation: current perspectives. Clin Ophthalmol (Auckland, NZ) 2016;10:593–602.
53. Kenyon KR. Limbal autograft transplantation for chemical and thermal burns. Dev Ophthalmol 1989;18:53–8.
54. Vazirani J, Basu S, Kenia H, et al. Unilateral partial limbal stem cell deficiency: contralateral versus ipsilateral autologous cultivated limbal epithelial transplantation. Am J Ophthalmol 2014;157(3):584–90 e1–2.
55. Rama P, Matuska S, Paganoni G, et al. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 2010;363(2):147–55.
56. Vazirani J, Mariappan I, Ramamurthy S, et al. Surgical management of bilateral limbal stem cell deficiency. Ocul Surf 2016;14(3):350–64.
57. Baylis O, Figueiredo F, Henein C, Lako M, Ahmad S. 13 years of cultured limbal epithelial cell therapy: a review of the outcomes. J Cell Biochem 2011;112(4):993–1002.
58. Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med 2004;351(12):1187–96.
59. Soma T, Hayashi R, Sugiyama H, et al. Maintenance and distribution of epithelial stem/progenitor cells after corneal reconstruction using oral mucosal epithelial cell sheets. PlosOne 2014;9(10):e110987.
60. Satake Y, Higa K, Tsubota K, Shimazaki J. Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency. Ophthalmology 2011;118(8):1524–30.
61. Khan B, Dudenhoefer EJ, Dohlman CH. Keratoprosthesis: an update. Curr Opin Ophthalmol 2001;12(4):282–7.
62. Srikumaran D, Munoz B, Aldave AJ, et al. Long-term outcomes of boston type 1 keratoprosthesis implantation: a retrospective multicenter cohort. Ophthalmology 2014;121(11):2159–64.
63. Sareen D, Saghizadeh M, Ornelas L, et al. Differentiation of human limbal-derived induced pluripotent stem cells into limbal-like epithelium. Stem Cells Transl Med 2014;3(9):1002–12.
64. Nguyen MTB, Thakrar V, Chan CC. EyePrintPRO therapeutic scleral contact lens: indications and outcomes. Canadian J Ophthalmol J 2018;53(1):66–70.
2. Thoft RA, Wiley LA, Sundarraj N. The multipotential cells of the limbus. Eye 1989;3:109.
3. Thoft RA, Friend J. Biochemical transformation of regenerating ocular surface epithelium. Invest Ophthalmol Vis Sci 1977;16(1):14–20.
4. Shapiro MS, Friend J, Thoft RA. Corneal re-epithelialization from the conjunctiva. Invest Ophthalmol Vis Sci 1981;21(1 Pt 1):135–42.
5. Sun TT, Lavker RM. Corneal epithelial stem cells: past, present, and future. The journal of investigative dermatology Symposium proceedings 2004;9(3):202–7.
6. Tseng SCG. Concept and application of limbal stem cells. Eye 1989;3:141.
7. Jawaheer L, Anijeet D, Ramaesh K. Diagnostic criteria for limbal stem cell deficiency-a systematic literature review. Surv Ophthalmol 2017;62(4):522–32.
8. Le Q, Yang Y, Deng SX, Xu J. Correlation between the existence of the palisades of Vogt and limbal epithelial thickness in limbal stem cell deficiency. Clin Exp Ophthalmol 2017;45(3):224–31.
9. Bobba S, Di Girolamo N, Mills R, et al. Nature and incidence of severe limbal stem cell deficiency in Australia and New Zealand. Clin Exp Ophthalmol 2017;45(2):174–81.
10. Schwartz GS, Holland EJ. Iatrogenic limbal stem cell deficiency. Cornea 1998;17(1):31–7.
11. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol 2000;44(5):415–25.
12. Zaidi FH, Bloom PA, Corbett MC. Limbal stem cell deficiency: a clinical chameleon. Eye (Lond) 2003;17(7):837–9.
13. Holland EJ. Management of limbal stem cell deficiency: a historical perspective, past, present, and future. Cornea 2015;34 Suppl 10:S9–15.
14. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal deficiency. Invest Ophthalmol Vis Sci 1990;31(7):1301–14.
15. Huang AJ, Tseng SC. Corneal epithelial wound healing in the absence of limbal epithelium. Invest Ophthalmol Vis Sci 1991;32(1):96–105.
16. Hogan MJ AJ, Weddell JE. Histology of the human eye. 1971:112-26.
17. Le Q, Xu J, Deng SX. The diagnosis of limbal stem cell deficiency. Ocul Surf 2018;16(1):58–69.
18. Vazirani J, Nair D, Shanbhag S, Wurity S, Ranjan A, Sangwan V. Limbal stem cell deficiency-demography and underlying causes. Am J Ophthalmol 2018;188:99–103.
19. Donisi PM, Rama P, Fasolo A, Ponzin D. Analysis of limbal stem cell deficiency by corneal impression cytology. Cornea 2003;22(6):533–8.
20. Kim KH, Kim WS. Corneal limbal stem cell deficiency associated with the anticancer drug S-1. Optom Vis Sci 2015;92(4 Suppl 1):S10–3.
21. Kim BY, Riaz KM, Bakhtiari P, et al. Medically reversible limbal stem cell disease: clinical features and management strategies. Ophthalmology 2014;121(10):2053–8.
22. Martin R. Corneal conjunctivalisation in long-standing contact lens wearers. Clin Exp Optom 2007;90(1):26–30.
23. Jeng BH, Halfpenny CP, Meisler DM, Stock EL. Management of focal limbal stem cell deficiency associated with soft contact lens wear. Cornea 2011;30(1):18–23.
24. Nguyen DQ, Srinivasan S, Hiscott P, Kaye SB. Thimerosal-induced limbal stem cell failure: report of a case and review of the literature. Eye Contact Lens 2007;33(4):196–8.
25. Termote K, Schendel S, Moloney G, Holland SP, Lange AP. Focal limbal stem cell deficiency associated with soft contact lens wear. Can J Ophthalmol J. 2017;52(6):552–8.
26. Holden BA, Stephenson A, Stretton S, et al. Superior epithelial arcuate lesions with soft contact lens wear. Optom Vis Sci 2001;78(1):9–12.
27. Rossen J, Amram A, Milani B, et al. Contact lens-induced limbal stem cell deficiency. Ocular Surface 2016;14(4):419–34.
28. Holland EJ, Schwartz GS. Iatrogenic limbal stem cell deficiency. Trans Am Ophthalmol Soc 1997;95:95–107; discussion -10.
29. Chan CC, Holland EJ. Severe limbal stem cell deficiency from contact lens wear: patient clinical features. Am J Ophthalmol 2013;155(3):544–9 e2.
30. Ksander BR, Kolovou PE, Wilson BJ, et al. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 2014;511(7509):353–7.
31. Dua HS. The conjunctiva in corneal epithelial wound healing. Br J Ophthalmol 1998;82(12):1407–11.
32. Kim KH, Mian SI. Diagnosis of corneal LSCD. Curr Opin Ophthalmol 2017;28(4):355–62.
33. Bron AJ, Mengher LS. The ocular surface in keratoconjunctivitis sicca. Eye (Lond). 1989;3 ( Pt 4):428–37.
34. Araujo AL, Ricardo JR, Sakai VN, et al. Impression cytology and in vivo confocal microscopy in corneas with total LSCD. Arq Bras Oftalmol 2013;76(5):305–8.
35. Sacchetti M, Lambiase A, Cortes M, et al. Clinical and cytological findings in limbal stem cell deficiency. Graefes Arch Clin Exp Ophthalmol 2005;243(9):870–6.
36. Lathrop KL, Gupta D, Kagemann L, Schuman JS, Sundarraj N. Optical coherence tomography as a rapid, accurate, noncontact method of visualizing the palisades of Vogt. Invest Ophthalmol Vis Sci 2012;53(3):1381–7.
37. Espandar L, Steele JF, Lathrop KL. Optical coherence tomography imaging of the palisades of Vogt to assist clinical evaluation and surgical planning in a case of limbal stem-cell deficiency. Eye Contact Lens 2017;43(5):e19–e21.
38. Banayan N, Georgeon C, Grieve K, Borderie VM. Spectral domain optical coherence tomography in limbal stem cell deficiency. A Case Control Study Am J Ophthalmol 2018.
39. Chan EH, Chen L, Yu F, Deng SX. Epithelial thinning in limbal stem cell deficiency. Am J Ophthalmol 2015;160(4):669–77 e4.
40. Chidambaranathan GP, Mathews S, Panigrahi AK, et al. In vivo confocal microscopic analysis of limbal stroma in patients with limbal stem cell deficiency. Cornea 2015;34(11):1478–86.
41. Pellegrini G, Rama P, Di Rocco A, et al. Concise review: hurdles in a successful example of limbal stem cell-based regenerative medicine. Stem Cells 2014;32(1):26–34.
42. Cheung AY, Sarnicola E, Govil A, Holland EJ. Combined conjunctival limbal autografts and living-related conjunctival limbal allografts for severe unilateral ocular surface failure. Cornea 2017;36(12):1570–5.
43. Shoughy SS, Jaroudi MO, Tabbara KF. Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Clin Ophthalmol (Auckland, NZ) 2016;10:643–7.
44. Chahal HS, Estrada M, Sindt CW, et al. Scleral contact lenses in an academic oculoplastics clinic: epidemiology and emerging considerations. Ophthal Plastic Reconstr Surg 2017.
45. Paolin A, Cogliati E, Trojan D, et al. Amniotic membranes in ophthalmology: long term data on transplantation outcomes. Cell Tissue Banking 2016;17(1):51–8.
46. Sabater AL, Perez VL. Amniotic membrane use for management of corneal limbal stem cell deficiency. Curr Opin Ophthalmol 2017;28(4):363–9.
47. Kheirkhah A, Johnson DA, Paranjpe DR, et al. Temporary sutureless amniotic membrane patch for acute alkaline burns. Arch Ophthalmol 2008;126(8):1059–66.
48. Kolomeyer AM, Do BK, Tu Y, Chu DS. Placement of ProKera in the management of ocular manifestations of acute Stevens-Johnson syndrome in an outpatient. Eye Contact Lens 2013;39(3):e7–11.
49. Baradaran-Rafii A, Asl NS, Ebrahimi M, et al. The role of amniotic membrane extract eye drop (AMEED) in in vivo cultivation of limbal stem cells. Ocul Surf 2018;16(1):146–53.
50. Daya SM. Conjunctival-limbal autograft. Curr Opin Ophthalmol 2017;28(4):370–6.
51. He H, Yiu SC. Stem cell-based therapy for treating limbal stem cells deficiency: A review of different strategies. Saudi J Ophthalmol 2014;28(3):188–94.
52. Atallah MR, Palioura S, Perez VL, Amescua G. Limbal stem cell transplantation: current perspectives. Clin Ophthalmol (Auckland, NZ) 2016;10:593–602.
53. Kenyon KR. Limbal autograft transplantation for chemical and thermal burns. Dev Ophthalmol 1989;18:53–8.
54. Vazirani J, Basu S, Kenia H, et al. Unilateral partial limbal stem cell deficiency: contralateral versus ipsilateral autologous cultivated limbal epithelial transplantation. Am J Ophthalmol 2014;157(3):584–90 e1–2.
55. Rama P, Matuska S, Paganoni G, et al. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med 2010;363(2):147–55.
56. Vazirani J, Mariappan I, Ramamurthy S, et al. Surgical management of bilateral limbal stem cell deficiency. Ocul Surf 2016;14(3):350–64.
57. Baylis O, Figueiredo F, Henein C, Lako M, Ahmad S. 13 years of cultured limbal epithelial cell therapy: a review of the outcomes. J Cell Biochem 2011;112(4):993–1002.
58. Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med 2004;351(12):1187–96.
59. Soma T, Hayashi R, Sugiyama H, et al. Maintenance and distribution of epithelial stem/progenitor cells after corneal reconstruction using oral mucosal epithelial cell sheets. PlosOne 2014;9(10):e110987.
60. Satake Y, Higa K, Tsubota K, Shimazaki J. Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency. Ophthalmology 2011;118(8):1524–30.
61. Khan B, Dudenhoefer EJ, Dohlman CH. Keratoprosthesis: an update. Curr Opin Ophthalmol 2001;12(4):282–7.
62. Srikumaran D, Munoz B, Aldave AJ, et al. Long-term outcomes of boston type 1 keratoprosthesis implantation: a retrospective multicenter cohort. Ophthalmology 2014;121(11):2159–64.
63. Sareen D, Saghizadeh M, Ornelas L, et al. Differentiation of human limbal-derived induced pluripotent stem cells into limbal-like epithelium. Stem Cells Transl Med 2014;3(9):1002–12.
64. Nguyen MTB, Thakrar V, Chan CC. EyePrintPRO therapeutic scleral contact lens: indications and outcomes. Canadian J Ophthalmol J 2018;53(1):66–70.