CORNEA

CLINIC
INTERACTIVE
Massimo Busin

???
???

DIFFERENTIAL
DIAGNOSIS
Infections
Ocular Surface Diseases
Immunologic Diseases
Tumors
Dystrophies and
Degeneratons

DIFFERENTIAL
DIAGNOSIS
History
Associated Diseases
(ocular and
extraocular)

Characteristics
the Lesion (site,
morphology,
number)

of

CLINICAL HISTORY
Onset
Duration
Response to
Treatment
Previous Eye
Surgery

ASSOCIATED DISEASES
Ocular
Innervation
Eyelids
(Trichiasis)
Adnexa (Tear
Production)
Sytemic Diseases

CORNEAL INFECTIONS

MYTH # 1:
CORNEAL ULCER = INFECTION

CORNEAL INFECTIONS
FACT # 1:
DIFFERENT MECHANISMS !!!
Microbial Activity
Complement (Immune-Complexes)
Mechanical Action
Exposure
Neurotrophic Damage

CORNEAL INFECTIONS
MYTH # 2:
ULCER TREATMENT = ANTIBIOTICS

CORNEAL INFECTIONS
FACT # 2:
DIFFERENT TREATMENT !!!

Antibiotics
Steroids
Lid Surgery
(Lubricants)

DIFFERENTIAL DIAGNOSIS
SITE OF THE LESION !!!
Periphery

Center

Sup. 1/3

Upper
Imm. Mech. Infection
Eyelid

Inf.1/3

Exposure
Trichiasis

DIFFERENTIAL DIAGNOSIS
SITE OF THE LESION !!!

Peripheral
Immunologic Mechanism

Moorens Peripheral Ulcer

Uni- or Bilateral
Autoimmune
Previous Trauma
Negative Serology
(R.A. -)

Peripheral Ulcer in R.A.

Peripheral Ulcers Are
Sustained by an
Immunologic
Mechanism
(Antigene-Antibody
Complexes with
Complement
Activation)

Staphyilococcal Infiltrates/Ulcers
BLEPHARITIS with Growth
of Staphylococcus Species and
Formation of Immune
Complexes (Endotoxin Antigen)
Steroids Block the Formation
of Immune Complexes.
TETRACYCLINES Are
Causative Treatment !!!
Other Antibiotics Are Less
Effective

Acnes Rosacea

Blepharitis

HYPERMETROPIA !!!

Terriens
Degeneration
Peripheral
Thinning
Neovessels
Lipids
Astigmatism

Bowens
Carcinoma

Removal
Cryotherapy
Mitomycin

Corneal Pterygoid
62-Year-Old
Hispanic Male
2-year-History
of Pterygion
Progressive
Visual Loss
(<20/400)

Corneal Pterygoid
Solid Mass
Optical Zone
Involvement
Infiltrating
Abnormal

Corneal Pterygoid
Clinical Features
+
Biopsy

Squamous Cell Carcinoma

Two-Step Surgical
Treatment

Step 1

Extensive Mass Removal

(Including Superficial
Cornea +
Sclera)
Cryoapplication
Conjunctivoplasty

Post Step 1

Week 2

Week 4

Histology

Carcinoma

Infiltrated Cornea

Two-Step Surgical
Treatment

Step 2
LARGE LK
(Small Bubble Technique)

Post Step 2
BCVA 0.8
No Recurrence

Week 2

Month 12

DIFFERENTIAL DIAGNOSIS
SITE OF THE LESION !!!

Central (Non-Peripheral)
Infection

CORNEAL INFECTIONS
External
Inflammation
Non-Peripheral
Ulceration
Stromal Infiltration
(Hypopion)

DIFFERENTIAL DIAGNOSIS
SITE OF THE LESION !!!

Superior 1/3
Upper Eyelid

DERMATITIS
ATOPICA

SHIELD
ULCER

STEROIDS
!!!

DIFFERENTIAL DIAGNOSIS
SITE OF THE LESION !!!

Inferior 1/3
Exposure/Trichiasis

EXTRAOCULAR ORIGIN
Ocular Innervation
Eyelids
(Trichiasis)
Eyelids (Lagophthalmos)
Adnexa
(Tear
Production)

DIFFERENTIAL DIAGNOSIS
LESION MORPHOLOGY!!!
Crystalline
Dendritic
Arborescent
Multiple Sites

Saltzmann
Degeneration
Multiple Lesions
EpithelialCysts
Mechanical
Removal

Aspergillus fumigatus
Satellite Lesions!!!

Fusarium solani
Dendrites

CLINICAL CASE
60-Year-Old Woman, CL Wearer
Arborescent
One Site
Vessels Non-Peripheral
Inflammation

Low Virulent
Bacteria, Fungi
(Streptococcus,
Candida, etc.)
Steroids
Immunity +/Post-PK
Resistance to AB

CORNEAL INFECTIONS
MYTH # 3:

HSK = DENDRITES

CORNEAL INFECTIONS
FACT # 3:
HSK = CAN MIMIC ANYTHING !!!
Interstitial
Keratitis
Limbal
Vasculitis
Endothelitis
Hypopyon

HSV KERATITIS
Direct Cytolytic Effect of HSV

Abnormal Immunologc Reaction

HSV KERATITIS

ANTIVIRALS

STEROIDS

HSV & CORNEA (EYE)

Infectious Epithelial Ulcer (Dendrite)
Trophic Epithelial Ulcer
(Metaherpetic)
Stromal Keratitis (Complees
AntigenAntibody or [T]Cell- Mediated)
Uveitis and Trabeculitis

HSV EYE DISEASE

Infectious Epithelial Ulcer
(Dendrite)
Virus +++
SPK
Dendrites
Geographic Ulcers

HSV EYE DISEASE

Trophic Epithelial Ulcer
(Metaherpetic)
Virus - (Sterile)
Basement Membrane
Damage
Innervation Damage

HSV EYE DISEASE

HSV & Type III
Reaction
Interstitial
Keratitis

HSV EYE DISEASE

HSV & Type III
Reaction
Wessely Ring

HSV EYE DISEASE

HSV & Type III
Reaction
Limbal
Vasculitis

HSV EYE DISEASE

Limbal Vasculitis
Atypic
Presentation
Resistant to Tx

HSV EYE DISEASE

HSV & Type IV
Reaction
Disciform
Edema

CLINICAL CASE
13-Year-Old Male, CL Wearer
Arborescent One Site
Vessels +
Non-Peripheral
Inflammation +

CLINICAL CASE
DAY 1 DAY 15

Cultures Smears

Fortified Drops (Ceftazidime, Vancomycin,

AMikacin, Voriconazole)

CLINICAL CASE
DAY 1 DAY 15
Neutrophilic
Infiltration
No
Microrganisms

CLINICAL CASE
DAY 16
Acyclovir Systemic
(800 mg x 5 daily)
Acyclovir topical
(2 hourly)
Prednisone Systemic
(1/2 mg/Kg x 2 daily)

CLINICAL CASE

Month 1

Month 3

Month 6

CLINICAL CASE

Mushroom PK

CLINICAL CASE

VA=LP(DAY 0)

VA=1.0 (Year 2)

CLINICAL CASE
90-Year-Old Man, BK (Fuchs???)
Diffuse Edema
No Surgery
2-Year History
Peripheral Vessels
Inflammation

CLINICAL CASE
90-Year-Old Man, BK (Fuchs???)
Other Eye
Normal
Endothelium !!!

CLINICAL CASE
90-Year-Old Man, BK (Fuchs???)
Treat HSV!!!
Systemic & Topical
ANTIVIRALS
Systemic (Topical)
STEROIDS

HSV ENDOTHELITIS

DAY 0

Month 6

HSV ENDOTHELITIS

VA=HM(DAY 0) VA=0.3(s/p Phaco)

HSV EYE DISEASE

Medical Therapy

ANTIVIRAL
Acyclovir topical (ointment)
Gancyclovir topical (gel)
Systemic Therapy?
(deep
involvement)

HSV EYE DISEASE

Medical Therapy

ANTIINFLAMMATORY
Steroids topical (IOP!!!)
Steroids systemic
Antiviral Coverage
(topical e/o systemic)

HSV EYE DISEASE

Vaccine
Prophyilaxis
Treatment of
Recurrences
J.S. Pepose et al. Am. J. Ophthalmology 2006

Herpetic Vaccine
Prophylaxis

Protection against NS Infection

Antibody- and CellMediated Immunity
Viral Adhesion, Lysis of
Infected Cell, Citokines
J.S. Pepose et al. Am. J. Ophthalmology 2006

Herpetic Vaccine
Therapy

Stimulate Immune
Response
Reduce Shedding
Immune-Mediated HSV
Disease
!!! (Uveitis,
Stromal Keratitis, ecc.)

J.S. Pepose et al. Am. J. Ophthalmology 2006

HSV EYE DISEASE

HSV &
Conventional PK
Medium-Term
Success 60%
Frequent
Recurrences

HSV EYE DISEASE

HSV Recurrence in
PK:
Epithelial Defect
Often Not Dendrite

!!!
L. Remeijer et al. Ophthalmology 1997

HSV EYE DISEASE

Prophylaxis of HSV
Recurrences
Acyclovir 400 mg.
bid p.o.
Acyclovir oint.
qd ?!
J. Van Rooij et al. Ophthalmology 2003

PK SURGERY
SMALL Grafts

LARGE Grafts

LOWER
Rejection Rate

HIGHER
Rejection Rate

HIGHER
Refractive Error

LOWER
Refractive Error

MUSHROOM PK

ANTERIOR LK = HAT
(thickness = 250 m; diameter = 9-9.5 mm)

POSTERIOR LK = STEM
(thickness = 300 m; diameter = 5-6 mm)

HSV EYE DISEASE

HSV & Mushroom PK
Minimal Endothelial
Transplantation
Reduced Postoperative
Refractive Errore
(Anterior Diameter
9 mm !!!)

Adenoviral Infection
Adenovirus:
DNA-Virus (Cell
Nucleus)
Icosahedral
Capside
>40 Serotypes
(Capsomere Ag)

VIRIONS

CELL NUCLEUS

Adenoviral Infection
Epidemiology:
Almost All Serotypes
Associated with Ocular
Disease
Serotypes 1,2,4,5 e 6
Light Symptoms
Serotypes 3,7,8,10,19 e 30
Severe Symptoms

Adenoviral Infection
Transmission:
Direct Contact
Water (Pool)
Sexual
Ophthalmic Examination !!!
The Virus Can Survive on Non-Porous
Surfaces, i.e. Tonometer, up to 34 Days !!!

Adenoviral Infection
Clinical Entities
Epidemic
Keratoconjunctivitis
(Serotypes 8 e 19)
Pharyngeal
Conjunctival Fever
(Serotypes 3 e 7)

Epidemic Keratoconjunctivitis
Findings:
Conjunctivitis
Keratitis
Lid Chemosis
Preauricular Swelling (Lymph Node)
No Systemic Symptoms

Epidemic Keratoconjunctivitis
Ocular Findings:
External
Inflammation
Usually Bilateral
(non simultaneous)
2nd Eye Less Severly
Affected

Epidemic Keratoconjuntivitis
Conjunctivitis:
Follicular
Pseudomembranous
Haemorrhagic

Follicules

Pseudomembrane

Epidemic Keratoconjuntivitis
Keratitis:
SPK
Focal Epithelial
Keratitis
Active Viral
Infection

Epidemic Keratoconjuntivitis
Subepithelial Infiltrates:
Lymphocytic
Spontaneous Resolution
May Persist Very Long
(up to 10 Years !!!)
Immunologic Response
to Viral Ag

Clinical Course of Corneal Lesions

CLINICAL CASE
42-Year-Old Male
Previous Adenoviral
Infection
Recurrent Pain and
Redness
Scattered Superficial
Infiltrates
Responsive to Steroids

CLINICAL CASE
42-Year-Old Male
Thygeson Keratitis
CL
Steroids Tapered off
Very Slowly

Epidemic Keratoconjunctivitis
Treatment (Initial):
Prevention !!!
Antiviral Efficacy ???
Antibiotics Unnecessary
Palliative Care
(Hot Compresses,
Cycloplegics, ecc.)

Epidemic Keratoconjunctivitis
Treatment (Late):
Steroids Are Only
Symptomatic !!!
Only for Very Severe
Symptoms !!!
Addiction & Rebound
Side Effects

CORNEAL INFECTIONS
External
Inflammation
Ulcer
Stromal
Infiltration
Hypopion

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS
Establish Diagnosis
(D.D. with Other
Corneal Lesions)
Identify Pathogen
Select Proper
Treatment

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS
Corneal Smears &
Coltures (Confocal Micr.)
Multi-antibiotic Therapy
(wide spectrum)
Corneal Biopsy
Surgery (Conjunctival
flap, PK a chaud)

CORNEAL INFECTIONS
MYTH # 4:
GIVE SYSTEMIC ANTIBIOTICS
Hypopyon Is Sterile
in Corneal
Infections, Unless
the Ulcer Perforates

CORNEAL INFECTIONS
FACT # 4:

EFFECTIVE ROUTE
Topical
Subconj.
Systemic
Infiltration

Eyedrops every 1h
+/-

NO
???

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS

Mono- vs
Polyantibiotic
Topical Therapy

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS
Polyantibiotic Topical Therapy :
Aminoglycosides (vs gyrase inhibitors)
Cephalosporines (cephtazidime vs
cephazoline)
Vancomycin (Meth. Res. Staphylococcus)
Anphothericine B (Fungi !)

CORNEAL PHARMACOKINETICS OF NETILMICIN

imal
n
a
o
v
i
v
in
model

Concentration after Single Administration

Stefani, Meditime 2007

NETILMICIN - Sensitivity Spectrum

Sensitivity and Resistance of 146 Gram- strains

Vanzzini V et al, Rev Mex Oftalmol 83(1): 1-5, 2009

NETILMICIN Low Incidence of Resistance

Activity against 907 AG-Resistant Strains
14.3 %

Acinetobacter

100 %

Citrobacter
Enterobacter

94.6 %

E. Coli

80.6 %

Klebsiella

87.2 %

P. mirabilis

63.2 %
21.8 %

P.morgani/P. vulgaris
2.2 %

Providencia

46.3 %

Pseudomonas
Salmonella

8.3 %

Serratia

44.4 %

staphylococcus

91.5 %

20

40

60

80

100

Cumulative % susceptible

Muller et al, Chemotherapy, 1981

NETILMICIN - Safety

in vitro Corneal Toxicity

Human Corneal
Epithelium (HCE)

Effect of Increasing AB Concentration on Vitality

MTT (% of controllo)

120

Netilmicina
Ofloxacina

90

60

**

**

30

Commercially Available Concentration

(3.0 mg/ml)

**

0
0.08 0.16

0.3

0.6

1.25

2.5

5.0

Concentration (mg/ml)
*p<0.01, **p<0.001 (two way-ANOVA)

Papa et al, JOP&T 19(6): 535-545, 2003

NETILMICIN - Safety
Rabbit Corneal
Epithelium (SIRC)

in vitro Corneal Toxicity

Effect of Increasing AB Concentration on Cell
Morphology

0.3% Netilmicina 72 h

0.3% Ofloxacina 8 h

Scuderi et al, Cornea 22(5): 468-472, 2003

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS

Clinical Evaluation
Initial Therapy

BETTER

WORSE

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS

BETTER
Pathogen
Not Identified

Continue Therapy

Pathogen
Identified

Add Therapy

BETTER
HYPOPYON

Day 0

BETTER
INFILTRATE

BETTER
EPITHELIUM

SYSTEMATIC APPROACH TO
CORNEAL INFECTIONS

Worse
Pathogen Does Not
Respond to TX
Change Therapy

Pathogen
Not Identified
Change Approach

Confocal Microscopy
Sectional Images of Corneal Structures

Epithelium Basal Epi.

Anterior
Stroma

Middle
Stroma

Nerves

Endothel.

Confocal Microscopy
DIAGNOSIS
(INFECTION/INFESTATION)
EVALUATION OF CLINICAL
COURSE
EVALUATION OF STROMA

Keratocyte Density
Structure of sub-epithelial nerve plexus
Monitoring of haze

Confocal Microscopy

AMOEBIC KERATITIS
18 m

DAY 1

AMOEBIC KERATITIS
18 m

DAY 14

 2-Year-History of Transient Corneal Edema

Disappears with Topical Steroids
VA = 20/20

CONFOCAL MICROSCOPY
(43m)

AMOEBIC KERATITIS

DAY 1

DAY 20

AMOEBIC KERATITIS

DAY 1

DAY 20

CULTURES
Agar, Sabouraud, thioglycolate, E.

Coli

Acanthamoeba

PHMB (Biguanide) SIFI

Hexamidine

MICROSPORYDIUM KER.

338 m

AFTER SALK

1 Day

20 Days

???

VAcc = 20/50 !!!

THx

30 Days

Topical:
Fumagillin
(Galenical)
Systemic:
Albendazole
(Antihelmintic)
Test HIV: -

FINAL RESULT
18 Months

BCVA=CF

BCVA=20/60

COLD ULCER
65-Year-Old White
Female
Immunesuppression,
Diabetes
No CL Wear or HSV
History
BSCVA 1/20

COLD ULCER
Day 4 after Tx
Vancomycin
Ceftazidime
Amikacin
Voriconazole

q2h

CORNEAL BIOPSY

Repeat Culture + Biopsy

Candida
Voriconazole
+
FLUCONAZOLE
q 2h

Adjusted Tx: Day 1

Adjusted Tx: Week 2

Adjusted Tx: Week 2

CORNEAL BIOPSY
Tissue Gram, Giemsa, PAS, other

Acanthamoeba

Tx Resistant ULCER
61-Year-Old
White Female
PBK
No Response to
Multiantibiotic/
Antifungal
Treatment

CONJUNCTIVAL FLAP

s/p
Conjunctival
Flap
PK after
Conjunctival
Flap

Perforated
Corneal
Ulcer
(Sterile)
CornealPatch
+
Conjunctival
Flap

CORNEAL PATCH

Perforated
Corneal Ulcer
(Staphylococcus
Aureus)

PK
a Chaud
(1 week)

PK
a Chaud
(2 weeks)

PK
a Chaud
(4 weeks)

PK
a Chaud
(4 months)

Re-PK
(1 year)

EPITHELIAL DEFECT
MYTH # 5:

ALWAYS STOP STEROIDS

EPITHELIAL DEFECT
FACT # 5:
DIFFERENT MECHANISMS !!!
Mechanical Friction
Dry Eye Condition
Drug Toxicity
Exposure
Neurotrophic Damage

EPITHELIAL DEFECT

No Scientific Evidence of
Steroidal Detrimental Effect on
Epithelial Growth !!!

EPITHELIAL DEFECT
Ointment
CL + Ointment
(Eye Patch)
Botox
(Tarsorrhaphy)

EPITHELIAL DEFECT

EPITHELIAL DEFECT
Autoserum
(Physical/
Chemical?)
Amniotic
Membrane
(never for

BREAK !!
!