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- 1. Peripheral ulcerative keratitis 14 June 2022 ParindaPhinitkitanan, MD. Advisor Aj.Chakree Hirunpat
- 2. 2 1 3 5 6 4 2 Introduction Etiology Pathogenesis Differential diagnosis EpidemiologyClnical features Investigation Outline 7 Management
- 3. Introduction 3 ▫ Highly vascularand lymphatic tissue -> reservoir of inflammatory cells and cytokines ▫ The highest concentration and replicative potential of LESCs ▫ Higher density of Langerhans’ cells (APC) limbus = conjunctiva > central ▫ High level of IgM, C1 (high MW) ▫ Tight collagen bundle packing: suitable for high MW compound accumulation ▫ Less innervations and sensitivity ▫ Flatter curvature Peripheral cornea more prone to local and systemic inflammatory reaction Central Peripheral Thickness 0.52 mm 0.65-1 mm Nutrition tear film aqueous peri-limbal capillaries Central 50% - limbus where corneal stroma is bonded to the sclera (No clear cut border) Gupta Y, Kishore A, Kumari P, Balakrishnan N, Lomi N, Gupta N, Vanathi M, Tandon R. Peripheral ulcerative keratitis. Survey of Ophthalmology. 2021 Nov 1;66(6):977-98. Gomes BF, Santhiago MR. Biology of peripheral ulcerative keratitis. Experimental Eye Research. 2021 Mar 1;204:108458. Perilimbal capillaries extend 0.5 mm in the cornea Interrupt vss. -> peripheral necrosis and ulceration Conjunctiva stroma filled with plasma cell -> local production of Ig
- 4. 4 Epidemiology McKibbin M, IsaacsJD, Morrell AJ. Incidence of corneal melting in association with systemic disease in the Yorkshire Region, 1995–7. British Journal of Ophthalmology. 1999 Aug 1;83(8):941-3. Yagci A. Update on peripheral ulcerative keratitis. Clinical Ophthalmology (Auckland, NZ). 2012;6:747. Sharma N, Sinha G, Shekhar H, et al. Demographic profile, clinical features and outcome of peripheral ulcerative keratitis: a prospective study. British Journal of Ophthalmology 2015;99:1503-1508. •Peripheral ulcerative keratitis (PUK) = a destructive inflammatory disease of the juxtalimbal cornea associated with crescent-shaped corneal stromal thinning, an epithelial defect, and inflammatory cells in the corneal stroma •Rare condition; incidence of 0.2-3 per million per year •2nd most common ocular complication of autoimmune diseases (anterior uveitis-1st) •Generally a predilection for female sex, with a few reports of equal incidence in males and females •Inferior involvement is more common > superior
- 5. 5 5 Idiopathic (31.5%) diagnosis ofexclusion m/c cause: systemic collagen vascular diseases (50% of noninfectious PUK cases) m/c systemic disease (34%of noninfectious cause) m/c: S. aureus May occur after any ocular surgery, not necessarily close to the incision site asso. with severe cases Infection 2nd commonest cause of PUK (19.7%) Etiology 1 2 Gomes BA, Santhiago MR, Jorge PA, Kara-José N, Moraes Jr HV, Kara-Junior N. Corneal involvement in systemic inflammatory diseases. Eye & contact lens. 2015 May 1;41(3):141-4. Yagci A. Update on peripheral ulcerative keratitis. Clinical Ophthalmology (Auckland, NZ). 2012;6:747.
- 6. Hello! I am JaydenSmith I am here because I love to give presentations. You can find me at @username keratolysis Corneal Ag Exogenous Ag Humoral immunity Cellular immunity 1 2 Pannus formation: maintain immune cell clustering in the peripheral cornea Dana MR, Qian Y, Hamrah P. Twenty-.ve-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea. 2000;19(5):625–43. P A T H O G E N E S I S Corneal keratocytes -> ↑MMP-2 Lacrimal gland, conjunctival/corneal epi, inflam cell -> ↑ MMP-9 MMP-2,9 -> Hydrolyse type 4 collagen (BM) Granulocyte ->↑MMP-1,8 hydrolyse type 1 collagen (stroma)
- 7. 7 1 3 5 6 4 2 Introduction Etiology Pathogenesis Differential diagnosis Epidemiology Clnicalfeatures Investigation Outline 7 Management
- 8. Clinical Features ▫ Mostlyunilateral (If bilateral, often asymmetrical) ▫ Initial symptoms: injection, pain, tearing, and photophobia ▫ Pain out of proportion -> Mooren’s ulcer ▫ Acute PUK -> decreased vision vary from mild to severe due to inflammation ▫ Chronic PUK -> decreased vision due to corneal astigmatism and corneal opacity ▫ The most important sign: peripheral crescentic ulceration, an epithelial defect, corneal thinning, and infiltration at the limbus with overhanging edges ▫ Progress circumferentially and then centripetally ▫ Initially involves the superficial 1/3 of the cornea -> later progress to corneal perforation 8 Sharma N, Sinha G, Shekhar H, et al. Demographic profile, clinical features and outcome of peripheral ulcerative keratitis: a prospective study. Br J Ophthalmol. 2015;99(11):1503–8.
- 9. Healed peripheral keratitis inrheumatoid arthritis - Corneal scarring and thinning - Vascularization; bed of the ulcer up to its leading edge but not beyond Corneal perforation (white stars) and iris tissue prolapse Clinical Features central ulceration with perforation Sharma N, Sinha G, Shekhar H, et al. Demographic profile, clinical features and outcome of peripheral ulcerative keratitis: a prospective study. Br J Ophthalmol. 2015;99(11):1503–8.
- 10. “ 10 ▫ 25% casesPUK precedes the systemic manifestation ▫ Inflammation may involve the adjacent conjunctiva, episclera, and sclera ▫ No separation between the ulcerative process and the limbus ▫ Usually unilateral and sectoral, within 2 mm of limbus ▫ Initially begins as a breakdown of the corneal epithelium in the perilimbal area -> Without adequate disease control, the underlying corneal stroma undergoes lysis with whitish, sterile infiltrates at the edges of the necrosed tissue 10 PUK associated with systemic autoimmune disease The most frequent ocular manifestation = Dry eye disease (keratoconjunctivitis sicca) The concomitant keratoconjunctivitis sicca in these patients aid in this epithelial breakdown Ladas JG, Mondino BJ. Systemic disorders associated with peripheral corneal ulceration. Curr Opin Ophthalmol. 2000;11(6):468–71.
- 11. “ 11 ▫ Extra-articular involvementin RA occurs in 25% of patients; includes the heart, lung, skin, CNS ▫ Eye: 1st KCS 2nd Scleritis ▫ Pt. with scleritis -> found PUK 7.4% ▫ Necrotizing scleritis increases the probability of PUK (35%) Rheumatoid arthritis PUK associated with systemic autoimmune disease RA ▫ symmetrical swelling of the small joints of the hands and feet ▫ morning stiffness lasting more than 1 hour ▫ positive rheumatoid factor thickened scleral nodule diffuse nodular scleritis Necrotizing scleritis Scleromalacia perforans B. L. Silva, J. B. Cardozo, P. Marback, F. C. Machado, V. Galvão, and M. B. Santiago, “Peripheral ulcerative keratitis: a serious complication of rheumatoid arthritis,” Rheumatology International, vol. 30, no. 9, pp. 1267-1268, 2010.
- 12. “ 12 12 Rheumatoid arthritis PUK associatedwith systemic autoimmune disease PUK; sectoral location with associated scleritis, corneal infiltrate, and overlying epithelial defect ▫ Prevalence of the PUK in RA patients = 3% ▫ RA is observed in 34–42% of PUK cases ▫ PUK frequently occurs in patients with destructive RA for long duration (>20 years ) and with high titers of RF, anti-CCP Ab ▫ The onset of PUK = a marker of worsening of the rheumatoid process (rheumatoid vasculitic phase: PUK, necrotizing scleritis) ▫ The 5-year mortality rate for untreated RA with either PUK or scleritis = 50% ▫ Emergent treat! A. E. Levitt, K. T. McManus, A. L. McClellan, J. Davis, R. Goldhardt, and A. Galor, “Ocular inflammation in the setting of concomitant systemic autoimmune conditions in an older male population,” Cornea, vol. 34, no. 7, pp. 762–767, 2015.
- 13. “ 13 13 Limbal guttering • Adjacentto an area of active scleritis or an isolated finding • Corneal epithelium generally remains intact • The extent of peripheral thinning may be variable -> In severe cases, may progress to perforation with or without trauma Acute stromal keratitis • Stromal opacities can occur at any level of the cornea with accompanying stromal edema • Overlying epithelium may break down -> cause PUK diffuse anterior scleritis (m/c type) with marginal infiltrates Rheumatoid arthritis PUK associated with systemic autoimmune disease A. P. Vignesh and R. Srinivasan, “Ocular manifestations of rheumatoid arthritis and their correlation with anti-cyclic citrullinated peptide antibodies,” Clinical Ophthalmology, vol. 9, pp. 393–397, 2015.
- 14. “ 14 14 Granulomatosis with polyangiitis(GPA) PUK associated with systemic autoimmune disease ▫ Mid-40s male ▫ 2nd m/c cause of systemic PUK ▫ PUK often manifests at the onset of GPA compared to late occurrence in RA ▫ Ocular involvement = 50–60% ▫ 1st orbital inflammation 2nd scleritis (including PUK) ▫ Small vessel vasculitis of the intrascleral part of anterior ciliary arteries and perilimbal arteries -> necrotizing scleritis and PUK ▫ Retinal vasculitis ▫ Adjacent scleritis almost always present ▫ C-ANCA: 99% specificity, 96% sensitivity ▫ ANCA titers correlate with the severity and extent of the disease and tend to decrease in remission of the disease • ENT: Nasal or oral inflammation • Lung: Abnormal chest radiograph • Kidney: microhematuria or RBC casts • Biopsy: granulomatous inflammation (lung, orbit) • Positive ANCA Focal necrotizing scleritis with peripheral keratitis B. Kubaisi, S. K. Abu, and C. S. Foster, “Granulomatosis with polyangiitis (Wegener’s disease): an updated review of ocular disease manifestations,” Intractable Rare Diseases Research, vol. 5, no. 2, pp. 61–69, 2016.
- 15. “ 15 Granulomatosis with polyangiitis(GPA) PUK associated with systemic autoimmune disease Peripheral anterior stromal and subepithelial infiltrates Grainy anterior stromal opacities Conjunctival mass (rare) Patho: necrotizing granulomas, necrotizing / granulomatous vasculitis B. Kubaisi, S. K. Abu, and C. S. Foster, “Granulomatosis with polyangiitis (Wegener’s disease): an updated review of ocular disease manifestations,” Intractable Rare Diseases Research, vol. 5, no. 2, pp. 61–69, 2016.
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- 17. 17 Mooren’s ulcer ▫ Severepain out of proportion to the inflammation ▫ The adjacent sclera is uninvolved ▫ Central edge of the ulcer is infiltrated with overhanging margins ▫ Etiology: unknown suggesting an autoimmune basis + possibly genetic and environmental factors ▫ Sensitization to calgranulin C, Ag in corneal stromal keratinocytes -> unveiling of this hidden corneal antigen after trauma or infection ▫ Associated with HCV infection, parasitic /hookworm infestation Cytokine-induced calgranulin C expression in keratocytes. Clin Immunol, 1999. 91(1): p. 34-40.
- 18. 18 Mooren’s ulcer Early Moorenulcer Interpalpabral limbus is involved most often, followed by the inferior and then superior limbus Disease progresses circumferentially and then centripetally Healing: conjuctivalization, scarring and thinning Advanced cases cornea is replaced by a vascularized, opaque thinned tissue leaving behind a central island of corneal tissue Srinivasan, M., et al., Clinical characteristics of Mooren's ulcer in South India. Br J Ophthalmol, 2007. 91(5): p. 570-5.
- 19. 19 Typical or benign(m/c) Atypical young black African males Parasitemia Watson in 1997 divided Mooren ulcer into three distinct varieties based on clinical presentation and anterior segment fluorescein angiographic findings Superficial vascular plexus Deep vascular plexus Vascularization of ulcer Normal Intense deep leakage Deep vessels Normal Vasodilation Deep vessels Mooren’s ulcer Anterior segment FA Obliterate Intense deep leakage superficial and deep vessels iritis, intense AC inflammation, secondary infections, glaucoma, cataract, and corneal perforation in ∼35–40% of cases Watson, P.G., Management of Mooren's ulceration. Eye (Lond), 1997. 11 ( Pt 3): p. 349-56. > 60 yr 14-40 yr
- 20. 20 Type 1 Typical unilateral Type2 Bilateral aggressive Watson in 1997 divided Mooren ulcer into three distinct varieties based on clinical presentation and anterior segment fluorescein angiographic findings Superficial vascular plexus Deep vascular plexus Vascularization of ulcer Normal Intense deep leakage Deep vessels Normal Vasodilation Deep vessels Mooren’s ulcer Anterior segment FA Obliterate Intense deep leakage superficial and deep vessels Watson, P.G., Management of Mooren's ulceration. Eye (Lond), 1997. 11 ( Pt 3): p. 349-56. Type 3 Bilateral indolent
- 21. 21 1 3 5 6 4 2 Introduction Etiology Pathogenesis Differential diagnosis Epidemiology Clnicalfeatures Investigation Outline 7 Management
- 22. 22 Congenital/Developmental • Lattice dystrophytype II • Wilson’s disease • Cornea plana • Sclerocornea • Posterior embryotoxin • Axenfeld–Rieger anomaly Inflammatory/Autoimmune • RA, GPA, PAN • Marginal keratitis (Staph) • Fuchs’ superficial marginal keratitis • Phlyctenulosis • Mooren ulcer • Vascular pannus • Dermoid Degenerative disorders + corneal thinning • Terrien marginal degeneration • Pellucid marginal degeneration • Dellen Degenerative disorders No corneal thinning • Dry eye/tear film deficiency • Corneal arcus • Lipid keratopathy • Calcific band keratopathy • White limbal girdle of Vogt • Furrow degeneration • Limbal stem cell deficiencies Neoplastic • Pterygium • Benign squamous metaplasia • CIN, SCC • Melanoma Infectious • Bacterial • Fungal • Viral • Miscellaneous Differential diagnosis Peripheral corneal disease
- 23. 23 PUK associated withinfection • Important to rule out adjacent infectious scleritis • Limbal erythema, usually with edema and infiltrate: 1st sign that spreads to the limbus • When infection spreads to the scleral tissue, treatment becomes more difficult due to the lack of vascularization and antibiotic penetration in the scleral tissue. Signs ▫ Conjunctival injection ▫ Purulent infiltration ▫ Vascularization ▫ Corneal edema ▫ Descemet’s folds ▫ Endothelial exudates ▫ Hypopyon Peripheral corneal disease • Congenital • Infection • Inflammation • Autoimmune • Malignancy • Degenerative
- 24. Gram-negative bacteria (m/cP.aeruginosa) can spread from the cornea to the sclera (keratoscleritis) 24 PUK associated with infection Systemic ▫ VZV, TB, Sy, AIDS, HCV, Lyme Disease, bacillary dysentery, parasite ▫ The systemic infections related to PUK are usually associated to immune reactions. Infectious PUK with hypopyon in a case of syphilis Peripheral corneal disease • Congenital • Infection • Inflammation • Autoimmune • Malignancy • Degenerative Exogenous ▫ Bacteria, Virus, Fungus, Acanthamoeba ▫ Less frequent than in the central cornea ▫ RF: CL wear, trauma, surgery and corneal exposure
- 25. 25 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Phlyctenular keratoconjunctivitis (PKC) • Phlyctenule (Greek ‘phlyctena’) = “blister” -> conjunctival/corneal nodule • Children (6 months to 16 years old) • Type IV hypersensitivity reaction (cell-mediated) to a microbial antigen in a sensitized individual • M/C tuberculoprotein and staphylococcal antigen (Herpes simplex, Chlamydia, Streptococcus viridians, Dolosigranulum pigram and intestinal parasites) • Staphylococcal-related: less photophobia than tuberculous phlyctenules Thygeson P. The etiology and treatment of phlyctenular keratoconjunctivitis. Am J Ophthalmol. 1951;34:1217-1236. Suzuki T, Mitsuishi Y, Sano Y, et al. Phlyctenular keratitis associated with meibomitis in young patients. Am J Ophthalmol. 2005;140:77-82.
- 26. 26 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Phlyctenular keratoconjunctivitis (PKC) Corneal phlyctenule • More severe symptoms • Sequelae as scar: more common • Subsequent corneal phlyctenules can arise at the central edge of a pannus from prior attacks “marching/wandering phlyctenules” elevated leading edge trailed by a leash of vessels Conjunctival phlyctenule • Pink fleshy nodule standing out in the background of surrounding conjunctival injection • M/C near the limbus Mondino BJ. Inflammatory diseases of the peripheral cornea. Ophthalmology. 1988;95:463-472.
- 27. 27 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Phlyctenular keratoconjunctivitis (PKC) Nodule Necrosis Ulcer staining with fluorescein R/O infectious corneal ulcers Healing: anterior stromal scarring (triangular in shape with the base of the triangle at the limbus) + superficial vascularization +thinning Michelle Steenbakkers. Corneal Phlyctenule in a Steroid Responder. Clinical and Refractive Optometry 28:5, 2017
- 28. 28 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative The mainstays of therapy • Acute inflammation -> topical corticosteroids • Decreasing the load of bacterial antigens to eliminate recurrences -> topical antibiotics + lid hygiene • If multiple recurrence / steroid dependent -> topical cyclosporine A = effective option • Underlying infections should be treated -> TB (IRZE), Chlamydia (azithromycin, doxycycline) Phlyctenular ulcers usually resolve rapidly (in 2 weeks) with topical corticosteroid therapy alone ≠ infectious corneal ulcers - worsen Phlyctenular keratoconjunctivitis (PKC) 2 weeks 6 months Neiberg MN, Sowka J. Phlyctenular keratoconjunctivitis in a patient with Staphylococcal blepharitis and ocular rosacea. Optometry. 2008;79:133-137. Lindsay A. Sicks, et al., Phlyctenular Keratoconjunctivitis: a Teaching Case Report. Journal.opted, 2021.
- 29. 29 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Staphylococcal marginal keratitis Thygeson P. Marginal corneal infiltrates and ulcers. Trans Am Acad Ophthalmol Otolaryngol 1947;51:198-209. • Type III hypersensitivity reaction -> immune complex deposition in the peripheral cornea -> activate the complement pathway -> attracting neutrophils to the site -> opacity (catarrhal infiltrate) • No age predilection • Sterile peripheral corneal infiltrates separated from the limbus by a clear zone; circular zone of the cornea (1-2 mm from the limbus may have Ag:Ab ratio that is conducive to larger, more inflam immune complexes • Thygeson first reported the frequent association with chronic conjunctivitis due to Staphylococcus, concurrent blepharitis
- 30. 30 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Staphylococcal marginal keratitis • Infiltrates are usually round 0.1-1.5mm but can coalesce into broader lesions, associated with adjacent area of conjunctival hyperemia • Circumferential progression • Location: lid margin crosses the limbus 2, 4, 8, 10 o’clock positions • With prolonged inflammation, the corneal epithelium overlying the stromal infiltrates can break down -> ulceration • Epithelial defect: smaller than the area of infiltration • Little or no anterior chamber reaction Mannis M., Holland E.: Cornea. Elsevier Health Sciences. 2016; 1079-1081.
- 31. 31 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Staphylococcal marginal keratitis Stiff AH, Ricca AM, Goins KM. Corneal Marginal Ulcer: Marginal keratitis with ulceration in a 45 year-old male. EyeRounds.org. posted March 14, 2017 Management • Spontaneous resolution in 2-3 wks with few long-term sequelae • Respond rapidly to topical steroid • Treat blepharitis!! • In cases with epithelial breakdown and stromal ulceration -> broad-spectrum topical antibiotic 2 days topical corticosteroids
- 32. 32 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Terrien marginal degeneration (TMD) • Middle-aged 20-40 years males (now; no sexual predilection) • Bilateral, painless • Initiates commonly at the superior / superonasal aspect of the cornea • Histopathologic: innumerable intracellular and extracellular vacuoles in the affected stroma Hallmarks: 1) thinning and furrow formation of the peripheral cornea 2) superficial vascularization with a radial trajectory, some tortuosity and occasional circumferential appearance in the thinned area 3) lipid deposition the leading edge of the affected area 4) intact corneal epithelium without apparent inflammatory signs or symptoms thinning meridian at superior -> flattening relative steepening against-the-rule astigmatism Ding Y, Murri MS, Birdsong OC, Ronquillo Y, Moshirfar M. Terrien marginal degeneration. Survey of Ophthalmology. 2019 Mar 1;64(2):162-74.
- 33. 33 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Terrien marginal degeneration (TMD) Complication: • Perforation rate 11.6-15% (spontaneous or traumatic) • Partial and total Descemet membrane detachments • Corneal hydrops (intracorneal sac of aqueous humor) • In some cases, sac can extend under the conjunctiva -> filtering bleb formation -> hypotony Superificial NV Demarcation gray line from the central cornea Furrow extend 360 degree circumferentially Opacification of central cornea Ding Y, Murri MS, Birdsong OC, Ronquillo Y, Moshirfar M. Terrien marginal degeneration. Survey of Ophthalmology. 2019 Mar 1;64(2):162-74.
- 34. 34 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Fuchs’ superficial marginal keratitis (rare) Mejía LF, Santamaría JP, Gaviria AM, Rodríguez AM. Fuchs' superficial marginal keratitis managed with circumferential marginal corneoscleral lamellar patch graft. Eur J Ophthalmol. 2013 Nov-Dec;23(6):925-7. • Affects the limbus at any localization • Accompanying epithelial defects • Epithelial delimitation gray line without lipid deposition • Pseudo-pterygium more common • Chronic course with recurrent red eye, pain, and tearing • Acute phase: lubricants, topical steroids, oral doxycycline, vitamin C • Definitive treatment in advanced cases: circumferential corneoscleral lamellar patch graft -> good anatomical and functional reconstruction Differentiates from Terrien’s marginal degeneration -> Different manifestations of the same disease spectrum
- 35. 35 Peripheral corneal disease • Congenital • Infection •Inflammation • Autoimmune • Malignancy • Degenerative Pellucid marginal degeneration (PMD) • 20-40 years of age, no sex predilection • Area of thinning is always epithelialized, clear, avascular, and without lipid deposition • Patho: collagen abnormalities, similar to keratoconus • Bilateral, asymmetric • Mostly affect inferior cornea, but may occur superiorly • Decreased VA due to against-the-rule astigmatism • Intact corneal sensation • Complications: vertical stress lines in Descemet membrane, acute hydrops > relatively rare • Treatment: Spectacles, RGP CL, scleral lenses, LK, PK Sridhar M, Mahesh S, Bansal AK et al: Pellucid marginal corneal degeneration. Ophthalmol 111:1102–1107, 2004 Transparent Narrow concentric bands of corneal thinning 1-2 mm above the inferior limbus Ectasia of normal-thickness central cornea
- 36. 36 1 3 5 6 4 2 Introduction Etiology Pathogenesis Differential diagnosis EpidemiologyClnical features Investigation Outline 7 Management
- 37. 37 CBC Anemia: connective tissuedisease Leukocytosis: PAN Leucopenia: SLE, RA Thrombocytopenia: 20% of SLE, APS Thrombocytosis: 1/3 of RA ANCA cANCA (classic perinuclear fluorescence pattern) produced by proteinase 3 (PR3) autoAb highly sensitive and specific for GPA pANCA (atypical ANCA; more diffuse staining pattern) directed against myeloperoxidase associated with MPA (70%), Churg-Strauss (30%) ANA: 95% of SLE (neg -> unlikely) Antiphospholipid Ab: LA, antiCL, antiB2GP1 RF: 80% of RA, chronic infections, other immunological diseases, (false pos 4%) Anti-CCP: low sense, high specific than RF Titres directly related to the disease severity Inflam ESR, CRP: rise in the connective tissue disorders -> assessment of the disease activity Microbiological workup corneal scrapings conjunctival swab R/O local infectious etiology CXR: TB, sarcoidosis, GPA, SLE, PSS TB: TST, IGRA (endemic area) UA: hematuria (GPA). proteinuria (vasculitis) Sero HBV: PAN (strong asso.) HCV: PAN, Mooren’s ulcer Anti-HIV Syphilis: VDRL, FTA-ABS Investigation PAN: - Classic PAN: medium and small-sized ‘muscular’ arteries -> 10% c- or p-ANCA positive - Microscopic polyangiitis (MPA): smaller arteries, arterioles, capillaries and venules -> strongly ANCA-positive Radhika Tandon, Anat Galor, Virender Singh Sangwan, Manotosh Ray, Editors. Peripheral ulcerative keratitis a comprehensive guide. Switzerland: Springer; 2017
- 38. 38 Bonnet C, DebillonL, Al-Hashimi S, Hoogewoud F, Monnet D, Bourges JL, Brézin A. Anterior segment optical coherence tomography imaging in peripheral ulcerative keratitis, a corneal structural description. BMC Ophthalmol. 2020 May 25;20(1):205. Anterior segment OCT: normal limbus Epithelium Bowman Stroma Descemet Epithelium Substantia propria Conjunctiva Cornea
- 39. 39 Bonnet C, DebillonL, Al-Hashimi S, Hoogewoud F, Monnet D, Bourges JL, Brézin A. Anterior segment optical coherence tomography imaging in peripheral ulcerative keratitis, a corneal structural description. BMC Ophthalmol. 2020 May 25;20(1):205. Anterior segment OCT Acute stage • Absence of corneal epithelium • Scrambled appearance of the anterior stroma -> residual fragments/ digested/ ischemic necrotic epithelial cells or stromal anterior keratocytes • Heterogeneous stromal reflectivity Monitoring ocular disease’s level of activity More sensitive than the clinical examination to detect subclinical changes
- 40. 40 Bonnet C, DebillonL, Al-Hashimi S, Hoogewoud F, Monnet D, Bourges JL, Brézin A. Anterior segment optical coherence tomography imaging in peripheral ulcerative keratitis, a corneal structural description. BMC Ophthalmol. 2020 May 25;20(1):205. Anterior segment OCT Healing stage • Irregular hyporeflective epithelium • Smoother anterior stroma • Homogenous hyperreflective stroma
- 41. 41 Bonnet C, DebillonL, Al-Hashimi S, Hoogewoud F, Monnet D, Bourges JL, Brézin A. Anterior segment optical coherence tomography imaging in peripheral ulcerative keratitis, a corneal structural description. BMC Ophthalmol. 2020 May 25;20(1):205. Anterior segment OCT Healed stage • Filling of the corneal defect by a hyporeflective thick epithelium • Persistence of the hyperreflective underlying stroma • Demarcation line between the healed and unaffected stroma
- 42. 42 Bonnet C, DebillonL, Al-Hashimi S, Hoogewoud F, Monnet D, Bourges JL, Brézin A. Anterior segment optical coherence tomography imaging in peripheral ulcerative keratitis, a corneal structural description. BMC Ophthalmol. 2020 May 25;20(1):205. Anterior segment OCT • Acute stage: absence of corneal epithelium, a scrambled appearance of the anterior stroma and a heterogeneous stromal reflectivity • Healing stage: an irregular hyporeflective epithelium, a smoother anterior stroma, and a homogenous hyperreflective stroma • Healed stage: a filling of the corneal defect by a hyporeflective thick epithelium, the persistence of the hyperreflective underlying stroma, and a demarcation line
- 43. 43 Takezawa Y, SuzukiT, Shiraishi A. Observation of Retrocorneal Plaques in Patients With Infectious Keratitis Using Anterior Segment Optical Coherence Tomography. Cornea. 2017 Oct;36(10):1237-1242. Anterior segment OCT Fungal keratitis Retrocorneal plaques showed an unclear boundary between the cornea and plaque Bacterial keratitis Herpetic keratouveitis Retrocorneal plaques showed a clear boundary between the cornea and plaque make a diagnosis when the slit lamp examination remains limited because of corneal opacification Retrocorneal plaques -> infection
- 44. 44 1 3 5 6 4 2 Introduction Etiology Pathogenesis Differential diagnosis EpidemiologyClnical features Investigation Outline 7 Management
- 45. Management 45 • Etiological diagnosis •Severity of ocular findings • The extent and nature of the systemic disease Gupta Y, Kishore A, Kumari P, Balakrishnan N, Lomi N, Gupta N, Vanathi M, Tandon R. Peripheral ulcerative keratitis. Survey of Ophthalmology. 2021 Nov 1;66(6):977-98.
- 46. Stepwise treatment forMooren’s Ulcer 46 Escalate treatment upon severity De-escalate treatment as clinical response Ashar JN, Mathur A, Sangwan VS. Immunosuppression for Mooren’s ulcer: evaluation of the stepladder approach-topical, oral and intravenous immunosuppressive agents. Br J Ophthalmol. 2013;97(11) 1391 LP - 1394. Treatment with interferon α2b is indicated in cases of MU with hepatitis C infection
- 47. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 47 Medical management Infectious PUK: appropriate and specific topical and/or systemic antimicrobial agents Noninfectious immune-inflammatory PUK Local therapy • Topical lubrication with preservative-free artificial tear supplements = the mainstay -> washout of the inflammatory mediators on the ocular surface • Topical collagenase inhibitors: 20% acetylcysteine, 1% medroxyprogesterone acetate -> prevent further stromal lysis • Topical corticosteroids: caution with underlying auto-immune conditions (e.g., RA) inhibit new collagen formation -> increase the chances of corneal perforation and delay epithelial healing • Topical cyclosporine A 2% and topical tacrolimus 0.03% (calcineurin inhibitors): inhibit T- cell receptor-mediated IL-2 synthesis from T-lymphocytes -> promotes ulcer healing Primary goals of treatment • Promote epithelial healing • Halt any further stromal lysis by minimizing inflammation • Prevent superinfection Yagci A. Update on peripheral ulcerative keratitis. Clin Ophthalmol. 2012;6(1):747–54.
- 48. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 48 Medical management Systemic therapy Management of ocular morbidity - Oral NSAIDs: relieve the pain and inflammation in cases of severe PUK / scleritis - Oral ascorbic acid (500 mg bid): in case of peripheral corneal melting Help corneal epithelial wound healing Reduce the formation of corneal opacity from healing - Oral doxycycline (100 mg bid) Prevent local collagenolysis by irreversibly inhibiting MMP Halt the migratory keratocytes or fibroblasts that lead to formation of scar tissue Promote complete coverage of the ocular surface by epithelial basal cells Management of the underlying systemic condition - Initial aggressive systemic immunosuppressants (systemic corticosteroids + IMT) = Mainstay to treat inflammatory PUK Galor A, Thorne JE. Scleritis and peripheral ulcerative keratitis. Rheum Dis Clin North Am. 2007;33(4):835–54.
- 49. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 49 Medical management Systemic therapy Management of the underlying systemic condition Oral corticosteroids • Oral prednisone: starting dose 1mg/kg/day (maximum 100 mg/day) with slow tapering • In vision-threatening: IVMP 1g/day x 3 days + switching to oral prednisone to prevent further ocular complications Immunosuppressive agents “corticosteroid-sparing agents” • Start along with high dose systemic steroid -> usually become effective after 6 months • Adequate systemic immunosuppression: reduce disease mortality and ocular morbidity (Mean estimated survival of 24.7 years with immunosuppressive therapy compared to 10.7 years without therapy) • IMT is recommended even in PUK without any diagnosed underlying systemic condition Ogra S, Sims JL, McGhee CNJ, Niederer RL. Ocular complications and mortality in peripheral ulcerative keratitis and necrotising scleritis: The role of systemic immunosuppression. Clin Experiment Ophthalmol. 2020;48(4):434–41.
- 50. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 50 Medical management Immunosuppressive agents 1st line in RA Repeat CBC q 2-3 wk safer but lesser efficacy severe systemic side effects Gupta Y, Kishore A, Kumari P, Balakrishnan N, Lomi N, Gupta N, Vanathi M, Tandon R. Peripheral ulcerative keratitis. Survey of Ophthalmology. 2021 Nov 1;66(6):977-98. 1st line in GPA
- 51. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 51 Medical management Biological therapy if refractory to all conventional immunosuppressant agents Gupta Y, Kishore A, Kumari P, Balakrishnan N, Lomi N, Gupta N, Vanathi M, Tandon R. Peripheral ulcerative keratitis. Survey of Ophthalmology. 2021 Nov 1;66(6):977-98. most useful agent to maintain remission in ANCA-associated vasculitis Anti-TNF now increasingly use but beware SE GPA Remission phase: cyclophos + steroid Maintenance phase: rituximab Infliximab - M/C binds to both soluble and transmembrane TNF-α Absolute contraindications = congestive heart failure Only soluble TNF-α receptors
- 52. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 52 Surgical management Ang M, Mehta JS, Sng CC, Htoon HM, Tan DT. Indications, outcomes, and risk factors for failure in tectonic keratoplasty. Ophthalmology. 2012;119 (7):1311–9. In general, for PUK, surgery should be delayed until adequate immunosuppression has been achieved, due to high chances of graft melts, graft rejection and recurrence of PUK Aim • Tectonic support: to preserve the globe integrity in patients with perforations / descemetocele or progressive annular/central extension advancing close to the visual axis • Visual rehabilitation: severe astigmatism not improving with glasses or contact lens Minimalist approach—performing anterior lamellar surgery when possible, avoiding unnecessary replacement of unaffected central cornea, and minimizing limbal stem cell damage Surgical options base on • the size of perforation or thinning • the extent of ocular disease
- 53. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 53 Surgical management Hanada K, Shimazaki J, Shimmura S, et al. Multilayered amniotic membrane transplantation for severe ulceration of the cornea and sclera. Am J Ophthalmol. 2001;131:324-31 Ngan D, Chau HT. Amniotic membrane transplantation for Mooren’s ulcer. Clin Exp Ophthalmol. 2011;39:386-92 Multilayered amniotic membrane graft (AMG) • Reduce inflammation, promote epithelialization, healing • Tectonic support in severe peripheral corneal thinning, corneal ulcers, and perforations • With or after unsuccessful conjunctival resection Conjunctival flaps = Contraindicate! in Mooren’s ulcer -> bring inflammatory mediators closer to the melt (Other autoimmune disease – unclear) • Surrounding 2-3 clock hours of the conjunctiva, adjacent to the inflamed area • Remove inflammatory cells, collagenases, and other mediators • Recurrences are common in conjunctival resection alone Conjunctival resection/recession Mooren’s ulcer
- 54. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 54 Surgical management Vote B, Elder M. Cyanoacrylate glue for corneal perforations: a description of a surgical technique and a review of the literature. Clin Exp Ophthalmol. 2000;28:437-42 • Temporary measure to defer the surgery till inflammation resolves • Waiting for healing to occur with systemic treatment for the underlying disease • Glue: acts as a barrier preventing PMNs from reaching (and destroying) corneal stroma + provides tectonic stability -> reduce the risk of perforation • BCL must be placed over the glued cornea -> antibiotic drop prophylaxis for CL-induced bacterial superinfection (Pseudomonas M/C) • Perforations of size ≤ 3mm Cyanoacrylate glue
- 55. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 55 Surgical management Shi W, Liu M, Gao H, et al. Penetrating keratoplasty with small-diameter and glycerin-cryopreserved grafts for eccentric corneal perforations. Cornea. 2009;28:631-7 111. Siatiri H, Moghimi S, Malihi M, Khodabande A. Use of sealant (HFG) in corneal perforations. Cornea. 2008;27(9):988-91 Rectangular lamellar graft Perforations of size 3-5.5 mm Small-diameter therapeutic penetrating corneal graft • For eccentric perforations away from the visual axis • Small diameter reduces the risk of rejection Full-thickness corneal patch graft following full-thickness corneal dissection central and partial-thickness scleral dissection peripheral
- 56. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 56 Surgical management Maccheron LJ, Daya MS. Wedge resection and lamellar dissection for pellucid marginal degeneration. Cornea. 2012;31:708-15 Corneal wedge excision • For localized, small, nonprogressive thinning disorders • Removing the peripheral crescentic thin area of abnormal cornea and reapproximating the normal thickness stromal edges together with tight sutures. • Long time for vision to stabilize and long term F/U develop vascularization, loosening of sutures, against- the-rule astigmatic drift Crescentic lamellar wedge resection Full thickness crescentic wedge resection
- 57. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 57 Surgical management Javadi MA, Karimian F, Hosseinzadeh A. Lamellar crescentic resection for pellucid marginal corneal degeneration. J Refract Surg. 2004;20:162-5 Crescentic lamellar keratoplasty with or without compression • Ring-shaped lamellar graft is placed and sutured in the prepared host bed in the corneal periphery • Respect the central corneal contour, minimizing the amount of postoperative astigmatism
- 58. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 58 Surgical management Compressive crescentic lamellar keratoplasty • Undersized graft and tight sutures -> flattening perpendicular to the circumference + corrects the steepening and high astigmatism • Reduce the risks of graft rejection and failure Gao H, Wang X, Echegaray JJ, et al. Partial lamellar keratoplasty for peripheral corneal disease using a graft from the glycerin-preserved corneoscleral rim. Graefes Arch Clin Exp Ophthalmol 2014;252:963–8.
- 59. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 59 Surgical management Cheng CL, Theng JT, Tan DT. Compressive C-shaped lamellar keratoplasty: a surgical alternative for the management of severe astigmatism from peripheral corneal degeneration. Ophthalmolo. 2005;112(3):425– 30. C-shaped lamellar corneal patch graft “Match and Patch” • Minimally sized graft width along with strong compression sutures • semi-circular “C”-shaped or “banana”-shaped area of tissue immediately around the peripheral melt, which fully encompasses the melting area, but minimally involved unaffected corneal tissue • The donor tissue is carefully sized to “match” the recipient bed, and “patches” the peripheral defect accordingly
- 60. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 60 Surgical management “Match and Patch” Cheng CL, Theng JT, Tan DT. Compressive C-shaped lamellar keratoplasty: a surgical alternative for the management of severe astigmatism from peripheral corneal degeneration. Ophthalmolo. 2005;112(3):425– 30.
- 61. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 61 Surgical management Kaushal S, Jhanji V, Sharma N, et al. “Tuck In” Lamellar Keratoplasty (TILK) for corneal ectasias involving corneal periphery. Br J Ophthalmol. 2008;92:286-90 Tuck-in lamellar keratoplasty (type of LK) • Provide central and peripheral structural support in conditions that have both central and peripheral corneal thinning • Central part of the graft is full-thickness stroma devoid of Descemet membrane and endothelium • Peripheral 2-3 mm of the graft is partial- thickness flange of the lamellar corneal tissue • Lesser graft rejections compared to PK as the peripheral donor flange is tucked in the intrastromal pocket and protected from limbal vessels
- 62. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 62 Surgical management Partial tuck-in lamellar keratoplasty The peripheral intrastromal tuck is only limited to the area of partial peripheral thinning -> tectonic support in cases with central and partial peripheral thinning Kaushal S, Jhanji V, Sharma N, et al. “Tuck In” Lamellar Keratoplasty (TILK) for corneal ectasias involving corneal periphery. Br J Ophthalmol. 2008;92:286-90
- 63. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 63 Surgical management Lim LS, Arundhati A, Tan DT. Sequential therapeutic penetrating keratoplasty with cryopreserved and fresh corneal tissue for severe infectious keratitis: a case-control study. Cornea. 2011;30(7):739–43. stabilization with penetrating keratoplasty and clear corneal graft Annular lamellar keratoplasty for PUK with impending perforation 9 months
- 64. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 64 Surgical management Skeens HM, Holland EJ. Large-diameter penetrating keratoplasty: indications and outcomes. Cornea. 2010;29:296-301 Large-diameter penetrating keratoplasty (9-9.5 mm) • In advanced cases: hydrops, advanced protrusion, large areas of peripheral or circumferential involvement • 20-40% graft survival at 6 months, and many patients therefore require multiple grafts • Higher risk of graft rejection due to proximity to limbal vessels (64% rejection rate vs. 7-38% for keratoconus grafts) • Higher risk of secondary glaucoma because of damage to trabecular meshwork by suture passage through it and a higher incidence of PAS
- 65. Management • Medical therapy -Local therapy - Systemic therapy • Surgical management 65 Surgical management Postoperative care • Continue treatment of the underlying disease – Anti-microbial therapy for infections, systemic and topical anti-inflammatory or immunosuppressive therapy for the primary condition • Management of the graft – Reduce inflammation (both systemically and locally), Antibiotic prophylaxis to prevent recurrent or secondary • Management of the ocular surface – Promote re-epithelialzation of the peripheral donor graft surface with the use of bandage contact lenses, and preservative-free medications • Visual Rehabilitation with appropriate and timely suture removal, astigmatic correction and secondary surgeries if necessary • Chronic steroid therapy—predisposes to glaucoma and cataract formation • Limbal stem cell deficiency—potentially lead to persistent epithelial defects, ulceration and melting Ang M, Mehta JS, Sng CC, Htoon HM, Tan DT. Indications, outcomes, and risk factors for failure in tectonic keratoplasty. Ophthalmology. 2012;119 (7):1311–9.
- 66. 66 Take home message PUKis a harbinger of active systemic vasculitis, with high risk of morbidity and mortality Early diagnosis and treatment -> better prognosis
- 67.
Editor's Notes
- #7 abnormal T cell responses initiate antibody production from plasma cells, with subsequent formation of immune complexes that get deposited in the stroma of the peripheral cornea.110 This results in the activation of the complement pathway, which leads to chemotaxis of furthermore in- -ammatory cells and release of collagenases and proteases, which cause invasion and stromal destruction of the peripheral cornea
- #18 helminthic antigen that cross-reacts with calgranulin C
- #28 elevated corneal phlyctenule with surrounding neovascularization and associated scarring, which demonstrates a classic triangular shape.
- #30 The distance between the central cornea and limbal blood vessels slows down the diffusion of high molecular weight proteins, like IgM and C1 protein, which occur at higher concentrations in the peripheral cornea. The peripheral cornea also has a higher concentration of Langerhans Cells.
- #31 elevated corneal phlyctenule with surrounding neovascularization and associated scarring, which demonstrates a classic triangular shape.
- #32 The distance between the central cornea and limbal blood vessels slows down the diffusion of high molecular weight proteins, like IgM and C1 protein, which occur at higher concentrations in the peripheral cornea. The peripheral cornea also has a higher concentration of Langerhans Cells.
- #35 elevated corneal phlyctenule with surrounding neovascularization and associated scarring, which demonstrates a classic triangular shape.
- #36 ≠ the thinning in keratoconus is in the area of maximal corneal protrusion high and irregular "against-the-rule" astigmatism of up to 20 diopters and a flattening of the vertical meridian. The astigmatism can instead be "with the rule" if the inferior curvature is steeper than the horizontal curvature
- #46 During the treatment of the ocular lesions, a simultaneous referral to a rheumatologist will help in the initiation of therapy targeting the underlying cause
- #59 Mooren’s ulcer.
- #65 . A penetrating keratoplasty was performed. There was recurrence of Mooren’s ulcer in the cornea, with the characteristic overhanging edge between areas of involved and uninvolved cornea.