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Limbal Stem Cell Deficiency & its management
1) Limbal stem cells are located in the palisades of Vogt region of the limbus and are responsible for maintaining the normal corneal epithelium. Limbal stem cell deficiency occurs when the source of these cells is damaged, causing severe problems to the ocular surface. 2) Limbal stem cell deficiency can be partial or total, and is classified based on extent and etiology. Common causes include chemical/thermal burns, Stevens-Johnson syndrome, and multiple ocular surgeries. 3) Management is based on the extent and severity of deficiency, and involves steps from conservative treatment to more invasive procedures like limbal stem cell transplantation or keratoprosthesis. The goal is to replace
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Limbal Stem Cell Deficiency & its management
- 1. LIMBAL STEM CELL DEFICIENCY& ITS MANAGEMENT Dr. Karan Bhatia DOMS, DNB Department of Cornea & Refractive Surgery M. M. Joshi Eye Institute, Hubli, Karnataka
- 2. Introduction – Conceptof stem cell Specialized Undifferentiated Self-renewing Capable of indefinite proliferation Responsible for cellular replacement & regeneration
- 3. Limbal stem cells •Present in the Palisades ofVogt in the Limbus • CHARACTERISTICS: 1.Poorly differentiated cells 2.Primitive cytoplasm 3.Long cell cycle duration • FUNCTIONS: 1.Maintain normal corneal epithelium 2.Barrier – Prevent conjunctivalization of cornea
- 4. Tseng, S. C.G. and Sun,T.T. (2000) In: Corneal Surgery:Theory,Technique, andTissue. (F. S. Brightbill, ed.), Mosby-Year Book, Inc., St. Louis, Missouri, pp. 12. SC (Parent) SC (Daughter ) SC SC SC TAC PMC TDC SC – Stem Cell TAC –Transiently Amplifying Cells PMC – Post-mitotic Cells TDC –Terminally Differentiating Cells Result of this migration & differentiation Corneal epithelium renewed every 7–10 days
- 5. THOFT’s XYZ Hypothesis •X vector – combination of proliferation & centripetal migration of basal epithelial cells • Y vector – As basal epithelial cells divide they give rise to suprabasal cells that form stratified layers of cornea • Z vector – shedding of squamous epithelial cells from surface of cornea into tear film Corneal epithelial maintenance X + Y = Z i.e. if corneal epithelium is to be maintained, cell loss must be balanced by cell replacement
- 6. Limbal stem celldeficiency - Definition Clinical entity where source for newly generated corneal epithelial cells damaged causing severe derangement of ocular surface
- 7. Classification (based onextent of deficiency) Partial/Focal Total • Partial/focal loss of stem cell function • Rest of limbus – normal • Total loss of limbal stem cells • No Normal area Examples • Multiple surgeries at limbus • Cryotherapy • Pterygium • Less severe thermal/chemical burns Examples • Severe chemical/thermal burns • Steven Johnson Syndrome • Advanced Cicatrical Pemphigoid • Contact lens wear
- 8. Limbal Stem cell– dysfunction versus destruction LSC DYSFUNCTION LSC DESTRUCTION • Usually, primary or hereditary • Can be part of ocular/systemic anomalies • Due to abnormal microenvironment of limbal tissues stem cells never achieve normal function • Bilateral • Less severe • Acquired loss of functioning of stem cells • Associated with severe ocular surface damage • Unilateral Examples • Aniridia • Keratitis associated with multiple endocrine deficiencies Examples • Chemical/thermal burns • SJS, ocular pemphigoid • Multiple surgeries, cryotherapy to limbus • Contact lens wear
- 9. Classification (based onetiology) Idiopathic Trauma Iatrogenic Autoimmun e Eye disease Congenital & Hereditary Chemical/ thermal burns A. Local • Ocular Surgery/Cryotherapy • Radiation/ Radiotherapy • Contact lens use • Topical medications (Mitomycin C) A. Systemic • Medications (Hyroxyurea) • Graft vs Host disease • SJS • Ocular pemphigoid • Pterygium • Neurotrophic keratitis • Infections (herpetic/ trachoma) • Atopy • Peripheral corneal ulcers • Anterior segment ischaemic syndrome • Aniridia • Sclerocornea • Multiple endocrine neoplasia • KID Syndrome • Xeroderma pigmentosa
- 10. Clinical features 1 • Conjunctivalization 2 •Neovascularization 3 • Chronic inflammation Symptoms – • Decreased vision • Redness • Watering • Photophobia • Recurrent attacks of Pain (due to epithelial breakdown TRIAD
- 11. Jain R, SurekaS, DasAV, Basu S, SangwanVS. Cell BasedTherapy for Ocular Surface Reconstruction. DOSTimes. 2013; 19(4);17-28 Fibrovascular pannus Persistent Epithelial Defects Loss of limbal palisades ofVogt Scarring Extensive symblepharon Destruction of BM Corneal Melting Lid Anomalies
- 12. Diagnosis History &Clinical signs Impression Cytology • Can detect presence of goblet cells on cornea • Can be used to perform immunohistochemistry of for different markers • Corneal epithelium specific K3/K12 • Conjunctiva K-19 Histopathology of pannus Flurophotometry
- 13. Management – stepwise approach Corneal transplantation Limbal stem cell transplantation Dry eye management Associated Adnexal conditions Acute phase of inflammation Topical Steroids Lubricants Amniotic membrane Transplantation ProKera Lid abnormalities Symblepharon Ankyloblepharon
- 14. Algorithm for Managementof LSCD Acute Stage Chronic Stage Unilateral Bilateral Partial Diffuse Partial Diffuse Topical Steroids AMT Prevent Perforation (PK, tenonplasty) Conservative Mx Scleral CL SSCE AMT CLAU CLET SLET KLAL (one eyed) Allo-CLET CLET Allo-CLET KLAL CLAL-lr/lnr KLAL Allo-CLET KLAL Keratoprosthesis PK = Penetrating Keratoplasty, SSCE = Sequential Sector Conjunctival Epitheliectomy,AMT = Amniotic Membrane Transplantation, CLAU = Conjunctival Limbal autograft, SLET = Selective Limbal EpithelialTransplant, CLET = Cultivated Limbal EpithelialTransplantation, Allo-CLET = AllogenicCLET, KLAL = Keratolimbal allograft, CLAL- lr/lnr = Conjunctival Limbal Allograft-live related/nonrelated Lal I, Gupta N, Purushotam J, SangwanVS. Limbal stem cell deficiency:Current Management. Journal of Clinical Ophthalmology and Research. 2016 (4)
- 15. Surgery steps • Releasesymblepharon • Insert speculum • Conjunctival peritomy (4-5 mm from limbus) • Remove conjunctival pannus • Haemostasis (cautery/adrenaline)
- 16. Conjunctival limbal autograft(CLAU) 1st described by Kenyon andTseng in 1989 Indication Unilateral partial/total LSCD chemical injury, multiple surgeries or contact lens use
- 17. • 2 stripsof limbal conjunctival grafts 6-7 limbal arc lengths removed • Lenticule 1 mm clear cornea + 1 mm limbus + 3 mm bulbar conjunctiva = 5 mm • Lenticules sutured with 10- 0 nylon & 8-0 vicry sutures AMT patch can be used to cover lesion site Recommendation (to prevent donor site LSCD) – <6 clock hours Partial thickness limbal graft (40-60µ)
- 18. Conjunctival limbal allograft •Indication – Bilateral LSCD, Unilateral LSCD (one eyed) • Donor – Living related person/ HLA matched cadaver Living related allograft Cadaver allograft Chance of LSCD Yes No 360˚ coverage Not possible with one donor Possible Simultaneous PK tissue Not available Available Chance of rejection Less More Viability of stem cells More Doubtful
- 19. Excision same asautograft Donor Lenticules Suturing of 4 lenticules from 2 donors inTotal LSCD
- 20. Keratolimbal allograft (KLAL) •Indication – Partial/Total Bilateral LSCD Unilateral LSCD (one eyed) • Donor – Cadaveric tissue within 72 hours of death (50 years) Conjunctival limbal gaft Keratolimbal allograft Chances of LSCD in donor More Less Suturing Easy, less mismatch Difficult, more mismatch Simultaneous PK tissue Not available Available Chances of rejection More Less Viability of stem cells More Doubtful
- 21. • Corneo-scleral Rim •Excised with 7.5 trephine • Excess peripheral rim excised (leaving 1 mm sclera peripheral to limbus • Posterior 1/2 to 2/3 of ring removed (lamellar dissection) • Ring shaped limbal tissue sutured to recipient limbal area • + Penetrating/Lamellar Keratoplasty
- 22. Cultured LSC transplantation •Principle – Harvesting a small population of limbal epithelium which presumably contains LSC cultivating these cells under controlled laboratory conditions • Donor – Autograft/ Allograft • Indications - Autograft Allograft U/L LSCD B/L Partial LSCD B/LTotal LSCD U/LTotal LSCD (one eyed) • Amniotic membrane with cultured stem cells is transferred sutured with limbus by 10-0 Nylon & conjunctiva with 8-0 vicryl • BCL put • Simultaneous PK/DALK can be done
- 23. Selective limbal epithelialtransplantation Combines benefits of – CLAU + cultivated limbal epithelial transplant Single stage procedure + Cost effective
- 24. Jain R, SurekaS, DasAV, Basu S, SangwanVS. Cell BasedTherapy for Ocular Surface Reconstruction. DOSTimes. 2013; 19(4);17-28
- 25. Keratoprosthesis Boston KP •For wetsurface Osteo-Odonto KP • Severe dry ocular surface
- 26. Post-operative care • Topicalantibiotics - till defects heal • Topical corticosteroids • Tear substitutes (preservative free) • Topical CyclosporinA • Oral Immunosuprresants – For atleast a year (sometimes lifelong) • Follow up – Close till 6-8 weeks, thereafter monthly
- 27. Future directions Alternatives to AMT Human embryonic stemcells Skin epidermal stem cells Hair follicle cells Bone marrow- derived mesenchymal stem cells Immature dental pulp stem cells
- 28.
Editor's Notes
- #5 Ocular surface epithelia covering the cornea, limbus, and conjunctiva. The conjunctival epithelium differs from the limbal corneal epithelium in that it has mucin-expressing goblet cells. Some of the limbal basal epithelial cells are considered to be stem cells (SCs) for the corneal epithelium. By means of centripetal movement (open arrow), SCs generate corneal transient amplifying cells (TACs) located in the corneal epithelial basal layer. Both SCs and TACs are regarded as progenitor cells in the proliferative compartment, and they give rise to postmitotic cells of the suprabasal layers, as well as terminally differentiated cells of the super fi cial layers. The latter two cell types belong to the differentiative compartment. Suprabasal cell movement at the limbus creates a barrier to separate the conjunctival epithelium from the corneal epithelium (solid arrow).
- #14 1. Any surgical treatment in an inflamed eye NOT give desired results Active inflammation detrimental to transplanted stem cells. Inflammation causes greater Stem cell damage than primary injury itself Supportive therapy to prevent further complications AMT application in acute stage of insult serves as a biological bandage Prabasawat et al reported that AMT within 5 days of grade II-III chemical burns resulted in faster epithelial healing as well as decreased corneal haze and LSCD. A newer approach involves the implantation of ProKera—an FDA-approved class II medical device consisting of a sheet of cryopreserved amniotic membrane clipped into a dual symblepharon ring system — during the acute stage of chemical injury or SJS. It allows for an early intervention, at bedside, promoting the beneficial effect of reduction of inflammation and early healing of epithelial defect of the corneaand conjunctiva.
- #15 Conservative Mx- lubricants, anti-inflammatory agents, BCL Gas permeable Scleral CL fluid interphase appears to aid re-epithelialization through oxygenation, moisture & protection. Definitive treatment of Partial LSCD – surgical SSCE – removal of conjunctival epithelium that is covering a sector of cornea and limbus or adjacent bulbar conjunctiva, so that corneal epithelial cells may regrow over denuded surface.