PUK ppt

Peripheral
ulcerative
keratitis
14 June 2022
Parinda Phinitkitanan, MD.
Advisor Aj.Chakree Hirunpat

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1 3 5
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Introduction
Etiology
Pathogenesis
Differential
diagnosis
Epidemiology Clnical features Investigation
Outline
7
Management

Introduction
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▫ Highly vascular and 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

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Epidemiology
McKibbin M, Isaacs JD, 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

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Idiopathic (31.5%)
diagnosis of exclusion
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.

Hello!
I am Jayden Smith
I am here because I love to give
presentations.
You can find me at @username
keratolysis
Corneal Ag
Exogenous Ag
Humoral immunity
Cellular immunity
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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)

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1 3 5
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Introduction
Etiology
Pathogenesis
Differential
diagnosis
Epidemiology
Clnical features
Investigation
Outline
7
Management

Clinical Features
▫ Mostly unilateral (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
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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.

Healed peripheral keratitis
in rheumatoid 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.

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▫ 25% cases PUK 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
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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.

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▫ Extra-articular involvement in 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
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.

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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.

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Limbal guttering
• Adjacent to 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
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.

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Granulomatosis with polyangiitis (GPA)
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.

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Granulomatosis with polyangiitis (GPA)
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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Mooren’s ulcer
▫ Severe pain 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.

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Mooren’s ulcer
Early Mooren ulcer
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.

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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
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

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Type 1
Typical unilateral
Type 2
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
Deep vessels
Normal
Vasodilation
Deep vessels
Mooren’s ulcer
Anterior segment FA
Obliterate
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

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1 3
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Introduction
Etiology
Pathogenesis
Differential
diagnosis
Outline
7
Management

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Congenital/Developmental
• Lattice dystrophy type 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

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PUK associated with infection
• 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

Gram-negative bacteria (m/c P.aeruginosa) can spread
from the cornea to the sclera (keratoscleritis)
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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

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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.

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Peripheral
corneal
disease
• Congenital
• Infection
• Inflammation
• Autoimmune
• Malignancy
• Degenerative
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.

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Peripheral
corneal
disease
• Congenital
• Infection
• Inflammation
• Autoimmune
• Malignancy
• Degenerative
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

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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
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.

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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

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Peripheral
corneal
disease
• Congenital
• Infection
• Inflammation
• Autoimmune
• Malignancy
• Degenerative
• 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.

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Peripheral
corneal
disease
• Congenital
• Infection
• Inflammation
• Autoimmune
• Malignancy
• Degenerative
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

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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.

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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.

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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

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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

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1 3 5
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Introduction
Etiology
Pathogenesis
Differential
diagnosis
Epidemiology Clnical features
Investigation
Outline
7
Management

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CBC
Anemia: connective tissue disease
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

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Bonnet C, Debillon L, 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

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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

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Healing stage
• Irregular hyporeflective
epithelium
• Smoother anterior
stroma
• Homogenous
hyperreflective stroma

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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

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• 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
Takezawa Y, Suzuki T, Shiraishi A. Observation of Retrocorneal Plaques in Patients With Infectious Keratitis Using Anterior Segment Optical Coherence Tomography. Cornea. 2017 Oct;36(10):1237-1242.
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
1 3 5
6
4
2
Introduction
Etiology
Pathogenesis
Differential
diagnosis
Outline
7
Management

Management
45
• Etiological diagnosis
• Severity of ocular findings
• The extent and nature of the systemic disease

Stepwise treatment for Mooren’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

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.

Management
• Medical therapy
- Local therapy
- Systemic therapy
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.

Management
• Medical therapy
- Local therapy
- Systemic therapy
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.

Management
• Medical therapy
- Local therapy
- Systemic therapy
50
Medical management
Immunosuppressive agents
1st line in RA
Repeat CBC q 2-3 wk
safer but lesser efficacy
severe systemic side effects 
1st line in GPA

Management
• Medical therapy
- Local therapy
- Systemic therapy
51
Medical management
Biological therapy if refractory to all conventional immunosuppressant agents
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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.

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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.

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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

Management
• Medical therapy
- Local therapy
- Systemic therapy
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
Take home message
PUK is a harbinger of active systemic vasculitis, with high risk of morbidity and mortality
Early diagnosis and treatment -> better prognosis

PUK ppt

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