Grand Rounds

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Grand Rounds
Shivani V. Reddy, M.D. University of
Louisville Department of Ophthalmology and Visual
Sciences
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History

• CC eyelashes turned in
• HPI 72 y/o WM referred to oculoplastics clinic
  for a progressive trichiasis over 3-4 years.
  Patient states that growth is much more
  pronounced in the left eye . Also c/o chronic
  tearing, irritation and yellowish-white discharge
  in both eyes, worse on the left. States that
  overall symptoms have been progressing over about
  a 5 year span

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History

• POHx Retinal detachment OS 1997, CE IOL OU
• PMHx Bullous Pemphigoid, Peripheral neuropathy,
  Asthma,
• Hypothyroidism, HTN
• FAMHx noncontributory
• ROS joint pain, muscle aches and difficulty
  swallowing
• intermittently
• MEDS dapsone, zioptan, avodart, bystolic,
  cymbalta,
• nexium, b12, synthroid,
• NKDA

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Exam
VA
P
RAPD OS
EOM full OU CVF superior field limitation OU
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Anterior Segment

OD
OS Lids/Lashes
mild entropion
ULLL entropian
few trichiatic lashes
trichiasis Conj
mild injection
symblepharon


2 injection Cornea
multiple SPE
multiple SPE

inferonasal corneal
erosion Iris
WNL
WNL Lens
PCIOL
PCIOL
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Physical Exam
HENT single tense vesicular lesion on soft
palate Thorax 2 vesicular lesions on upper
back Extremities single vesiculo-bullous
lesion on right leg
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Skin Lesion
erupted bullous lesion on the right lower
extremity
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Summary
72 y/o WM presents with trichiasis OU 2/2
entropion, decreased visual acuity OS,
symblepharon OS , 2 conjunctival injection OS
with an inferonasal corneal erosion. Dermatologic
exam reveals vesicular lesions on the soft
palate, upper back and lower extremity

• DDx
• Autoimmune Cicatricial Conjunctivitis
• MMP, Sarcoidosis , SLE, Lichen Planus, IgA
  dermatosis
• Atopic Keratoconjunctivitis
• Ocular Rosacea
• Chronic Infectious Conjunctivitis
• Adenovirus , streptococcus
• Pseudopemphigoid (drug-induced )
• Conjunctival Trauma

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Treatment

• Same day UL LL epilation OS, aggressive
  lubrication
• OS cicatricial entropion repair MMG of Upper
  and lower lid
• Pathology results
• Acutely inflamed tissue infiltrated with
  histiocytes, lymphocytes and neutrophils.
  Sub-epithelial fibrosis lacking elastic fibers
  indicative of scarring
• Immunofixation not performed

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One Month Post-Op Visit
Grafts healing well, significant inflammation
persistent, no residual
trichiasis
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Mucous Membrane Pemphigoid

• Group of heterogeneous diseases characterized by
  inflammatory blistering of the oral, ocular,
  pharyngeal, laryngeal and genital mucosa
• Main pathological feature linear deposits of
  IgG, IgA and C3 in the epithelial basement
  membrane zone
• When MMP presents as a chronic scarring
  conjunctivitis, it is known as Ocular Cicatricial
  Pemphigoid

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Ocular Cicatricial Pemphigoid Clinical features

• Early on, signs of chronic or relapsing
  conjunctivitis with vesicles detected on the
  conjunctiva
• Tearing , burning, mucous drainage
• Loss of goblet cells
• As the disease progresses, conjunctival shrinkage
  can cause impaired eye movements and
  lagophthalmos
• Lid margin inflammation and scarring ? trichiasis
• Eventually trichiasis and gland loss lead to
  progressive corneal keratinization and scarring

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Ocular Cicatricial Pemphigoid Epidemiology

• Incidence 1/8000 1/46000 ophthalmic patients
• Average age of diagnosis 60 70 years
• FemaleMale 1.51 31
• No geographic or racial predilection

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Ocular Cicatricial Pemphigoid Pathogenesis

• Binding of circulating autoantibodies (IgG, IgA,
  C3 and other complement factors) to the BMZ
  (lamina lucida of the dermal- epidermal junction)
• 205 kd ß4 peptide of a6ß4 integrin most frequent
  target
• Why scarring instead of bullae formation?
• Autoantibody binding to BMZ ? secretion of
  cytokines (TNF-a, IL-1, migration inhibiting
  factor) ? recruitment of inflammatory cells ?
  release of pro-fibrotic cytokines such as
  TGF-beta and IFN-gamma ? scarring
• Inciting Event unknown

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Ocular Cicatricial Pemphigoid 4 Stages
Stage I Chronic conjunctivitis with
subepithelial fibrosis
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Ocular Cicatricial Pemphigoid 4 Stages
Stage II Shortening of the inferior fornix
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Ocular Cicatricial Pemphigoid 4 Stages
Stage III Symblepharon formation
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Ocular Cicatricial Pemphigoid 4 Stages
Stage IV End stage disease manifesting as
ankyloblepharon, severe sicca syndrome, severe
ocular surface keratinization
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Ocular Cicatricial Pemphigoid Diagnosis

• Most cases are caught in stage 2 to 3 and beyond
  due to the often insidious nature of progression
• Diagnosis is based on
• Clinical Features
• Tissue Biopsy
• Should be performed perilesionally
• Conj biopsy best during active disease
• Specimen handling is extremely important as using
  the wrong specimen fixative can lead to false
  negative results

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Ocular Cicatricial Pemphigoid
Hematoxylin Eosin Staining

• inflammatory infiltrate of variable intensity .
  Contains neutrophils, macrophages, plasma cells,
  lymphocytes, and Langerhans cells
• Essentially nonspecific

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Ocular Cicatricial Pemphigoid
Direct Immunofluorescence

• Characteristic finding Linear deposition of
  IgG, IgA, and/or C3 in basement membrane
• However, diagnostic sensitivity is only around
  50 . Therefore a negative result does not rule
  out a disease process

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Ocular Cicatricial Pemphigoid
Immunoperoxidase Assay

• Performed if immunofluorescence is negative but
  strong clinic suspicion
• Increases sensitivity of testing from 52- 831

1. Power WJ, Neves RA, Rodriguez A, Dutt JE,
Foster CS. Increasing the diagnostic yield of
conjunctival biopsy in patients with suspected
ocular cicatricial pemphigoid. Ophthalmology.
1995102(8)1158
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Ocular Cicatricial Pemphigoid Treatment

• Mild to Moderate Disease
• Dapsone 50 200 mg/day for 12 weeks
• Important to check labs hemolytic anemia risk
• MTX, mycophenolate, azathioprine can also be
  used, but more serious side effect profile
• Severe Disease
• Cyclophosphamide /- Prednisone for 12 months
  or less
• Must beware of leukopenia
• Newer Therapies
• IVIG
• Rituximab

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Ocular Cicatricial Pemphigoid Treatment

• Surgical Intervention
• Entropion repair
• Symblepharon excision
• limbal stem cell transplantation, PK,
  keratoprosthesis
• Maintainence Measures
• Aggressive ocular lubrication
• Lid hygiene for infection prevention
• Epilation
• PROGNOSIS? Current literature shows long term
  remission in 1/3 of patients for an average of 34
  months with IM therapy

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References
1. BSCS Volume 8, External Diseases and Cornea .
2013 2. Pepose,Holland, Wilhelmus. Ocular
Infection Immunity. 1996 3. 1. Power WJ, Neves
RA, Rodriguez A, Dutt JE, Foster CS. Increasing
the diagnostic yield of conjunctival biopsy in
patients with suspected ocular cicatricial
pemphigoid. Ophthalmology. 1995102(8)1158 4.
Ahmed M, Zein G, Khawaja F, Foster CS. Ocular
cicatricial pemphigoid pathogenesis, diagnosis
and treatment. Prog Retin Eye Res 2004
23579. 5.Fleming TE, Korman NJ. Cicatricial
pemphigoid. J Am Acad Dermatol 2000 43571. 6.
Foster CS. Cicatricial pemphigoid. Trans Am
Ophthalmol Soc 1986 84527. 7. Chan LS, Ahmed
AR, Anhalt GJ, et al. The first international
consensus on mucous membrane pemphigoid
definition, diagnostic criteria, pathogenic
factors, medical treatment, and prognostic
indicators. Arch Dermatol 2002 138370. 8.Letko
E, Bhol K, Foster SC, Ahmed RA. Influence of
intravenous immunoglobulin therapy on serum
levels of anti-beta 4 antibodies in ocular
cicatricial pemphigoid. A correlation with
disease activity. A preliminary study. Curr Eye
Res 2000 21646. 9. 60.Foster CS, Chang PY,
Ahmed AR. Combination of rituximab and
intravenous immunoglobulin for recalcitrant
ocular cicatricial pemphigoid a preliminary
report. Ophthalmology 2010 117861.
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Thank You