Cornea Clinic Interactive Part 1.ppt

CORNEA CLINIC

INTERACTIVEMassimo Busin

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DIFFERENTIAL DIAGNOSIS

Infections Ocular Surface

Diseases Immunologic

Diseases Tumors Dystrophies and

Degeneratons

History Associated Diseases

(ocular and extraocular)

Characteristics of the Lesion (site, morphology, number)

DIFFERENTIAL DIAGNOSIS

CLINICAL HISTORY

Onset Duration Response to

Treatment Previous Eye

Surgery

ASSOCIATED DISEASES

Ocular Innervation Eyelids

(Trichiasis) Adnexa (Tear

Production) Sytemic Diseases

MYTH # 1:CORNEAL ULCER = INFECTION

CORNEAL INFECTIONS

FACT # 1:DIFFERENT MECHANISMS !!!

Microbial ActivityComplement (Immune-Complexes)Mechanical ActionExposureNeurotrophic Damage

CORNEAL INFECTIONS

MYTH # 2:ULCER TREATMENT = ANTIBIOTICS

CORNEAL INFECTIONS

FACT # 2:DIFFERENT TREATMENT !!!

Antibiotics Steroids Lid Surgery (Lubricants)

CORNEAL INFECTIONS

SITE OF THE LESION !!!Periphery Center

Imm. Mech. Infection

Sup. 1/3 Inf.1/3

UpperEyelid

ExposureTrichiasis

DIFFERENTIAL DIAGNOSIS

SITE OF THE LESION !!!

Peripheral

Immunologic Mechanism

DIFFERENTIAL DIAGNOSIS

Mooren’s Peripheral Ulcer

Uni- or BilateralAutoimmunePrevious TraumaNegative Serology

(R.A. -)

Peripheral Ulcer in R.A.Peripheral Ulcers Are

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

Staphyilococcal Infiltrates/UlcersBLEPHARITIS 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 !!!

Terrien’s Degeneration

Peripheral Thinning

Neovessels Lipids Astigmatism

Bowen’s Carcinoma

RemovalCryotherapyMitomycin

Corneal Pterygoid62-Year-Old Hispanic Male

2-year-History of “Pterygion”

Progressive Visual Loss (<20/400)

Solid Mass Optical Zone

Involvement Infiltrating Abnormal

Vascularization

Corneal Pterygoid

Squamous Cell Carcinoma

Clinical Features +

Biopsy

Corneal Pterygoid

Two-Step Surgical Treatment

Extensive Mass Removal (Including Superficial Cornea + Sclera)

Cryoapplication

Conjunctivoplasty

Step 1

Post Step 1

Week 2 Week 4

Histology

Carcinoma Infiltrated Cornea

Two-Step Surgical Treatment

LARGE LK (“Small Bubble Technique”)

Step 2

Week 2

BCVA 0.8 No Recurrence

Post Step 2

Month 12

SITE OF THE LESION !!!

Central (Non-Peripheral)

Infection

DIFFERENTIAL DIAGNOSIS

CORNEAL INFECTIONS External

Inflammation Non-Peripheral

Ulceration Stromal

Infiltration (Hypopion)

SITE OF THE LESION !!!

Superior 1/3

Upper Eyelid

DIFFERENTIAL DIAGNOSIS

DERMATITIS ATOPICA

SHIELD ULCER

STEROIDS !!!

SITE OF THE LESION !!!

Inferior 1/3

Exposure/Trichiasis

DIFFERENTIAL DIAGNOSIS

EXTRAOCULAR ORIGIN Ocular Innervation Eyelids

(Trichiasis) Eyelids

(Lagophthalmos) Adnexa (Tear

Production)

LESION MORPHOLOGY!!!DIFFERENTIAL DIAGNOSIS

Crystalline Dendritic Arborescent Multiple Sites

SaltzmannDegeneration

Multiple Lesions Epithelial“Cysts” Mechanical Removal

Aspergillus fumigatusSatellite Lesions!!!

Fusarium solaniDendrites

CLINICAL CASE

Arborescent ± One Site Vessels - Non-Peripheral Inflammation ±

60-Year-Old Woman, CL Wearer

Low Virulent Bacteria, Fungi (Streptococcus, Candida, etc.)

SteroidsImmunity +/-Post-PKResistance to AB

MYTH # 3:

HSK = DENDRITES

CORNEAL INFECTIONS

FACT # 3:HSK = CAN MIMIC ANYTHING !!!

CORNEAL INFECTIONS

Interstitial Keratitis

Limbal Vasculitis

EndothelitisHypopyon

HSV KERATITISHSV KERATITIS

Direct Cytolytic Effect of HSV

Abnormal Immunologc Reaction

ANTIVIRALS

STEROIDS

HSV KERATITIS

HSV & CORNEA (EYE) Infectious Epithelial Ulcer (Dendrite) Trophic Epithelial Ulcer

(“Metaherpetic”) Stromal Keratitis (Complees Antigen-

Antibody or [T]Cell- Mediated) Uveitis and Trabeculitis

HSV EYE DISEASEInfectious Epithelial Ulcer

(Dendrite) Virus +++

SPK

Dendrites

Geographic Ulcers

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

HSV EYE DISEASE

CLINICAL CASE

Arborescent - One Site Vessels + Non-Peripheral Inflammation +

13-Year-Old Male, CL Wearer

CLINICAL CASE

Smears - Cultures - Fortified Drops -

(Ceftazidime, Vancomycin, AMikacin, Voriconazole)

DAY 1 DAY 15

CLINICAL CASEDAY 1 DAY 15

Neutrophilic Infiltration

No Microrganisms

CLINICAL CASE

Acyclovir Systemic (800 mg x 5 daily)

Acyclovir topical (2 hourly)

Prednisone Systemic (1/2 mg/Kg x 2 daily)

DAY 16

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

Diffuse Edema No Surgery2-Year History Peripheral Vessels Inflammation ±

90-Year-Old Man, BK (Fuchs???)

CLINICAL CASE

Other Eye Normal

Endothelium !!!

90-Year-Old Man, BK (Fuchs???)

CLINICAL CASE

Treat HSV!!!Systemic & Topical

ANTIVIRALSSystemic (Topical)

STEROIDS

90-Year-Old Man, BK (Fuchs???)

DAY 0 Month 6

HSV ENDOTHELITIS

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

HSV ENDOTHELITIS

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

HSV EYE DISEASE

Herpetic VaccineProphylaxis

Protection against NS Infection Antibody- and Cell- Mediated

Immunity Viral Adhesion, Lysis of

Infected Cell, Citokines

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

Therapy Stimulate Immune Response Reduce “Shedding” Immune-Mediated HSV

Disease !!! (Uveitis, Stromal Keratitis, ecc.)

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

Herpetic Vaccine

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

HSV EYE DISEASE

PK SURGERY

SMALL Grafts

LOWER

Rejection Rate

HIGHER Refractive Error

LARGE Grafts

HIGHER

Rejection Rate

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 & “Mushroom” PK Minimal Endothelial

Transplantation Reduced Postoperative

Refractive Errore(Anterior Diameter 9 mm !!!)

HSV EYE DISEASE

Adenoviral InfectionAdenovirus: DNA-Virus (Cell

Nucleus) Icosahedral Capside >40 Serotypes

(Capsomere Ag)

VIRIONS

CELL NUCLEUS

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

Adenoviral Infection

Transmission:Direct ContactWater (Pool)SexualOphthalmic 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)

Adenoviral Infection

Epidemic Keratoconjunctivitis

Conjunctivitis Keratitis Lid ChemosisPreauricular Swelling (Lymph Node)No Systemic Symptoms

Findings:

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

Affected

Epidemic Keratoconjunctivitis

Conjunctivitis: Follicular Pseudomembranous Haemorrhagic

Epidemic Keratoconjuntivitis

Follicules

Pseudomembrane

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

Epidemic Keratoconjuntivitis

Clinical Course of Corneal Lesions

CLINICAL CASE

Previous Adenoviral Infection

Recurrent Pain and Redness

Scattered Superficial Infiltrates

Responsive to Steroids

42-Year-Old Male

CLINICAL CASE

Thygeson KeratitisCLSteroids Tapered off

Very Slowly

42-Year-Old Male

Treatment (Initial): Prevention !!! Antiviral Efficacy ??? Antibiotics Unnecessary Palliative Care

(Hot Compresses, Cycloplegics, ecc.)

Epidemic Keratoconjunctivitis

Steroids Are Only Symptomatic !!! Only for Very Severe

Symptoms !!! Addiction & Rebound Side Effects

Epidemic Keratoconjunctivitis

Treatment (Late):

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

Corneal Smears & Coltures (Confocal Micr.)

Multi-antibiotic Therapy (wide spectrum)

Corneal Biopsy Surgery (Conjunctival

flap, PK “a chaud”)

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

MYTH # 4:GIVE SYSTEMIC ANTIBIOTICS

CORNEAL INFECTIONS

Hypopyon Is Sterile in Corneal Infections, Unless the Ulcer Perforates

FACT # 4:

EFFECTIVE ROUTE

CORNEAL INFECTIONS

Topical Eyedrops every 1hSubconj.

SystemicInfiltration

+/-

NO???

Mono- vs Polyantibiotic

Topical Therapy

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

Aminoglycosides (vs gyrase inhibitors)Cephalosporines (cephtazidime vs

cephazoline)Vancomycin (Meth. Res. Staphylococcus)Anphothericine B (Fungi !)

Polyantibiotic Topical Therapy :

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

Stefani, Meditime 2007

CORNEAL PHARMACOKINETICS OF NETILMICIN

Concentration after Single Administration

in vivo animal

model

Sensitivity and Resistance of 146 Gram- strains

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

NETILMICIN - Sensitivity Spectrum

0 20 40 60 80 100

Acinetobacter

Citrobacter

EnterobacterE. Coli

Klebsiella

P. mirabilis

P.morgani/P. vulgaris

Providencia

Pseudomonas

Salmonella

Serratia

staphylococcus

14.3 %

100 %

94.6 %80.6 %

87.2 %

63.2 %

21.8 %

2.2 %

46.3 %

8.3 %

44.4 %

91.5 %

Cumulative % susceptible

Activity against 907 AG-Resistant Strains

Muller et al, Chemotherapy, 1981

NETILMICIN – Low Incidence of Resistance

**

**

***

0.08 0.16 0.3 0.6 1.25 2.5 5.0

Concentration (mg/ml)

0

30

60

90

120

MTT

(% o

f con

trollo

)

Ofloxacina

Netilmicina

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

Human Corneal

Epithelium (HCE)

*p<0.01, **p<0.001 (two way-ANOVA)

in vitro Corneal ToxicityEffect of Increasing AB Concentration on Vitality

NETILMICIN - Safety

Commercially Available Concentration(3.0 mg/ml)

0.3% Ofloxacina – 8 h0.3% Netilmicina – 72 h

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

Rabbit Corneal Epithelium (SIRC)

NETILMICIN - Safety

in vitro Corneal ToxicityEffect of Increasing AB Concentration on Cell Morphology

Clinical Evaluation

Initial Therapy

BETTER WORSE

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

BETTER

PathogenNot Identified

PathogenIdentified

Continue Therapy Add Therapy

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

HYPOPYON ↓↓↓BETTER

Day 0 Day 3

BETTERINFILTRATE ↓↓↓

Day 0 Day 7

BETTEREPITHELIUM ↑↑↑

Day 3 Day 7

Worse

Pathogen Does Not Respond to TX

PathogenNot Identified

Change Therapy Change Approach

SYSTEMATIC APPROACH TO CORNEAL INFECTIONS

Confocal MicroscopySectional Images of Corneal Structures

Epithelium Basal Epi. Nerves

AnteriorStroma Endothel.

MiddleStroma

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

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

Confocal Microscopy

Confocal Microscopy

18 µm

DAY 1

AMOEBIC KERATITIS

AMOEBIC KERATITIS

18 µm

DAY 14

2-Year-History of Transient Corneal Edema Disappears with Topical Steroids VA = 20/20

CONFOCAL MICROSCOPY (43µm)

AMOEBIC KERATITIS

DAY 1 DAY 20

AMOEBIC KERATITIS

DAY 1 DAY 20

CULTURESAgar, Sabouraud, thioglycolate, E. Coli

Acanthamoeba

PHMB (Biguanide) SIFIHexamidine

MICROSPORYDIUM KER.

338 µm

AFTER SALK

1 Day 20 Days ???VAcc = 20/50 !!!VAcc = 20/50 !!!

THx• Topical:‣Fumagillin

(Galenical) • Systemic:

Albendazole (Antihelmintic)

• Test HIV: -

30 Days

FINAL RESULT

BCVA=CFBCVA=CF BCVA=20/60BCVA=20/60

18 Months

65-Year-Old White Female

Immunesuppression, Diabetes

No CL Wear or HSV History

BSCVA ↓ ↓ ↓ 1/20

“COLD” ULCER

VancomycinCeftazidimeAmikacinVoriconazole

Day 4 after Tx“COLD” ULCER

q 2 h

CORNEAL BIOPSY

Repeat Culture + BiopsyCandida

Voriconazole+

FLUCONAZOLEq 2h

Adjusted Tx: Day 1

Adjusted Tx: Week 2

Adjusted Tx: Week 2

CORNEAL BIOPSY

Tissue Gram, Giemsa, PAS, other

Acanthamoeba

61-Year-Old White Female

PBK No Response to

Multiantibiotic/Antifungal

Treatment

“Tx Resistant” ULCER

CONJUNCTIVAL FLAP

PK after Conjunctival

Flap

s/p Conjunctival

Flap

Corneal“Patch”+

ConjunctivalFlap

Perforated Corneal

Ulcer(Sterile)

CORNEAL PATCH

PK “a Chaud”

(1 week)

Perforated Corneal Ulcer

(Staphylococcus Aureus)

PK “a Chaud” (4 weeks)

PK “a Chaud” (2 weeks)

Re-PK (1 year)

PK “a Chaud” (4 months)

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

EPITHELIAL DEFECT Autoserum (Physical/Chemical?)

Amniotic Membrane (never for Infection!)

BREAK !!!