Comparison of Efficacy and Safety of 0.5 ml and

0.25 ml of Supratarsal injection of Triamcinolone

Acetate in the Treatment of Severe and Refractory

Vernal Keratoconjunctivitis

DISSERTATION SUBMITTED FOR

MS (Branch III) Ophthalmology

THE TAMILNADU DR. M.G.R. MEDICAL

UNIVERSITY

CHENNAI

APRIL - 2014

CERTIFICATE

Certified that this dissertation entitled “ Comparison of Efficacy and

Safety of 0.5 ml and 0.25 ml of Supratarsal injection of Triamcinolone

Acetate in the Treatment of Severe and Refractory Vernal

Keratoconjunctivitis ” submitted for MS (Branch III) Ophthalmology, April

2014, is the bonafide work done by DR.SHRUTI DHEEP, under our

supervision and guidance in the Ocular Microbiology Services of Aravind Eye

Hospital and Post Graduate Institute of Ophthalmology, Madurai, during her

residency period from May 2011 to April 2014.

Dr.JEENA MASCARENHAS Dr. M.SRINIVASAN Medical consultant, Cornea services Director Aravind Eye Hospital, Aravind Eye Hospital, Madurai Madurai

ACKNOWLEDGEMENT

I take this opportunity to pay my respects and homage to

Dr.G.Venkatasamy, our founder and visionary, who has dedicated his life to

eliminating needless blindness, through patient outreach and affordable care, and

through whose life example, students like us, find inspiration.

I am deeply indebted to my guide and mentor, Dr. Jeena Mascarenhas, who

has been a constant source of support and motivation throughout my thesis work.

She has ingrained in me the value of perfection, and I am forever grateful to her.

My heartfelt gratitude goes to Dr.V.Prajna, Director of Academics, Aravind

Eye Care System, for being a wonderful teacher, an inspirational leader and above

all, a catalyst of positive change throughout my residency programme.

I am very grateful to Dr.R.D.Ravindran, Chairman of Aravind Eye Care

System for having created an environment enriched with all the facilities for

learning and gaining knowledge . I thank Dr. P. Namperumalsamy, Chairman

emeritus and Director of research, Dr.G.Natchiar, Director emeritus (human

resource department), Dr.M.Srinivasan, Director emeritus and other scholars of

ophthalmology at Aravind Eye Care System .

I thank Dr. Palepu Srikanthi and Dr. Santhosh Suman for recruiting and

evaluating patients for my study. I also thank the biostatistician Mr. Vijaykumar,

whose timely help with the analysis has been of immense help.

I am much grateful to Mrs. Kumaragurubari, librarian, for her prompt and

efficient response to my innumerable requests for articles and information.

I thank my parents for being my pillars of strength and my husband

Dr. Nishanth, whose kindness and support has seen me through my difficult times.

Lastly, I thank the patients who have patiently listened to and complied with

this study, for without them, this study would not have been possible.

CONTENTS

PART – I

S. No Title Page No

1 Introduction 1

2 Review of literature 4

a. History of VKC 4

b. Epidemiology 5

c. Pathogenesis 6

d. Clinical manifestations 13

e. Diagnosis 21

f. Differential diagnosis 23

g. Treatment 25

h. Supratarsal steroid injections 48

3 Articles - Review 56

PART – II

S. No Title Page No

1 Aim 60

2 Objectives 60

3 Materials and methods 61

4 Results 70

5 Complications 89

6 Discussion 92

7 Summary 98

8 Conclusion 99

INTRODUCTION

Vernal kerato-conjunctivitis (VKC) is a chronic, bilateral, sometimes

asymmetrical, seasonally exacerbated, recurrent, allergic inflammation of the

conjunctiva and cornea, characterized by

Cobblestone papillae on the upper tarsal conjunctiva

Discrete or confluent papillary hypertrophy on limbal conjunctiva

White chalky appearing concretions, called Horner-Tranta’s dots

Corneal erosions and shield ulcer.

The word Vernal is derived from the Greek word meaning ‘occurring in

spring’. It is common in young adolescents and adults during the season of

spring. It was first described as ‘conjunctiva lymphatica’,more than 150 years

ago.

Itching, burning, redness, photophobia, and the need to use eye drops were

the most frequent distressing symptoms reported by children>14 yrs. with

VKC.112 However, these children also experienced disease-related limitations

in their daily life and social interactions such as playing sports and meeting

friends.

Patients reported limitations in activities that cause exposure to allergens

such as playing outdoors and to irritant stimuli, such as going to the pool

because of the notoriously powerful irritating effects of chlorinated air and

water. These findings suggest that treatment of VKC should improve not only

the children’s signs and symptoms, but also their daily life and functioning.

The south of India, especially Tamilnadu finds itself increasingly

burdened with this crippling form of disease, affecting young, school going

children. It takes away the innocence and happiness of their years, not to

mention distracting them from their education and growth. The prolonged

natural course of the disease lasting 4 to 10 years, steals precious years of

productivity from the working population. Every year, Aravind Eye hospital

witnesses hundreds of patients walking in with varying degrees of vernal

kerato-conjunctivitis.

Despite the many advances in the our understanding and in treatment of

this condition, no permanent cure has been found. Treatment options only

include temporary measures of controlling the inflammation. Topical steroids,

mast cell stabilizer (Olopatadine, Lodoxamide, Nedocromil)1 topical NSAID’s

(suprofen)2 are commonly used, while immunotherapeutic agent (cyclosporine-

A)3 and ganglioside derivative (Mipragoside)4 have been used for resistant

cases of VKC. Unfortunately, most of these therapeutic modalities are

relatively ineffective for severe refractory VKC.

Hence, it becomes frustrating for the patient as well as the treating

physician to control this disease and bring symptomatic relief. Repeated

hospital visits mar the patient’s patience.

Thus, we decided to scientifically explore whether a supratarsal

injection of steroid would bring measurable relief to the patient by controlling

the inflammation for an extended period lasting months, with relief from

having to instill multiple topical medications. The flipside of this technique,

however, is it’s adverse effects, the most severe being steroid-induced

glaucoma. This brings us to the question of how much quantity of steroid in

this form can be deemed safe.

Various studies have been published citing the success of this technique,

but each with a different dosage as practiced by the ophthalmologist

undertaking the study. However, there have been no studies comparing dosages

of the drugs, which becomes crucial, considering the chronicity of the disease,

the age group affected and the need for repeated injections. That being the

motivation behind this study, the efficacy and safety of two dosages (0.25ml

and 0.5ml) of Triamcinolone acetonide were considered for analysis.

REVIEW OF LITERATURE HISTORY The limbal form of the disease was first identified. Arlt (1846)5 – first

described the disease entity as ‘Conjunctivitis lymphatica’

Desmarres (1847)6 – described it as ‘perikeratic hypertrophy’.

Von Graefe7 : associated this ‘gelatinous perilimbal infiltrate’ with pavement

proliferations of tarsal conjunctiva.

Saemisch8 (1876) : characterized as a clinical entity called ‘Spring Catarrh’

This is a misnomer, as the disease recurs in early summer than in spring, and

pathologically is essentially interstitial inflammation of the conjunctiva rather

than a catarrh.

Other historical names for this disease : Phlyctena pallida (Hirschberg,1871)

Circumcorneal hypertrophy (Burnett,1881)

Recurrent vegetative conjunctivitis (Terson,1902)

Conjunctivitis verrucosa (Goldzeiher,1906)

Conjunctivitis aestivale (Hansen-Grut, 1888)

EPIDEMIOLOGY:

Incidence:

The incidence of this disease was reported to be between 0.1% to 0.5%.9

Age :

Affected age group is usually between 3-25 years, with a peak incidence

between 11-13 years.10 The oldest reported affected individual was 75 years

old, and the youngest being a baby of 1 month age.

Sex:

It has been found to be more prevalent in boys ,but the gender affinity evens

out in adults.

Season :

In the northern hemisphere, it is more prevalent during early spring/summer,

from which the disease derives it’s name of ‘Spring catarrh’. In the southern

hemisphere, it is more prevalent in winter/fall. However, Bonini11 reports 23%

to have a perennial disease.

Geography :

It is more commonly seen in the warm climates of Middle East Countries like

Italy, Greece, Israel and India, South Africa. The duration of the disease is

usually 4-10 years.

There is a family history of atopy seen with 49-65% having 1 or more relatives

with a major atopic disease11(Asthma, Hayfever, eczema, allergic rhinitis).

PATHOGENESIS :

In the earlier days, Schmeichler and Schiele12 theorized that exposure to

the sun’s UV light could be the causative factor for vernal

keratoconjunctivitis.

However, with time, it became evident that ALLERGY played a

dominant role in the aetio-pathogenesis in this disease, owing to the

following reasons :

It affects the younger population

It is seasonal

There is a strong associated family history

Positive skin tests of airborne allergens(eg. Grass, Ragweed)

Presence of eosinophils in conjunctival scrapings

Presence of inflammatory cytokines and interleukins 3,4,5,10,13,

GMCSF

Relieved by Cromolyn sodium and steroids

The other mechanisms that have been discussed to play a role in this disease

are :

Anaphyllactic mechanism :

Leonardi13 proposed this mechanism owing to its

Incidence in spring

Presence of Reaginic antibody(IgE mediated)

Cutaneous Basophil Hypersensitivity :

This theory was propounded due to the increased levels of basophils, mast cells

and collagen found in the upper tarsal conjunctiva.

Immediate hypersensitivity :

IgE antibodies-----attach to vasoactive amine containing cells(mast cells and

basophil cells) in upper tarsal conjunctiva----when pollen, dust and moulds

dissolve in tear film----they pass into the conjunctiva----combine with IgE

antibody attached to mast cell and basophil----enormous release of toxic

mediators like histamine----recruitment of more cells with itching, swelling and

corneal damage.

Endocrine 14:

This was due to the

Increased presence of oestrogen and progesterone receptors on the

conjunctiva

Gender affinity

Resolution around puberty

Nervous factors15:

Factors like Substance P and Nerve Growth Factor(NGF) also play a

supplemental role in the pathogenesis of this disease.

HISTOPATHOLOGY ( Figure 1)

Exposure of appropriately sensitized IgE coated mast cells to airborne

allergens is the initiating stimulus in the drama of allergy. An exclusively local

hyperproduction of IgE only in tears was shown in 30-50 %, who were other

wise non-atopic16

, thereby supporting the theory of a Th-2 driven

hyperproduction of IgE at local level.

There is a complex interplay between the mast cells, basophils and eosinophils,

which is explained below.

IgE mediated mechanism :

The first time an allergy prone person comes across an airborne allergen,

the antigen is carried by the antigen presenting cell(APC) to the T-

helper-2 cells through the T-cell receptor.

This , in turn, stimulates the IgE producing B cell to produce specific

IgE antibodies against the specific antigen.

These IgE antibodies bind to circulating mast cells and attach to their Fc

receptor, thereby priming them.

There are about 10,000 to 50,000 IgE receptors in 1 mast cell of which

16% are occupied17.

These primed mast cells remain in circulation for extended periods of

time.

When the person is exposed to the same antigen for the second time,

these specific IgE-primed mast cells undergo cross-linking, which causes

de-granulation of the primary and secondary mediators of inflammation.

MAST CELLS :

Mast cells can be categorized on the basis of neural proteases18They are of two

types19 :

Connective type(MCTC) - stimulated by IL-4,13 ; contains tryptase and

chymase.

Mucosa type(MCT) – stimulated by IL-5,6 ; contains only tryptase.

The connective type is the most common type of mast cell seen in the

epithelium of VKC patients.

Contents of mast cells:

Group 1 : Histamine and prostaglandins

Group 2 :Eosinophilic Granule MBP

Group 3 : Eosinophil chemotactic factor

Group 4 : Platelet activating factor

MECHANISM OF DEGRANULATION (Figure 2) :

This cross-linking sends signals for degranulation to the cytoplasmic

lysosomes, which causes degranulation of histamine, proteases and

other chemotactic factors like ECF and NCF. These are the primary

mediators of inflammation. They stimulate proliferation of fibroblasts

and recruitment of many cell types in the conjunctiva.

The cross linking also sends signals for activation of Phospholipase C,

which dissolves membrane phospholipids, thereby releasing

leukotrienes B4,C4,D4 and Prostaglandins D2, which are potent

instigators of inflammation. These are the secondary mediators of

inflammation.

Signals are sent for cytokine gene activation to the nucleus, allowing for

the production and release of cytokines, which is partly responsible for

the delayed phase of inflammation.

Substances are released which trigger the production of growth factors

like FGF, TGF-B, TNF-A, PDGF20.

Increased production of collagen 1,3,4,5,7 and fibronectin21 occurs .

However, collagen hyperproduction is triggered only in tarsal from of

the disease.22

Recruitment of Eosinophils :

The T-helper-2 cells also recruit eosinophils from the circulation via IL-

3,5 and GM-CSF.

The Eosinophils, when activated, release inflammatory granules, which

are responsible for the second, delayed phase of the inflammation.

Initial Response :

This is caused by the IgE mediated mechanism.

It consists of vasodilatation and vascular leakage.

Late-delayed phase :

This is caused by the release of cytokines from the IgE mediated

mechanism and from the eosinophil recruitment.

It consists of mucosal edema, mucous secretions, leucocyte infiltration

and epithelial damage.

There is a hyperplasia of fibrous tissue succeeded by hyaline

degeneration and associated with spectacular proliferation of epithelium

where there is a marked cellular infiltration of substantia propria,

consisting of eosinophils.

Involvement of the Basophils suggests a more delayed type of

hypersensitivity, involving Cytotoxic T cells causing activated

macrophages to transform into multinucleated giant cells on presentation

with certain intra-cellular pathogens.

The corneal epithelium, in turn, produces adhesion molecules like

ICAM-1,VCAM-1,ELAM-1, IL-8 eotaxin, MCP-1,MCP-3,RANTES

,etc, which cause massive infiltration of eosinophils into tissues.23

HISTOPATHOLOGY 24:

There is a dense inflammatory infiltrate consisting of eosinophils,

lymphocytes, basophils, dendritic cells and macrophages.

These are seen within the microvessel, outside the microvessel, in the

stroma and the epithelium

Lymphocytes- follicle like aggregates in sub-epithelial area without

forming a germinal centre.

Here, Langerhans cells and T-cells show increased expression of co-

stimulatory molecules that may contribute to developing Th-2 type

conjunctival immuno-reaction25

CLINICAL MANIFESTATIONS

SYMPTOMS :

Itching : It is the primary symptom of the patient. ‘NO ITCHING, NO

VKC ’ is the caveat for diagnosis .

Slight drooping of the upper lid (2-3mm) :

o This is due to increased tissue bulk, but also from the mediators

released into the tissue. It might also be asymmetrical.

Discharge :

o It is ropy, thick strands of dirty yellow material pulled out from

beneath the eyelids, which accumulate at inner canthus during

morning.

o The lids do not become crusted or stick together, unless a

secondary bacterial infection co-exists or disease is severely

unchecked with out topical medication.

o The discharge is alkaline in nature, containing mucus, epithelial

cells, poly-morpho nuclear cells, mononuclear cells, eosinophils,

mucopolysaccharides (hyaluronic acid) and intracytoplasmic

granules.

Tearing

Irritation : Patients complain of an ‘uncomfortable, hot tight sensitive

feeling’ of the eyes.

Photophobia :Indicates corneal involvement.

Blurry vision

Blepharospasm

SIGNS :

Tobgy26, in 1933, described three forms of VKC : Palpebral, Limbal and

Mixed.

According to him, the incidence of each was

Palpebral – 17.4%

Limbal – 11.2%

Mixed – 71.4%

Palpebral :

Consists of papillary hypertrophy seen in the upper tarsal conjunctiva.

Due to the pressure on the cornea, they become hard and flat(discrete or

clumped), resembling COBBLESTONE pattern.

They are usually seen on the superior border of tarsal plate.

It consists of tiny twigs of vessels seen pushing up through centers of

papillae. There may also be more than 1 central vessel.

A milky veil lies over the papillae. If a cotton-tipped applicator is gently

drawn over the everted lid, a diaphanous stringy material can be pulled

off.

A lardaceous yellow string of exudate may be pulled out from lower

fornix, which contains mucus, dead epithelial cells, mononuclear cells,

poly-morphonuclear cells and intra-cytoplasmic granules.

Forniceal conjunctiva does not show foreshortening or symblepharon.

Histopathology :

Each papilla is a dome shaped structure limited all around by the

anchoring septae. It is usually large and sessile.

The epithelium consists of >5-10 layers of conjunctival thickening of

both cuboidal and palisade type with cysts and cell nests.

Beneath the epithelium, is a layer of hyaline degeneration.

The stroma consists of dense fibrous material with lymphocytes, plasma

cells and eosinphils, with a central twig/twigs of blood vessels.

Grading of papillary reaction :

• (1) Grade 0: no papillary reaction.

• (2) Grade 1+: few papillae, 0.2 mm widespread over the tarsal

conjunctiva or around the limbus.

• (3) Grade 2+: papillae of 0.3–1 mm over the tarsal

conjunctiva or at the limbus.

• (4) Grade 3+: papillae of 1–3 mm all over the tarsal

conjunctiva or for 360 degrees around the limbus.

• (5) Grade 4+: papillae of more than 3 mm over the tarsal

conjunctiva or gelatinous appearance at the limbus covering the

peripheral cornea.

Limbal :

Seen more in warmer climates and in Africans and Asians(called

Epidemic limbo-conjunctivitis).

It consists of a thickened broad gelatinous opacification of upper limbus,

which forms a semi-opaque hood <3 mm

Limbal nodules, called HORNER-TRANTAS dots, are whitish,

chalklike deposits of concretions or macro-aggregates of eosinophils and

epithelial debris. They are evanescent and may appear at any stage.

Presence of HORNER-TRANTAS dots is PATHOGONOMIC of

VKC.

Clear cystoid structures may also occur.

Limbal VKC may be associated with corneal astigmatism.

Histopathology :

Epithelial cell overgrowth 30-40 layers deep sending down epithelial

plugs and cell nests, resembling an epithelioma (basement membrane is

however, intact) .

Decreased fibrous tissue proliferation.

CORNEAL INVOLVEMENT :

It is seen in 50% of patients of VKC.

1. Epithelial keratitis :

The mediators from the tarsal conjunctiva cause epithelial keratitis and

punctate stippling of cornea.

2. Corneal ‘SHIELD’ ulcer:

It has an incidence of 3-11%

It is called SHIELD due to the shield like shape of the ulcer.

It is usually located in the superior part of the cornea but inferiorly

located shield ulcer have also been reported.

Due to the pressure (Trophic) effect of the papillae on the superior part

of the cornea, an epithelial defect develops. Fibrin and mucus deposits

over the defect, turning it into a plaque. Epithelial wound healing is thus

impaired, leading to a shield ulcer.27

Inflammatory cells, cytokines and chemokines liberated from T helper

type 2 (Th2) cells and tear film instability may act concomitantly in the

pathogenesis of shield ulcer.28

It is a characteristic horizontally oval ulcer in the superior part of the

cornea.

It’s lower border is in the upper half of the visual axis.

An edge of shaggy, greyish white, dead epithelium is seen leading to a

shallow center of necrotic debris, leaving Bowman’s layer intact.

The ulcer is indolent and does not spread. It maybe present for weeks

despite treatment, as a sodden plaque that eventually heals, leaving

behind a sub-epithelial ring-like corneal opacity at Bowman’s layer.It

does not become vascularized.

Shield ulcers without plaque formation usually undergo rapid re-

epithelialisation, resulting in an excellent visual outcome, however,

patients with shield ulcers and visible plaque formation have delayed re-

epithelialisation. Tear film instability seen in the later stages of VKC

adversely affects the re- epithelialisation of shield ulcer.

Delayed epithelial healing may lead to secondaryinfections,29

strabismus, amblyopia,30 and corneal perforation.31

Cameron’s Grades of Shield ulcer32 :

• Grade 1: extend to basement membrane and have transparent base

• They have a favourable outcome and re-epithelialise with

mild scarring

• Grade 2: opaque base and filled with inflammation

• They have a higher complication rate with delayed re-

epithelialisation and poor response to medical therapy.

• Grade 3: filled with debris that protrude above surrounding

epithelium(plaque)

• They respond to surgical therapy.

Grade 1 shield ulcers respond well to medical therapy alone, whereas grade 2

ulcers occasionally may require additional debridement or AMT. Grade 3

ulcers, however, largely are refractory to medical therapy and require

debridement and AMT for rapid re-epithelialization.33

3.Keratitis epithelialis vernalis of Tobgy34 :

First described by Tobgy in 1935

Most frequently seen with palpebral form ofdisease.

Discrete, minute, dull, greyish points on the epithelium, which often

grouped to extend over an area of 2-3mm, involving upper 1/3rd to 2/3rd

of cornea.

In severe form, the entire cornea appears to be ‘dusted with flour’.

Microscopically, there is an extensive degeneration involving all

epithelial layers varying in intensity to complete necrosis of cells and

their replacement to constitute punctate epithelial erosions.

Stains with fluorescein but increases dramatically with Bengal rose.

4. Pseudogerontoxon :

Peripheral cornea may show waxing and waning of superficial stroma and

greyish white deposits, not associated with iritis.

5. Pannus, which might be superficial.

6.The other manifestations are corneal plaque, bacterial or fungal keratitis,

keratoconus, hydrops, and corneal opacification.35

ASSOCIATIONS OF VKC : Keratoconus : due to eye rubbing and release of certain

metalloproteinases.

Hyperimmunoglobulin E syndrome36

Atopy

Atopic cataract

DIAGNOSIS :

• Typical history

• Signs and symptoms (e.g Horner-trantas dots)

• Conjunctival scrapings : upto 80% of giemsa smears show presence of

eosinophils.

Presence of >2 eosinophils per 25X objective field is diagnostic of VKC.

If no eosinophils seen, then it might be the following reasons :

Nonactive phase of disease

Patient on anti-inflammatory drugs

Misdiagnosis

Other cells found in scrapings: lymphocytes, macrophages, neutrophils,

basophils and mast cells.

• Tear cytology :

An exclusively local hyperproduction of IgE only in tears were

shown in 30-50% individuals, who were otherwise atopic.16

An increased level of IgG antibodies to pollen is found in tears.37

Histamine content of tears in VKC ptients higher than normal.38

Immunoflouresence of upper tarsal conjunctiva may show presence of

IgA,G,E forming plasma cells.

Tissue histopathology :

Better histologic preservation by glutaraldehyde fixation, plastic

embedding and viewing sections, allows counting of cells by type and

location.

Mast cells and Basophils are normally absent from conjunctival

epithelium, but are present in VKC.

1mm3 of conjunctiva will contain > 5000 cells in substantia propria of a

VKC patient.

• Skin prick tests(RAST) :

RAST/skin prick test may be negative in 42-47% of cases, confirming it

is not solely an IgE mediated disease.

• Serum specific IgE – This may be normal or increased.

• Blood cell count – shows increased IgE.

DIFFERENTIAL DIAGNOSIS :

1. Atopic Kerato-conjunctivitis :

Vernal keratoconjunctivitis Atopic keratoconjunctivitis

Younger Older

Male No sex predilection

Resolves at puberty Chronic

Seasonal Perennial

Upper tarsus Lower tarsus

Conjunctivalcicatrization- rare Common

Cornea- shield ulcer Persistent ED

Scar-uncommon Common-vision threatening

Corneal vascularization-rare common

2. Trachoma :

Trachoma VKC

True follicles with germinal center Papillae with central twigs of blood

vessels

No eosinophilic infiltration Increased eosinophilic infiltration

Scarring of tarsus may occur No scarring occurs

3. Hay fever conjunctivitis :

Presence of edema with less eosinophils, no mast cells in epithelium and

no increase in mast cells in substantia propria and no basophils helps in

differentiating this entity from VKC.

4. Atopic eczema

5. Giant papillary conjunctivitis :

• Seen in hard/soft contact lens wearers.

• Fewer eosinophil infiltrations.39

TREATMENT

HISTORY OF TREATMENT MODALITIES :

In the early days, splenic extracts were injected to neutralize the effect of

eosinophilia.

Administration of preparation of ductless glands to rectify imbalance 40

Radiation of thymus41

Cryoablation of the upper tarsal conjunctiva was done earlier, which

resulted in a lot of scarring.

Surgical removal of upper tarsal conjunctiva with forniceal conjunctival

advancement or buccal mucosal graft. However, it caused obliteration of

fornix.

CURRENT TREATMENT OPTIONS :

CONSERVATIVE MANAGEMENT:

Avoidance of allergen

Cool compresses

Climatotherapy- Using the air conditioner or relocating from a warmer

to a cooler environment.

Alternate occlusive therapy- Preventing the eye from exposure to

allergen.

Hyposensitization

TYPES OF TREATMENTS: Medical and surgical

MEDICAL TREATMENT :

Antihistamines :

Olopatadine 0.2%

Levocabastine 0.05%

NSAIDS :

Flurbiprofen 0.03%

Ketorolac 0.5%

oral aspirin 2400 mg daily

Indomethacin 1%

Mast cell stabilizers :

Sodium cromoglycate 2-4%

Lodoxamide 0.1%

Nedocromil sodium 2%

Steroids :

Fluoromethalone 0.1%

Dexamethasone acetate 0.1%

Loteprednol etabonate 0.5%

Anti-metabolites :

Cyclosporine 1-2%

Mitomycin-c 0.01%

ANTIHISTAMINES :

History and source :

Histamine was first synthesized in 1907, and it’s biological activity was

discovered as a uterine stimulant in extracts of ergot in 1910.

In 1979, Abelson et al demonstrated that topical instillation of histamine

produced, in a dose dependent fashion, the itching and redness associated with

allergic conjunctivitis.42

If sensitized patients are ocularly challenged with a pollen or dander,

histamine levels increase by a factor of 60 from baseline in 3 minutes. By 8

minutes, histamine returns to 3 times baseline levels, which corresponds

clinically with peak itching and onset of redness of conjunctiva.

Drugs :

Olopatadine hydrochloride is a relatively selective histamine H1 receptor

antagonist that inhibits the in-vivo and in-vitro type 1 immediate

hypersensitivity reaction including inhibition of histamine induced effects on

human conjunctival epithelial cells. It also has a dual action of binding to

S100A12, which is a member of the S100 family of calcium binding proteins

that exerts multiple pro-inflammatory activities.

Levocabastine hydrochloride, is a long-acting, highly potent and

selective H1 receptor antagonist. It counters the action of histamine by

decreasing systemic vasodilatation and erythema and decreasing edema due to

capillary dilatation and increased permeability. These drugs have a low affinity

for serotonin, dopamine, alpha adrenergic and beta adrenergic receptors.

The drugs commonly used are:

LevocabastineHcl 0.05% qid

EmcabastineHcl 0.05% bid-qid

Olopatadine Hcl 0.1% bid

Ketotifen fumarate 0.025% bid

Azelastine HCl 0.05% bid

Epinastine HCl 0.05% bid

The dosage is 1 to 2 drops every 3-4 hours.

Side-effects :

The systemic side-effects are very rare and mild. The most common side

effect is stinging sensation, which usually resolves within a few seconds of

application.

Medicamentosa and punctate keratitis have been associated with

preservative Benzalkonium chloride

Topical antihistamines are contra-indicated in patients with narrow angle

glaucoma.

Caution should be exercised in using combination products of

antihistamine/vasoconstrictor drugs with patients of poorly controlled

hypertension, cardiovascular disease with arrhythmias and poorly controlled

diabetes mellitus.

NSAIDS :

History and source :

The therapeutic effects of the willow bark, whose active ingredient was

salicylic acid, was discovered in the eighteenth century. In 1875, it was used in

the treatment of rheumatic fever as an anti-pyretic.

Dreser introduced it into medicine at the end of the nineteenth century under

the name of Aspirin.43They are used for their anti-pyretic, analgesic and anti-

inflammatory effect.

Drugs :

Ketorolac is a member of the pyrrolo-pyrolle group of NSAIDS. It is a

white crystalline powder with a molecular weight of 376.41. It blocks

prostaglandin synthesis by inhibiting the effect of cyclo-oxygenase, which is

responsible for the conversion of Arachidonic acid into

endoperoxides(PGG2,PGH2) in ocular and non-ocular tissues. However, they

do not inhibit the formation of eicosanoids such as the leucotrienes, which also

contribute to inflammation(lipoxygenase pathway).

The drugs and their dosages are:

Ketorolac tromethamine 0.4%- 0.5% qid.

Diclofenac Na 0.1% qid

Flurbiprofen Na 0.03% qid

Oral aspirin has proven successful in the relief of conjunctival and

episcleral hyperemia and resolution of keratitis and limbal infiltrates

associated with VKC44. 1.5g or less daily for 6 weeks showed

improvement in recalcitrant cases of VKC.

Indomethacin 0.1% showed significant reduction in itching, lacrimation,

conjunctival injection and papillae.45

Side-effects :

Stinging sensation, punctate keratitis may be seen with topical NSAIDS.

It also may cause increased bleeding time in ocular tissues in association with

surgery.

Oral NSAIDS like aspirin can cause GI irritation, which can lead to

anemia due to blood loss in ulcers. They may increase bleeding time by

inhibiting platelet production of thromboxane A2, a potent aggregating agent.

A single dose of 0.65 g of aspirin may approximately double the mean bleeding

time of normal persons from 4-7 days.

MAST CELL STABILIZERS :

History and source :

The first mast-cell stabilizing compound was developed in the 1960s

from khellin, a chromone (benzopyrone) derived from Ammivisnaga, an

eastern Mediterranean plant.Rall46 later isolated the drug cromolyn sodium and

showed that it inhibited the release of histamine and other granule contents

from sensitized mast cells.

Drugs :

Cromolyn sodium is a clear colourless solution with a molecular weight

of 512.34.

Lodoxamide tromethamine is a white, crystalline, water soluble powder

with a molecular weight of 553.91.

They inhibit Type 1 hypersensitivity reactions, thereby inhibiting the

degranulation of mast cells, preventing the release of histamine, leukotrienes

and slow-reaction substances of anaphylaxis(SRS-A) and inhibits eosinophil

chemotaxis. This is achieved through the prevention of calcium influx into

mast cells after antigen stimulation.

They are available as :

Cromolyn Na 2%-4% qid

Nedocromil Na 2% bid

Lodoxamidetromethamine 0.1% bid

Pemirolast Potassium 0.1% bid

Side-effects :

The most common side-effects of topical mast-cell stabilizers are

transient stinging sensation. The other adverse events were itching, hyperemia,

blurred vision, tearing, dry eye symptoms and foreign body sensation. Some of

the very rare side-effects are corneal erosion, eye pain, edema, chemosis,

blepharitis and epitheliopathy. Systemic absorption is negligible.

CYCLOSPORINE :

It is a fungal metabolite, discovered by Borel at Sandoz laboratories.It

was first used by Nussenblatt et al47 in treating autoimmune uveitis.

Ben Ezra, Matamoros and Cohen48 used topical cyclosporine 2% in oil,

to treat severe VKC, almost three decades ago. Since then, many studies have

shown topical cyclosporine (0.5 to 2 per cent) emulsion in olive or castor oil,

instilled four times daily, to be effective in the treatment of VKC. Cyclosporine

is lipophilic, so it must be dissolved in an alcohol-oil base.

Mechanism of action :

Blocks the T-lymphocyte proliferation and IL-2 production.

Inhibits histamine release from mast cells, basophils through a reduction

in IL-5 production.

Reduces the recruitment and effects of eosinophils on the conjunctiva.

Reduces the fibrosis by reducing the conjunctival fibroblast proliferation

rate and IL1beta production.

Cetinkaya et al49 studied 4 patients with shield ulcers treated with

cyclosporine and found that healing of ulcers with no epithelial defect occurred

in 10 days with 2% CSA

The only side effect was burning sensation. Recurrences was seen when the

concentration came to 0.05% in 3 cases. It was effectively treated with 1%

soln. (MIC).It has less effect on wound healing than steroids. Also it does not

induce cataract or glaucoma like steroids do.50

Limited availability of a commercial preparation of topical cyclosporine,

technical difficulties in dispensing cyclosporine eye drops and legal restrictions

in many countries on the use of such locally prepared topical formulations

precludes its wide-spread use. In our country, it is available in 0.05% , 0.1%

and 2% solutions

TACROLIMUS :

Tacrolimus (formerly, FK-506) is another immunomodulatory agent,

which is similar to cyclosporine A in mechanism but with much higher potency

(up to 100 times).51

It suppresses T-cell activation, T helper cell-mediated B-cell

proliferation, and formation of cytokines, especially interleukin-2.

In ophthalmology, tacrolimus has mainly been used to suppress immune

reactions in corneal and limbal transplantations,52 uveitis,53 and allergic eye

disease.54

Topical tacrolimus with concentrations of 0.02–0.1% in ointment form

has successfully been used for treatment of atopic keratoconjunctivitis (AKC),

giant papillary conjunctivitis, and VKC.

The side effects are mainly burning sensation55. Activation of herpes

simplex dendritic keratitis56 and development of molluscum contagiosum55

have also been reported.

STEROIDS :

History and source :

The physiologic importance of adrenal glands were first appreciated in

1855, when Adison described the clinical syndromes associated with their

impaired function.

In 1929, Hench recognized that arthritic patients experienced temporary

remission when pregnant or jaundiced. He tested them for cortisone and found

it to have an anti-inflammatory response. Soon thereafter, the therapeutic

affects of adrenocorticotrophic hormone was demonstrated.57

In 1942, 28 steroids had been isolated from the adrenal cortex and structures

established. Five of these compounds- cortisone, cortisol, 11-dehydro-

corticosterone, corticosterone, 11-desoxycorticosterone exhibited biological

activity.

By 1950, corticosteroids and ACTH were introduced into clinical

practice by Gordon and McLean.58

Drug :

Cortisone, a 21 carbon 4 ring structure, was the first steroid to be used in

ocular therapy for it’s anti-inflammatory properties. Alterations made at

various sites of the molecular structure resulted in modification of biologic

potency, transcorneal penetration, protein binding, rate of metabolic

transformation, rate of excretion, ability to traverse membranes and intrinsic

effectiveness of the molecule at it’s site of action.59These alterations can be

summarized as follows :

1. Prednisolones have, in addition to the basic nucleus, a 1,2 double bond

in ring A. This modification increases their carbohydrate regulating

potency and prolongs their metabolism as compared to cortisol.

2. Methylation of carbon 6 in ring B leads to a 6-alpha methyl

prednisolone. This compound has a slightly greater anti-inflammatory

effect than prednisolone.

3. Flourination at 9 alpha position in ring B, as in flourocortisone

enhances it’s anti-inflammatory property.

4. 4. In ring D,17 alpha hydroxylation is present in most of the anti-

inflammatory steroids.

5. Most of the active synthetic analogues and all natural corticosteroids

have the hydroxyl group attached to carbon 21 in ring D.

Dexamethasone is a short acting steroid and Triamcinolone acetate is a long

acting steroid.

Pharmacology :

They act as both anti-inflammatory and immunosuppressive agents.

They freely penetrate the cell membrane and bind to a specific steroid-

binding protein receptor in the cytoplasm, forming a steroid-receptor

complex.

This complex enters the nucleus, where it binds to chromatin, signaling

the production of messenger RNA and coding for proteins that will determine

the response of that cell to the hormone.

The cytoplasmic steroid-binding receptor exhibits a high affinity for

glucocorticoids. Glucocorticoid receptors are found in the iris, ciliary body,

cornea, sclera, trabecular meshwork and Schlemm’s canal.60

The anti-inflammatory activity is accomplished through interface with

leucocyte chemotaxis, arachidonic acid cascade and normal function of

immunocompetentcells. The mechanisms involved are :

1. Constriction of blood vessels, which inhibit leakage of fluid, protein s

and inflammatory cells to the target site.

2. Stabilization of intracellular lysosomal membranes and inhibiton of the

expression of various damaging enzymes.

3. Stabilization of mast cells and basophils, which inhibits the

degranulation process and subsequent release of histamine, bradykinin,

PAF, proteases and eosinophilic chemotactic factors.

4. Mobilization of polymorphonuclear leucocytes from the bone marrow,

which results in neutrophilic leukocytosis. They also prevent adherence

of PMN to the vascular endothelium, inhibiting infiltration from vessel

to surrounding tissues.

5. Suppression of lymphocyte proliferation and lympopenia

6. Reduction of circulating eosinophils and monocytes.

7. Inhibition of macrophage recruitment and migration. It also interferes

with macrophages’ ability to process antigens.

8. Suppression of fibroplasia.

9. Depression of bactericidal activity of monocytes and macrophages.

10. Inhibition of phospholipase A2, through a protein called macrocortin,

resulting in inhibition of arachidonic acid degradation and subsequent

synthesis of prostaglandins and leucotrienes by cyclooxygenase and

lipoxygenase pathways.60

Clinical pharmacology :

Evaluation of these steroid derivatives for their anti-inflammatory

potential indicated prednisolone acetate(lipophilic) to have significantly more

anti-inflammatory effect than prednisolone sodium phosphate(lipophobic)

solution in eyes with intact epithelium.61

When the corneal epithelium was absent, no significant difference was

noted among them and also dexamethasone alcohol. The dexamethasone

sodium phosphate solution was clearly significantly inferior in eyes with

epithelium intact or absent.62 Increasing the concentration of prednisolone

actetate from 0.125% to 1.0% produces a significant increase in it’s corneal

concentration and anti-inflammatory effectiveness.62 Increasing concentration

above 1.0%(2.0%, 3.0%) increases the corneal concentration, but does not alter

its anti-inflammatory potency.63

The anti-inflammatory potency also largely depends on the frequency of

instillation. Hourly instillation of 1.0% prednisolone acetate produces much

more effective suppression of inflammation than does once every four hours.64

Maximum suppression is obtained if instilled once every 5 minutes.

A newer class of corticosteroids, termed the ‘soft steroids’ may offer the

therapeutic effects of a steroid with fewer side effects.

1. Flourometholone(FML) in 0.1% and 0.25% suspensions is far

less efficacious than prednisolone in penetrating the cornea65, but

does have moderate anti-inflammatory effects66.It is moderately

hydrophobic, concentrating in the corneal epithelial layer, to the

point of saturation, before passing through the layers of the

stroma. This may explain why FML penetrates the cornea in

comparatively low concentrations, yet produces moderate but

effective suppression of corneal inflammation.66

2. Loteprednol etabonate is a molecularly modified form of

prednisolone. A labile ester functional group occupies the 17-beta

position and stable carbonate group occupies the 17-alpha

position. After topical application and corneal penetration, the soft

steroid is rapidly hydrolyzed in the anterior chamber to the

inactive 17- beta carboxylic acid derivative.67

Drug Dosage:

Dexamethasone 0.1% 3-5times/day.

Prednisolone 1% 3-5times/day.

Fluoromethalone 0.1% 3-5times/day.

Loteprednol etabonate 0.5% qid.

Pharmacokinetics :

The modes of delivery of corticosteroids for ocular indications

Topical drops / ointment

Peri-ocular – subconjuctival / supratarsal

Oral

Parenteral

Intra-vitreal

Intra-lesional

Posterior sub-tenon’s

Topical preparations are available as solutions, suspensions or ointments.

Phosphate solutions are solutions because they are highly soluble in aqueous

vehicles.

Acetate and Alcohol peparations are suspensions, which can penetrate the

uninflamed cornea with intact epithelium.

Factors influencing penetration :68

Relative water and lipid solubility

Viscosity

Concentration

pH

Tonicity

Condition of corneal epithelium

Size of particles in suspension

Addition of preservatives or methyl-cellulose

The final concentration of a compound is decreased by the following factors

Dilution by tear film

Normal evaporation in tear film

Systemic absorption by vessels in conjunctiva

Non-productive absorption by surrounding tissues

Normal drainage from conjunctiva into naso-lacrimal duct

Breakdown by tear film enzymes.

Overflow from conjunctival sac

Binding with tear film proteins

Excretion :

Topically applied corticosteroid can drain through upper and lower

puncti into nasolacrimal duct. Once exposed to the highly vascular nasal

mucosa, it traverses into the circulatory system, where it binds to globulin(80%

as transcortin) and albumin(20%). It is this portion that diffuses into

extravascular fluid and bathes the tissue cells. Excretion is through liver and

partially through kidney, by means of conjugation reactions.59

Complications of steroid use69:

1. Rise in intra-ocular pressure

2. Steroid-induced glaucoma

Indiscriminate use of steroids is a common occurrence, due to poor awareness

of it’s side-effects , also due to it’s use in children, who use it without parents’

supervision. This can lead to serious complications like intra-ocular pressure

rise and steroid- induced glaucoma.

Steroid induced glaucoma is an iatrogenic secondary open angle

glaucoma. The connection between systemic steroids and glaucoma was first

demonstrated in the early 1950s.Armaly reported intra-ocular pressure rise

after topical administration of steroids70. That study also showed 90% of

patients with POAG showing elevated IOP of more than 6 mmHg after a 4

weeks course of topical steroids. Patients using steroids through topical or peri-

ocular route are a higher risk of intra-ocular pressure rise >23mmHg, than

those using systemic steroids71.Males showed a higher preponderance than

females.72

Steroid induced glaucoma begins to develop after two weeks of

continuous use, after which IOP starts rising any time from weeks to years73.

Withdrawal of steroids usually results in concomitant lowering of IOP within 8

– 18 weeks, but prolonged and indiscriminate use can result in glaucomatous

optic atrophy and visual loss even after the IOP returns to normal74.

Mechanism of rise in IOP in steroid use :

a. Alterations in the biochemical and morphological characteristics of the

trabecular meshwork cells, leading to increased outflow resistance.

b. Alterations in the size of trabecular meshwork, the extracellular matrix,

the cytoskeleton, cell adhesion and cell function75

c. Myocilin, a glycoprotein secreted from the trabecular meshwork cells,

which circulates in the aqueous humor, has been held responsible for

steroid induced glaucoma and primary open angle glaucoma.76

d. Prolonged use of topical steroids can significantly inhibit the phagocytic

activity of the trabecular meshwork cells leading to accumulation of

extracellular debris, resulting in steroid induced ocular hypertension.

e. Histopathology of steroid- induced glaucoma in humans has

demonstrated increased deposition of mucopolysaccharides and

glycosaminoglycans in the trabecular meshwork77.

Factors contributing to Rise in IOP are age, genetic tendencies, diabetes and

type of corticosteroid used. Approximately 5% of the general population are

considered to be steroid responders.78

Akingbehin79reported 15/24 eyes treated with 0.1% dexamethasone showed

an increase in IOP more than 5 mmHg, whereas only2/24 eyes treated with

0.1% FML showed such an increase.

Mindel et al80 compared increases in IOP after application of 0.1%

dexamthosone phosphate, 0.1% FML and 1% HMS 4 times daily for 6 weeks.

After the 6 week regimen, mean IOP rise were 63.1%, 33.8% and 8.3%

respectively.

The other important complications are :

3. Mydriasis

4. Ptosis

5. Loss of accommodation :

These effects could be due to the combination of agents in the vehicle

mixture which affects the selective semipermeability of the surface

membrane, thereby altering the physiologic function of the muscle cell.81

6. Corneal-scleral melting :

The steroid’s effect on the fibroblast results in delayed collagen

synthesis, which can cause or exacerbate corneal melting.82

7. Delayed corneal epithelial or stromal healing :

Topical steroids can slow corneal regeneration time by as much as 30%

after induced alkali corneal burns.83

8. Cataract :

Black et al84 reported a high incidence of cataracts in patients receiving long

term steroid systemic therapy. It was associated with the formation of

posterior sub-capsular cataract. Patients on 15mg/day prednisolone therapy

for 1-4 years showed PSCC incidence of 80%. If the dose was decreased to 10

mg/day, the incidence decreased to 11%. Thus, the incidence of PSCC was

directly related to the total cumulative dose and duration.

Hispanics and diabetics are more susceptible to cataract formation through

topical steroid therapy.

Pathogenesis :

Corticosteroids enter the lens and binds to its fibers. The steroid reacts

non-enzymatically with the amino group of lysine in the lens crystalline,

resulting in either exposure of protein sulfhydryl groups or an increased

susceptibility to oxidation. Diffuse cross-linking eventually occurs, generating

complexes that refract light (steroid-induced cataract).

9. Punctate staining

10. Optic nerve damage

11. Increased susceptibility to viral, fungal and bacterial infections85 :

These secondary infections can be conjunctivitis and keratitis(bacterial

or viral or fungal). It can be as severe as fungal endophthalmitis and

toxoplasmic chorioretinitis. Treatment includes discontinuation of the

steroid and initiating therapy with appropriate anti-infective agents.

12. Defects in visual acuity and visual fields.

Drug interactions :

1. Rifampin induces a gradual proliferation of hepatic smooth cell

endoplasmic reticulum, which is the locus of drug-metabolizing

enzymes, making the usual therapeutic dose less effective.86

2. Phenobarbital, Phenytoin and Ephedrine enhance the metabolic

clearance of corticosteroids, thus reducing their anti-inflammatory

and immune-suppressive effects.

3. Response to dicumarol and warfarin is inhibited when these drugs

are taken concomitantly with steroids.

Modes of corticosteroid delivery in VKCpatients :

1. Topical

2. Supra-tarsal

TOPICAL STEROIDS IN VKC :

Topical steroids have been used widely as the mainstay treatment of

ocular allergies since 1940.87It is a boon and a curse, where the patient wishes

to continue the drug but it has to be controlled to 1-2 weeks with no long term

usage.

Cromolyn sodium has to be added in low doses to prevent mast cell

degranulation induced by antigen-antibody reactions.

Indications of steroids in VKC :

3. Keratopathy

4. Breakthrough attacks of highly active inflammation

5. Conjunctival involvement with patient inconvenience.

Drugs used :Prednisolone, Dexamethosone sodium phosphate,

Flourometholone, Loteprednol etabonate

Steroid pulse Therapy :

Strong steroids such as Dexamethasone 1% may be given topically every

2 hours along with cromolyn sodium four times a day. After 2-4 days, taper the

steroids to four times a day for 2-4 days. When 2/3rds resolved, stop steroids

and continue cromolyn sodium.

SUPRATARSAL STEROID INJECTIONS IN VKC :

This form of steroid injection acts like a depot which causes slow

release of the drug into the periocular area, relieving the inflammation

without too much of intraocular penetration, thereby decreasing the chances

of steroid induced hypertension and glaucoma, as compared to the topical

mode of delivery. The mechanism is through iontophoresis or slow

diffusion. This allows the slow, steady sustained release of the

corticosteroid over the ocular surface.

Drug used:

1. Triamcinolone acetate

STRUCTURE

Triamcinolone acetonide is a long acting steroid suspension, designated

chemically as 9-fluoro-11b,16a,17,21-tetrahydroxypregna-1 4-diene-3,20-

dione cyclic 16,17-acetal with acetone. The empirical formula is C24H31FO6

and the molecular weight is 434.50 88

The relative anti-inflammatory strength of various corticosteroids is as

follows: desoxycorticosterone 0.0, cortisone 0.8, hydrocortisone 1, prednisone

4, methylprednisolone 5, triamcinolone acetonide 5, fludrocortisone 10,

betamethasone 25, and dexamethasone 25.3.89

It has been used in all branches of medicine, dermatology, and

orthopaedics. In ophthalmic practice triamcinolone acetonide is used in its

injectable form. The most commonly used dosages include 4 mg and 20 mg.

Thus there may be fundamental differences in pharmacokinetics. One

advantage to the higher dosage may be a longer duration of action.90

2. Dexamethasone sodium

3. Hydrocortisone

Procedure91 :

• “Staged Anaesthesia”

• Instill a drop of 4% topical anaesthetic, take a cotton tipped applicator /

Q tip and soak a few drops of 4%xylocaine HCl and hold it under the

superior border of everted tarsus.

• Lift the plate away from globe with applicator

• Inj 0.25ml 2% lignocaine with 30 G needle, 1mm above the tarsus

border to avoid the marginal arcade. Inject the steroid solution to cause

ballooning of potential space between the conjunctiva and Muller’s

muscle.

Complications specific to supra-tarsal injection form of steroid :

• Steroid induced glaucoma

• Steroid induced cataract

• Conjunctival necrosis and scarring

• Increased propensity for infections

• Eyelid necrosis or tissue atrophy following intra-lesional cortico-

steroid92

• Retinal and choroidal vascular occlusion following intralesional

corticosteroid injection93.

• De- pigmentation following intra-lesional corticosteroid94.

• Bilateral retinal embolization associated with intralesional corticosteroid

injection for an eyelid capillary hemangioma of infancy has also been re-

ported.95

• Inadvertent globe perforation, though rare. A case of ocular perforation

has been reported during regional anaesthesia for chalazion surgery.96

Advantages and disadvantages :

Comparison between topical and supra-tarsal form of steroid use :

Topical steroids show a higher rate of steroid induced ocular

hypertension as that compared to the supra-tarsal route. Mandal et al97

published an 8.7% incidence of steroid induced ocular hypertension among

a group of Indian children and adolescents. This corroborated well with

another study of a Vietnamese population which showed 8.5%98 incidence.

Other studies report higher incidences ranging from 11-21%. This could be

contrasted with the reported incidences of steroid induced ocular

hypertension through the supra-tarsal form which was 1-4% .Thus, supra-

tarsal form has been proven to be a safer alternative to the topical form of

steroid use, especially in cases of chronic refractory types of vernal

keratoconjunctivitis.

Studies :

Holsclaw et al91 prospectively studied 12 patients refractory to

conventional therapy using a short-acting corticosteriod and triamcinolone

acetonide. After supratarsal injection patients in both groups experienced

dramatic symptomatic relief within 1 to 5 days. Marked decrease in

cobblestone papillae was noted in 14.9 days (mean) after short-acting

corticosteroid injection and 12.8 days after triamcinolone acetonide injection (p

5 0.65). Three recurrences were seen in the patients receiving triamcinolone

acetonide and were observed at 180--290 days. Two of these patients received

reinjection without further recurrence. Shield ulcers and limbal involvement

resolved in 1 to 3 weeks, independent of the corticosteroid used (p 5 0.90). No

complications were observed with supratarsal injection of short-acting

corticosteroid. One patient developed persistent increase of IOP after injection

of triamcinolone acetonide.

Saini et al99 compared the efficacy of supratarsal injection of

dexamethasone sodium phosphate to triamcinolone acetonide. The study was a

prospective, randomized, double-blind, case-controlled trial, including 38 eyes

of 19 patients with recalcitrant VKC. Each patient was randomly assigned to

receive either 2 mg of dexamethasone sodium phosphate or 20 mg of

triamcinolone acetonide. A significant symptomatic response was noted in all

patients within 1 to 3 days. Moreover, a 50% reduction in size of papillae was

noted by 3 weeks in both groups. Complete healing of epithelial shield ulcers

was noted within 3 weeks.

In a prospective study of 90 eyes, Singh et al100 compared

dexamethasone sodium phosphate, triamcinolone acetonide, and

hydrocortisone sodium succinate. The study found that all of the three drugs

were equally effective with no statistically significant difference in the time of

resolution of cobblestone papillae, lid edema, conjunctival discharge and

chemosis, Tranta’s dots, and shield ulcers. Singh noted that disease recurred

within 6 months in all patients to the same level of pre-study severity.

SURGICAL MANAGEMENT :

Several treatments have been used in various combinations to achieve rapid re-

epithelialization of shield ulcers.

supratarsal steroid injection,91,99,100

surgical excision of giant papillae with101 or without mitomycin,

temporary mattress sutures to the lids27

surgical debridement of ulcer base,102

Superficial keratectomy31

amniotic membrane transplant103

autologous conjunctival graft

excimer laser phototherapeutic keratectomy104

CO2-assisted removal of giant papillae105

Cryosurgery113

FUTURE THERAPIES FOR VKC :

Despite the development of newer drugs in the last decade, the statement

of Professor Lightman – ‘at present however, the current situation for those

with severe VKC remains a disturbing dependence upon topical steroids,

with all the attendant risks’, emphasizing the need for more selective drugs

for better and long-lasting control of VKC – is still appropriate106

(Hingorani&Lightman 1995).

1. Anti- chemokine receptor antibodies inhibit eosinophil chemotaxis.

Inhibition of CC chemokine receptor-3 may be a treatment for corneal

ulceration in patients with VKC 107.

2. So far, results with topical cyclosporine are very encouraging at present

but its use in VKC is limited to that of a steroid sparing drug where

topical steroid are contraindicated or need to be given in very low dose.

Future developments in the manipulation of eosinophilic products,

cytokines and adhesion molecules may also be relevant.

3. High levels of leukotrienes in the tears of patients with VKC and

improvements in the signs and symptoms of VKC when given oral

montelukast, a leukotriene receptor antagonist, suggest that anti-

leukotrienes have therapeutic potential and need further trials108,109

(Akman et al. 1998; Lambiase et al. 2003).

4. Macrobiomolecules have been shown to inhibit ocular allergic

responses. Anti-flammins, a macrobiomolecule, inhibit phospolipase A2.

Topical anti-flammins have been shown to inhibit allergic responses in

murine allergic conjunctivitis.

5. Immuno-stimulatory oligonucleotides (ISS) or CpG motiff, another

macrobiomolecules, inhibits ongoing TH2 response in murine allergic

conjunctivitis110 (Tuo& Chan 2003).

6. Probiotics have been shown to improve allergic inflammation.

Furthermore, a report by Iovie- no et al. (2008)111 has shown that

Lactobacillus acidophilus diluted in saline solution administered as eye-

drops improves signs and symptoms in patients with VKC.

CURRENT MANAGEMENT STRATEGIES :

• Mild :

Cold compress,

Topical antihistamines,

Decongestants, Mast cell stabilizers

Environment modulation

• Moderate :

Low dose of soft steroids/NSAIDS, Mast cell stabilizers

• Advanced :

Topical Steroids

Supratarsal injection of steroids,

Moderate treatment+ Topical cyclosporine

Moderate treatment+ Tacrolimus

Surgical treatment :

ARTICLES - REVIEW

1. EFFICACY OF SURATARSAL DEXAMETHOSONE VERSUS

TRIAMCINOLONE INJECTION IN RECALCITRANT VERNAL

KERATOCONJUNCTIVITIS

Author :Jagjit S. Saini, Amit Gupta, Suresh K. Pandey, Vishali Gupta and

Pankaj Gupta Journal :ActaOphthalmol. Scand. 1999: 77: 515–518

This was a prospective, randomised, double masked case control study, of

thirty-eight eyes of nineteen patients with clinical diagnosis of advanced and

resistant VKC with disease related corneal complications (severe punctate

keratitis, shield ulcer or pannus). Diagnosis was confirmed with symptoms,

signs and cytological evaluation of conjunctival scrapings.

All the eyes were randomised such that one eye received dexamethasone

sodium phosphate (2 mg) and the second eye triamcinolone acetonide (20

mg). All patients were injected simultaneously in both the eyes.

The authors had defined Treatment success as the reduction of symptoms by

50% of pre- treatment severity and/or 50% reduction in the maximum pre-

treatment size of cobble stone papillae.

Disease recurrence was defined as status-quo or increase in symptoms and

maximum papillae size similar or exceeding the pre-treatment levels. All

patients were also observed for any side effects of steroid injection.

Treatment failures were those patients requiring re-administration of topical

steroids to control signs and symptoms within 6 weeks of steroid injection.

A 50% or more decrease in size of cobble stone papillae was noticed within 3

weeks in both the groups. The average time to fifty percent resolution in the

size of cobblestone papillae was 12.07 (range 10–21) days in the triamcinolone

group and 11.6 (range 12–21) days in the dexamethasone group.

Resolution of limbal edema in patients having the mixed type of VKC was

observed within 16 days after dexamethasone, and within 14 days after

triamcinolone injection. Complete healing of epithelial defects in patients with

shield ulcer and superficial punctate keratitis was seen over a 2 and 3 week

period, respectively.

4/17 patients in the dexamethasone group and 3/21 in the triamcinolone group

experienced recurrence.

The data did not demonstrate a statistically significant difference in the clinical

efficacy of intermediate acting triamcinolone acetonide compared with short

acting dexamethasone sodium phosphate. Both agents were equally quick

acting and effective in providing symptomatic relief. None of the patients in

either group developed any side effects of the therapy, including no increase in

intraocular pressure.

Thus, the authors concluded that both Dexamethasone and Triamcinolone

showed equal efficacy with a good safety profile.

2.SUPRATARSAL INJECTION OF CORTICOSTEROIDS IN THE

TREATMENT OF REFRACTORY VERNAL KERTOCONJUNCTIVITIS.

Author :S Singh, V Pal, CS Dhull Journal :Indian J Ophthalmol 2001;49:241-5

This study was a prospective, randomized, double masked case control study of

90 eyes of 45 patients. It included patients with advanced and refractory VKC

not responding or inadequately responding to month-long maximum topical

therapy.

Patients were randomly allocated to three groups of equal size. Group A

eyes received supratarsal injection of 2 mg dexamethasone, Group B eyes

received supratarsal injection of 10.5 mg triamcinolone, and Group C eyes

received supratarsal injection of 50 mg hydrocortisone. All patients had a

wash off period of two weeks prior to the administration of study drugs. Each

eye was evaluated at the third day, every week thereafter up to four weeks and

then every month up to 6 months.

Significant symptomatic improvement (p<0.001) was noticed in all

patients within 3 days of the supratarsal corticosteroid injection.

A reduction of 50% or more in size of cobblestone papillae was noticed

after 2 weeks in all patients and was independent of the type of corticosteroid

used. But mild recurrence of symptoms was noticed after 12 weeks and after 5

months moderate to severe symptoms and signs reappeared in all patients in the

three groups, requiring a repeat injection. However, there was no recurrence of

corneal shield ulcer in any eye in any group.

There was no statistically significant difference in the recurrence of

symptoms and signs in the three corticosteroid treated groups. No patient in

either group developed any side effects of the therapy, including increased

IOP.

The authors were of the opinion that there was good remission of

symptoms and signs in all three groups with equal efficacy and safety.

However, the effect lasted for five months, after which patients of all three

groups required repeat injections.

AIM

To compare the efficacy and safety of 0.25ml(10mg) and 0.5 ml(20 mg)

of triamcinolone acetate as a supra-tarsal injection in the treatment of 60

patients of severe or refractory vernal kerato-conjunctivitis.

OBJECTIVES

Primary :

To assess the subjective relief of symptoms of the patients.

To measure the objective improvement in clinical signs based on

grading.

To compare the complications, if any, in the two dosages, especially

intra-ocular pressure rise.

Secondary :

To assess and compare the recurrences of the symptoms and/or signs in

each dosage group.

MATERIALS AND METHODS

STUDY DESIGN:

Prospective,

Randomised,

Double-masked,

Interventional,

Comparative study.

STUDY SETTING:

This is a hospital-based study conducted in the Cornea department

of a tertiary level ophthalmic centre - Aravind Eye Hospital and Post-graduate

institute, situated in Madurai. The study was conducted from December 2011-

February 2013 over a period of 14 months. The follow-up was for 6 months.

SAMPLE SIZE:

As there were no previous studies comparing the dosages of supratarsal

steroid for vernal kerato-conjunctivitis, the sample size could not be calculated.

Hence, the patients who came to the outpatient department of Cornea clinic of

Aravind Eye Hospital over a period of 14 months, who fit into the inclusion

criteria of this study, were included in the study. A total of 60 patients were

enrolled into this study. The study was approved by the Institutional review

board and complied with the tenets of the Declaration of Helsinki. Written,

Informed consent was obtained from all study participants.

INCLUSION CRITERIA:

1. Persistence of vernal conjunctivitis despite adequate topical

corticosteroids for at least 3 weeks.

2. Vernal Kerato-conjunctivitis not responding to adequate and appropriate

topical drugs (NSAIDS, corticosteroids, antihistamines, mast cell

stabilizers).

3. Patients willing to participate in the study through informed consent.

EXCLUSION CRITERIA:

1. Glaucoma or raised IOP.

2. Cataract.

3. Previous history of ocular surgery.

4. Children <5 years.

5. Patients concurrently treated for other allergic disorders.

6. Patients with family history of glaucoma.

7. Patients with connective tissue disorders.

8. Patients with high myopia.

9. Patients with diabetes mellitus.

10. Past history of ocular trauma.

11. Concomitant presence of corneal krukenbergs spindle, keratic

precipitates, heterochromic iris or pigment dispersion.

12. Patients enrolled in other studies.

13. Patients not willing to participate in the study.

INFORMED CONSENT :

Patients were informed of the aims of the study and procedure of

injection and an informed consent was obtained before assessment for the

study and administration of supra-tarsal injection of corticosteroid. Patients

not willing to participate were assured of medical care as per our standard

treatment guidelines.

MATERIALS:

1. Snellen’s distance visual acuity chart.

2. TOPCON Slit lamp with 90 Diopter lens.

3. TOPCON CT-80 Non-contact tonometer.

4. Topical anesthetic Lignocaine 4%.

5. Cotton-tipped applicator.

6. 1 vial triamcinolone acetate 40mg(1 ml) out of which the randomized

amount of drug was withdrawn as per the randomization table.

7. Tuberculin syringe with 26 G needle.

8. Microscope for visualization and injection of drug into the supra-tarsal

space.

METHODS:

60 eyes of 48 patients were eligible and enrolled for this study. All 60

eyes were enrolled strictly on the basis of the inclusion and exclusion criteria.

Once enrolled, the patient’s case sheet was marked for study and the proforma

was attached to it. The patient was assigned to group 1 or 2 based on the

randomization table, group 1 being 0.5ml(20mg) and group 2 being

0.25ml(10mg). Patient’s name, age and gender was noted. The eye to be taken

up for study was also noted.

This was followed by an elaborate history consisting of duration of

symptoms, the chronicity of the disease and it’s character.( seasonal, perennial,

first episode). Any associations, including keratoconus and limbal stem cell

deficiency or any other history of atopy (bronchial asthma, eczema, allergy,

family history of allergy) was noted. Systemic illness like diabetes mellitus and

hypertension was also recorded.

Previous treatment for the ocular condition, including the name of the

drug, duration for which it was used and the duration of stoppage of drug prior

to the study drug were made note of.

Distant visual acuity was recorded with the help of Snellen’s visual

acuity chart at 6 meters. Pre-procedure intra-ocular pressure was recorded with

the help of TOPCON CT-80 non-contact tonometer.

The type of vernal kerato-conjunctivitis was described, depending on the

site of involvement.(tarsal, limbal, pan).

The measurement of symptoms and signs were done through a gradation

system from 0-3 representing nil, mild, moderate and severe.

All evaluation and grading (pre-procedure and follow-up) was done by the

same ophthalmologist, who was a cornea fellow in the Department of Cornea

in Aravind Eye Hospital.

The symptoms were graded by the study patient after explaining the

grading system to him/her. The symptoms elicited were itching, tearing,

discharge, redness, foreign body sensation, pain, photophobia.

The signs were graded by the masked evaluating ophthalmologist. They

were divided on the basis of lids, conjunctiva, limbus and cornea.

The lid sign was lid edema. Conjunctival signs were hyperemia,

discharge and chemosis. Papillae was graded as nil, micro, macro and giant(0-

3).

The limbal and corneal signs were marked as either present or absent.

The limbal signs were limbal hyperplasia and Horner-Tranta’s dots. The

corneal signs recorded were shield ulcer, epithelial keratitis and pannus.

Detailed anterior segment evaluation was done using TOPCON slit-

lamp. The papillae were noted on eversion of tarsal plate and corneal

involvement was noted after staining with fluorescein 1mg strip wetted with

lubricant.

Other ocular findings in anterior chamber and pupil were observed and

lens status was recorded. Dilated fundus evaluation using 90 Diopter lens

enabled slit lamp biomicroscopy was done and cup-disc ratio was noted.

Loading of the study drug :

Triamcinolone acetate is available in a vial of 40 mg(1 ml). With the

help of the 26 gauge needle and 1 ml syringe, the required amount of drug was

withdrawn from the vial.

Technique of injection :

All patients underwent the procedure under topical anesthesia(lignocaine

4%)except 2 eyes of 1 patient which had to be done under general anesthesia

due to non-cooperation.

Using a microscope, the superior tarsus was gently lifted from the globe

and a cotton-tipped applicator soaked in lignocaine was pressed against the site

of injection for a few seconds. Then, a 26-gauge needle of the tuberculin

syringe loaded with the intended dosage of the triamcinolone acetate, was

introduced into the supra-tarsal space between the conjunctiva and Muller’s

muscle, approximately 1 mm above the superior tarsal border. Care was taken

to avoid the marginal blood vessels. After ensuring the proper placement of the

needle, the study drug was injected. Successful placement of the injection was

indicated by the ballooning of the potential space between the conjunctiva and

Muller’s muscle. The patient was then asked to close the eye for 2 minutes. All

study eyes were given cromolyn sodium eye drops twice a day as medication to

be used at home.

Review was done at 3 weeks, 3 months and 6 months. Lee-way for

follow-up was given as ± 1 week for the 3 week follow-up, ± 2 weeks for 3

months and ± 3 weeks for 6 month follow-up.

In all follow-up visits, the symptoms and signs were graded and the intra-

ocular pressure noted. Other adverse events, if any, were noted.

Statistical analysis was performed by adding all the symptoms to a maximum

score of 21 and all the signs to 20.

Defining variables :

Treatment success was defined as reduction of symptoms to ≤ 5 ( the

maximum being 21), and signs to ≤ 5( the maximum being 20), including

reduction in size of cobble-stone papillae and the disappearance of epithelial

keratitis and limbal hyperplasia. The success of treatment in shield ulcers was

healing of epithelial defect, evidenced by a negative fluorescein stain.

Treatment failure was defined as similar or increased score of symptoms and

signs in the first post-procedure visit (3 weeks)as compared to baseline,

including status quo or worsening of epithelial keratitis, limbal hyperplasia and

shield ulcer.

Disease recurrence was defined as symptoms and signs score ≥ 5( the

maximum being 21), including increase in size of cobble-stone papillae or

persistence of shield ulcer or limbal hyperplasia >180 degrees or recurrence of

epithelial keratitis in the 3rd or 6th month follow-up.

Statistical analysis :

Mean (with Standard deviation) and Frequency (percentage) was used

for continuous and categorical variables respectively. Student t-test (if

parametric) or Mann-whitney U test/Wilcoxon signrank sum test was used to

assess the difference between the continuous variables. Fisher’s exact test or

chi-square test was used to assess the difference between the categorical

variables. P-value <0.05 was considered as statistically significant. All

statistical analysis was done by statistical software STATA 11.0.

RESULTS

Age:

The mean age in group 0.5ml was 16.3±7.3 years and group 0.25ml was

18.7 ±9.1 years. The overall mean age group was 17.5 ± 8.3 years. The

youngest was 6 years old and the oldest study patient was 48 years old.

Gender

Out of 60 eyes, there were 54 males(90%) and 6 females(10%). Group 0.5ml

had 26 males(86.7%) and 4 females(13.3%). Group 0.25ml had 28

males(93.3%) and 2 females(6.7%).

87%93%

13%7%

0%

20%

40%

60%

80%

100%

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Gender

Male Female

Laterality

In group 0.5ml, 17 had unilateral injection(73.9%) and 6 had bilateral

injections(26.1%). In group 0.25ml, 19 had unilateral(76%) and 6 had bilateral

injections(24%). Totally,36 patients had unilateral injections(75%) and 12

patients had bilateral injections(25%) . All patients who had bilateral injections

had it at different times, except one patient who underwent it simultaneously

under general anaesthesia, as he was only 6 years old and did not co-operate

under topical anaesthesia.

74% 76%

26% 24%

0%

20%

40%

60%

80%

100%

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Laterality

Unilateral Bilateral

Type of VKC:

The tarsal form was seen in 7 eyes(11.7%). Limbal form was seen in 4

eyes(6.7%). Pan form was seen in 49 eyes(81.7%). Group 0.5ml had 2

tarsal(6.7%),2 limbal (6.7%)and 26 pan form of VKC(86.7%). Group 0.25ml

had 5 tarsal(16.7%), 2 limbal(6.7%) and 23 pan form of VKC(76.7%).

7%17%

7% 7%

86%77%

0%

20%

40%

60%

80%

100%

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Type of VKC

Tarsal Limbal Pan

Character of VKC:

VKC was seasonal in 47 eyes(78.3%) (group 0.5ml -23, group 0.25ml- 24). It

was perennial in 6 eyes(10%),equally distributed between both the groups. It

was the first episode in 7 patients(11.7%), of which 4 were group 0.5ml and 3

were group 0.25ml.

77% 80%

10% 10%13% 10%

0%

20%

40%

60%

80%

100%

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Seasonal

Seasonal Perennial First episode

Ocular associations :

5 eyes(of 4 patients) out of 60(8.3%), had an association of keratoconus, out of

which 2 were in group 0.5ml and 3 were in group 0.25ml. 1 patient underwent

Deep Anterior Lamellar Keratectomy (DALK) 4 months after the injection.

The other ocular associations numbered 8(13.3%). They were 3 eyes of Limbal

stem cell deficiency, 1 eye with associated Coats disease in the other eye, 1 eye

with associated nystagmus and 2 eyes of 1 patient with centurion syndrome

with Medial canthal tendon disinsertion done.

7% 10%

77% 80%

16% 10%

0%

20%

40%

60%

80%

100%

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Ocular association

Keratoconnus Nil Others

Symptoms:

The score of the symptoms at baseline (out of 21) were overall 11±3.57, at 3

weeks was 0.68±1.66, at 3 months was 0.95±1.91 and at 6 months was

1.50 ± 2.47. The 0.5 ml group showed baseline symptom score to be

11.43±3.23, 3 week score to be 0.83±2.18, 3 month score to be 0.70±1.26 and

6 month score to be 1.53±2.36. The 0.25 ml group showed the baseline

symptoms to be 10.57±3.87, 3 week score to be 0.50±0.90, 3 month score to

be 1.20±2.38 and 6 month score to be 1.47±2.62.

11.43

0.87

0.71.53

10.57

0.5

1.2 1.47

0

2

4

6

8

10

12

Baseline 3week 3month 6month

Me

an

Symptoms

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Itching

:

Itching was the predominant symptom with 95% (57 eyes) complaining of the

symptom. Overall, it was mild in 5% of patients, moderate in 33% of patients

and severe in 57% of patients.

The 0.5 ml group at baseline showed 3%(1 eye) no itching, 33%(10 eyes)

moderate and 63%(19 eyes) severe itching. At 3 weeks follow-up, 90%(27

eyes) had no itching, 3% (1 eye) had mild itching and 7%(2 eyes) had

moderate itching. No eyes had severe itching. At the 3rd month follow-up,

80%(24 eyes) had no itching, 20%(6 eyes) had mild itching and no eyes had

moderate or severe itching. At the 6th month follow-up, 67%(6 eyes) had no

itching, while 20%(6 eyes) had mild and 13%(4 eyes) had moderate itching.

No eyes had severe itching.

3%

90%80%

67%

7%

93%80%

70%

3% 20%

20%

10%

7%

13%20%

33%

7% 13%

33%

7% 10%

63%50%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months 6months Baseline 3 weeks 3 Months 6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Itching

Nil Mild Moderte severe

The 0.25 ml group at baseline showed 7%(2 eyes) no itching, 10%(3 eyes)

mild, 33%(10 eyes) moderate and 50%(15 eyes) severe itching. At 3 weeks

follow-up, 93%(28 eyes) had no itching, 7% (2 eyes) had mild itching and

none had moderate or severe itching. At the 3rd month follow-up, 80%(24

eyes) had no itching, 13%(4 eyes) had mild itching and 7% (21 eyes) had

moderate itching. At the 6th month follow-up, 7-0%(6 eyes) had no itching,

while 20%(6 eyes) had mild and 10%(3 eyes) had moderate itching. No eyes

had severe itching.

Redness

:

3%

87% 80%70%

13%

80% 73% 73%

17%

10% 20%17%

17%

20%20% 17%

57%

13%

67%

7% 10%23%

3% 3%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6monthsBaseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Redness

Nil Mild Moderte severe

Redness was not experienced by 8%(5 eyes) of patients. It was mild in 17%(37

eyes), moderate in 62%(37 eyes) and severe in 13%(8 eyes).

The 0.5 ml group at baseline showed 3%(1 eye) no redness, 17%(5 eyes) mild,

57%(17 eyes) moderate and 23%(7 eyes) severe redness. At 3 weeks follow-

up, 87%(26 eyes) had no redness, 10% (3 eyes) had mild redness and 3%(1

eye) had severe redness. No eyes had moderate redness. At the 3rd month

follow-up, 80%(24 eyes) had no redness, 20%(6 eyes) had mild redness and no

eyes had moderate or severe redness. At the 6th month follow-up, 70%(21eyes)

had no redness, while 17%(5 eyes) had mild and 10%(3 eyes) had moderate

redness. No eyes had severe redness.

The 0.25 ml group at baseline showed 13%(4 eyes) no redness, 17%(5 eyes)

mild, 67%(20 eyes) moderate and 3%(1 eye) severe redness. At 3 weeks

follow-up, 80%(24 eyes) had no redness, 20% (6 eyes) had mild redness. No

eyes had moderate or severe redness. At the 3rd month follow-up, 73%(22

eyes) had no redness, 20%(6 eyes) had mild redness and 7%(2 eyes) had

moderate redness. No eyes had severe redness. At the 6th month follow-up,

73%(22 eyes) had no redness, while 17%(5 eyes) had mild and 10%(3 eyes)

had moderate redness. No eyes had severe redness.

Foreign body Sensation :

Foreign body sensation was experienced by 92% of eyes, with 37%(22 eyes)

mild, 40%(24 eyes) moderate and 15 %(9 eyes) severe.

The 0.5 ml group showed no foreign body sensation in 7% of eyes(2 eyes),

mild in 40%(12 eyes), moderate in 43%(13 eyes) and

The 3 week follow-up showed no foreign body sensation in 87%(26 eyes) and

mild foreign body sensation in 13%(4 eyes). The 3

no foreign body sensation in 93%(28 eyes) and mild in 7%(2 eyes). The 6

month follow-up showed 90%(27 eyes) with no foreign body sensation and

10%(3 eyes) with mild sensation.

7%

87%

40%

13%

43%

10%

0%

20%

40%

60%

80%

100%

Bas

elin

e

3 w

eeks

Triamcinolone acetate 0.5ml

Per

cen

tage

Foreign Body Sensation

on :

Foreign body sensation was experienced by 92% of eyes, with 37%(22 eyes)

mild, 40%(24 eyes) moderate and 15 %(9 eyes) severe.

The 0.5 ml group showed no foreign body sensation in 7% of eyes(2 eyes),

mild in 40%(12 eyes), moderate in 43%(13 eyes) and severe in 10%(3 eyes).

up showed no foreign body sensation in 87%(26 eyes) and

mild foreign body sensation in 13%(4 eyes). The 3rd month follow

no foreign body sensation in 93%(28 eyes) and mild in 7%(2 eyes). The 6

up showed 90%(27 eyes) with no foreign body sensation and

10%(3 eyes) with mild sensation.

87% 93% 90%

10%

90% 83%

13% 7% 10%

33%

10% 17%

37%

20%

3 M

on

ths

6m

on

ths

Bas

elin

e

3 w

eeks

3 M

on

ths

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Foreign Body Sensation

Foreign body sensation was experienced by 92% of eyes, with 37%(22 eyes)

The 0.5 ml group showed no foreign body sensation in 7% of eyes(2 eyes),

severe in 10%(3 eyes).

up showed no foreign body sensation in 87%(26 eyes) and

month follow-up showed

no foreign body sensation in 93%(28 eyes) and mild in 7%(2 eyes). The 6th

up showed 90%(27 eyes) with no foreign body sensation and

87%

13%

6m

on

ths

Triamcinolone acetate 0.25ml

The 0.25 ml group showed no foreign body sensation in 10% of eyes(3 eyes),

mild in 33%(10 eyes), moderate in 37%(11 eyes) and severe in 20%(6 eyes).

The 3 week follow-up showed no foreign body sensation in 90%(27 eyes) and

mild foreign body sensation in 10%(3 eyes). The 3rd month follow-up showed

no foreign body sensation in 83%(25 eyes) and mild in 17%(5 eyes). The 6th

month follow-up showed 87%(26 eyes) with no foreign body sensation and

13%(4 eyes) with mild sensation.

Signs :

The score of the signs at baseline (out of 20) were overall 8.17±2.61, at 3

weeks was 1.38±1.14, at 3 months was 1.73±1.66 and at 6 months was

2.22±1.89. The 0.5 ml group showed baseline symptom score to be 8.67±2.68,

8.67

1.57 1.572.07

7.67

1.21.9 2.37

0

2

4

6

8

10

Baseline 3week 3month 6month

Me

an

Signs

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

3 week score to be 1.57±1.45, 3 month score to be 1.57±0.97 and 6 month

score to be 2.07±1.60. The 0.25 ml group showed the baseline symptoms to be

7.67±2.48, 3 week score to be 1.20±0.66, 3 month score to be 1.90±2.14 and

6 month score to be 2.37±2.16.

Papillae

:

Papillae were absent in 3%(2 eyes), macro in 23%(14 eyes), giant in 70%(42

eyes) . In group 0.5 ml, papillae were macro in 23%(7 eyes) and giant in

63%(19 eyes), which decreased with each follow-up, however, by the 6th

month, the size had again increased to macro 57%( 10 eyes) and giant in

53%(10 eyes). In the 0.25 ml group, the papillae were macro in 23%(7 eyes)

and giant in 77%(23 eyes). In the subsequent follow-ups they decreased, but by

7% 3% 3% 7% 13% 13% 3%

23%

80% 77%57%

23%

83% 77%

63%

63%

10% 17%53%

77%

3% 7%33%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6months Baseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Papillae

Nil macro giant

the 6 th month follow-up, it had again increased to 33% giant(10 eyes) and

63% macro(19 eyes).

Limbal hyperplasia:

Limbal hyperplasia was present in 37 eyes(62%), out of which 21 eyes were

included in the 0.5 ml group and 16 eyes were included in the 0.25 ml group.

At 3 weeks follow-up, both 0.5 and 0.25 ml had limbal hyperplasia in only 1

eye (3%). However, at the 3rd month, 2 eyes(7%) of 0.5 ml had it, while 3

eyes(10%) of 0.25 ml had it. The difference was prominent at the 6th month

follow-up, where only 1 eye(3%) of 0.5 ml had limbal hyperplasia, while 4

eyes(13%) of 0.25 ml had it.

30%

97% 93% 97%

47%

97% 90% 87%

70%

3% 7% 3%

53%

3% 10% 13%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6monthsBaseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Limbal Thickening

Nil Present

Horner-Trantas’ dots :

This was seen in 25 eyes(41%), out of which 17 eyes were in group 0.5 ml and

8 eyes were in group 0.25 ml. However, the dots were not observed in any of

the follow-ups in the 0.5 ml group, but they were present in the 3rd month

follow-up in the 0.25 ml group(3 eyes-10%) and in the 6th month follow-up(2

eyes-7%).

43%

100% 100% 100%

73%

100% 90% 93%

57%

27%10% 7%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6monthsBaseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Tranta's dots

Nil Present

Shield Ulcer :

Shield ulcer was present in 11 eyes(18%), of which 6 eyes were included in

the 0.5 ml group and 5 eyes in the 0.25 ml group. There was no shield ulcer in

the 0.5 ml group in any of the follow-ups, while 2 eyes still had the ulcer at the

3rd week and 3 eyes at 3rd month and 6th month follow-up.

80%100% 100% 100%

83% 93% 90% 90%

20% 17% 7% 10% 10%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6monthsBaseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Shield's Ulcer

Nil Present

Epithelial keratitis :

This sign was present in 47 eyes(78%),with 29 eyes in group 0.5ml and 18 eyes

in group 0.25ml.At 3 weeks and 3rd month follow-up, 2 eyes(7%) of 0.5 ml

group had keratitis, while 1 eye(3%) of 0.25 ml had it. At 6th month follow-up,

6 eyes(20%) of 0.5 ml had it while 5 eyes(17%) of 0.25 ml had it.

3%

93% 93% 80%

40%

97% 97% 83%97%

7% 7% 20%

60%

3% 3% 17%

0%

20%

40%

60%

80%

100%

Baseline 3 weeks 3 Months

6monthsBaseline 3 weeks 3 Months

6months

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Epithelial Keratitis

Nil

Intra-ocular pressure :

The mean intra-ocular pressure at base-line was 11.31±3.21 mmHg in the 0.5

ml group and 12.27±3.70 mmHg in the 0.25 ml group. At the 3rd week, the

mean IOP was 17.17±5.99 mmHg for the 0.5 ml group and 16.18±7.27

mmHg for the 0.25 ml group. At the 3rd month follow-up, the mean IOP was

11

1717

16

13 16 1413

0

5

10

15

20

Baseline 3 weeks 3 months 6 months

Me

an

IOP

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

1113

17 1617

1416

13

0

4

8

12

16

20

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Me

an

IOP

Baseline 3 weeks 3 months 6 months

16.87±4.47 mmHg in the 0.5 ml and 14.43±3.18 mmHg in the 0.25 ml group.

At the 6th month follow-up, the 0.5 ml group showed a mean IOP of

15.57±3.31mmHg, while the 0.25 ml group showed 13.53±3.43mmHg. All

the values were statistically significant, with a p-value of <0.001. Spikes of

IOP were observed in 8 eyes with the mean IOP among the steroid responders

being 29.63mmHg(min-23 mmHg in group 0.5ml and max-42 mmHg in group

0.25ml).

Visual Acuity :

Visual acuity worse than 6/12 was seen in 20 % of patients in both the groups.

In the 6th month follow-up, vision worse than 6/12 was found to be 3% in the

o.5 ml and 10% in the 0.25 ml.

8097

8090

203

2010

0

20

40

60

80

100

Baseline Final Baseline Final

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Pe

rce

nta

ge

Visual Acuity

>=6/12 <6/12

5 patients were associated with keratoconus and thus exhibited poorer vision

than the others, thus acting as a confounding factor. Of these, 2 were from the

0.5 ml group and 3 were from the 0.25 ml group.

1 patient in the 0.25 ml group, who had an associated keratoconus, underwent

DALK surgery 4 months post the procedure and had a visual acuity of 6/36 at

his 6th month review.

The baseline mean logmar visual acuity in the 0.5 ml group was 0.19±0.22 and

the 6th month follow-up was 0.09±0.14. The mean logmar visual acuity at

baseline for the 0.25ml was 0.22 ±0.20 and the 6th month follow-up was

0.14±0.21. Both the values were statistically not significant(p-value 0.107 and

0.072 respectively).

COMPLICATIONS

Steroid-induced rise in IOP was observed in 8 eyes (of 5 patients) out of

60 eyes(13.33%). Of these 8 eyes, 6 eyes were of the 0.5 ml group(75%) and 2

eyes were of the 0.25 ml group(25%). 3 out of the 5 patients who had rise in

IOP, had bilateral injections. Out of the 3 patients, 2 of them had 0.5 ml

injected in both their eyes and one patient had 0.5 ml in one eye and 0.25 ml in

the other eye. All eyes presented with the complication in the 3rd week follow-

up, except one patient, who showed the rise in IOP in the 3rd month follow-up.

The mean IOP among the steroid responders was 29.63mmHg(min-23 mmHg

in group 0.5ml and max-42 mmHg in group 0.25ml). All the eyes with ocular

hypertension resolved within a month, on starting anti-glaucoma medication.

One eye of the 0.5 ml group with rise in IOP had steroid-induced

glaucoma, with a cup-disc ratio of 0.6(from 0.3) in the 3rd month follow-up.

Despite lowering of IOP to 20 mmHg with appropriate anti-glaucoma

medication by the 6th month, there was cupping of 0.6, till the 6th month

follow-up He was maintained on anti-glaucoma medications and did not need

surgery.

2 eyes (of 1 patient), out of 60 eyes(3.33%), developed posterior sub capsular

cataract, observed at the 6th month review. 1 eye was injected with 0.5 ml and

the other eye with 0.25 ml.

Treatment failure :

There was 1 treatment failure with a score of >5 out of 21 and 20 for

symptoms and signs respectivelyin 3rd week follow-up. He belonged to group

0.5 ml. He was treated with additional topical steroids and olopatadine.

Recurrence :

2926

1 0023 3

0

5

10

15

20

25

30

35

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Nu

mb

er

of

pa

tie

nts

Symptom recurrence

Baseline 3 weeks 3 months 6 months

There were a total of 8 recurrences out of 60 eyes(13.33%), with 3 in group

0.5ml(37.5%) and 5 in group 0.25ml(62.5%). All 3 eyes in group 0.5 ml

recurred at the 6th month follow-up. 2 eyes of the 0.25 ml group recurred at the

3rd month follow-up and 3 eyes recurred at the 6th month follow-up. They were

treated with topical steroids and olopatadine.

27

24

1 0021 2

0

5

10

15

20

25

30

Triamcinolone acetate 0.5ml Triamcinolone acetate 0.25ml

Nu

mb

er

of

pa

tie

nts

Signs recurrence

Baseline 3 weeks 3 months 6 months

DISCUSSION

Vernal kerato-conjunctivitis is a disease of young adults that, in it’s

severe form, could be debilitating for the patient. It is more common in the

tropics and is prevalent during the spring season, thus earning it’s nickname

“spring catarrh”.

In southern India, there is an overwhelming number of patients burdened

by this disease chronically, thus increasing the morbidity and decreasing the

productivity. Though blindness is not common in this disease, it becomes

essential to consider this entity in terms of the duration of disease and the age

that it affects.

Many treatment modalities have been extensively studied. Topical anti-

histamines, mast cell stabilisers1, NSAIDS2, corticosteroids, cyclosporine3 and

tacrolimus54 have a place in the treatment of this disease, yet fail to provide

long-term relief. They also fail when it comes to severe or recalcitrant kerato-

conjunctivitis.

Surgical excision102 and cryodestruction113 of cobblestone papillae have

been abandoned because of risk of severe scarring. Thus, Refractory vernal

kerato-conjunctivitis poses a challenge to ophthalmologists till date, in pursuit

of a cure or even just long term relief.

There is an urgent need to scientifically assess a new treatment modality that is

safe and effective for the treatment of refractory VKC.

Holsclaw et al91 had reported their initial experience by injecting short

and intermediate acting steroids in the supra-tarsal space of 12 eyes and found

dramatic relief from symptoms and improvement in signs. They had compared

0.5 ml(2 mg) of dexamethasone sodium phosphate and 0.5 ml(20 mg) of

triamcinolone acetate. They found no statistical difference between the two

drugs in terms of improvement. However, 1 patient who received

triamcinolone acetate, developed steroid induced ocular hypertension to

34mmHg, which was reversed within 4 months with anti-glaucoma medication.

They had also found that 3 patients who had rise in IOP with topical steroids

prior to the injection, did not show rise in IOP with the supra-tarsal steroid.

This showed that the supra-tarsal form of steroid might be a safer alternative to

chronic use of topical steroids.

Following this study, Saini et al99, reported another study in 1999, of 38

eyes of 19 patients with recalcitrant VKC, who underwent a supratarsal

injection of either 0.5 ml of dexamethasone sodium phosphate or 0.5 ml of

triamcinolone acetate. They also derived the same result as that of Holsclaw,

except that they observed the recurrence rate of the disease was lower (180-290

days) following triamcinolone. They did not observe any side-effects in their

study.

Singh et al100 followed it up with another study of 90 eyes, where they

compared the efficacy of 2 mg dexamethasone sodium phosphate, 10.5 mg

(0.25 ml) triamcinolone acetate and 50 mg hydrocortisone sodium succinate.

They noted that though there was no statistical difference between the three

drugs in terms of efficacy, there was a recurrence around 12 weeks for all three

drugs. They did not note any complication in their series.

There was one more study by Qamar et al114 , where he had injected 1 ml

of triamcinolone for 880 eyes and found that recurrence was seen at a mean of

4 months. Few other studies were done115,116, all using 0.5 ml of triamcinolone

acetate , with good efficacy and no side-effects.

In our series of patients comparing 60 eyes with 0.5ml and 0.25 ml of

triamcinolone acetate, the mean age of the patients were 17.46 years, which

establishes the fact that it is a disease of young adults. The gender ratio showed

90% male affliction, which can be explained due to the nature of work with the

male population, involving outdoors and dust exposure. The majority of the

VKC was pan or mixed type followed by tarsal and limbal. This could be

attributed to the selection of patients due to the stringent inclusion criteria,

allowing only severe or refractory cases of VKC to be included. The disease

was seasonal in 78% of eyes, following the pattern of spring-summer. As

previously reported, keratoconus was associated with 5 eyes, brought on by the

constant rubbing of eyes. The eyes with keratoconus, however, had relatively

poor visual acuity in the 6th month follow-up as compared to those who didn’t.

There was a marked improvement in the symptoms of both groups in the 3rd

week review following the injection.This response was independent of the

severity or duration of the disease. Both the groups showed the same

improvement with statistically insignificant difference. Itching was the most

common symptom, which was also the first symptom to disappear. Foreign

body sensation and redness also resolved in the follow-ups, but they had

recurred earlier in the 0.25 ml group ( around 3-6 months), as compared to 0.5

ml(around 6 months). This is comparable to other studies, reporting 90 days100

to 180-290 days99.

The signs also showed good improvement, with reduction in the size of the

papillae by the third week review, although they persisted as micro or macro-

papillae throughout and never disappeared, as opposed to Saini et al99 who

reported 4 patients with complete disappearance of papillae. The other signs

such as lid edema, hyperemia, discharge and chemosis, showed excellent

resolution by week 3, with no recurrences.

Limbal hyperplasia resolved by week 3, however, recurring in 2 patients in

both groups by 3rd month. Horner-Tranta’s dots disappeared by week 3 and

never recurred in the 0.5 ml group, with a couple of recurrences in the 3rd and

6th month in the 0.25 ml group.

Shield ulcer showed excellent response to the 0.5ml dosage of drug, with

all 6 eyes showing resolution by week 3 and no recurrences. However, the 0.25

ml group showed a relatively poor response with 3 out of 5 eyes showing no

resolution by 3rd month or recurrence by 6th month. This can be contrasted with

Singh et al’s100 observation of complete resolution of shield ulcers with 0.25 ml

of triamcinolone, with no recurrences. Hence, 0.5 ml seems to be the

appropriate dosage of triamcinolone acetate, for eyes with shield ulcer.

There were a total of 8 recurrences, with 5 in the 0.25 ml group showing

recurrence in the 3rd and 6th month. Thus, 0.25 ml allows for a slightly earlier

chance of recurrence than the 0.5 ml. There was 1 treatment failure in the 0.5

ml group, which could have been due to faulty injection method or highly

refractory nature of the VKC in that eye.

Visual acuity showed improvement in both groups, with more patients in

the 0.5 ml group showing vision >6/12. However, the associations of

keratoconus may act as confounding factors and distort the values.

The intraocular pressure showed statistically significant difference between the

2 dosages (p<0.001), with a mean IOP of 15.57 mmHg in the 0.5 ml group and

13.53 mmHg in the 0.25 ml group at the end of 6 months. This shows that there

is lesser rise of IOP in the 0.25ml group as compared to the 0.5 ml group.

Steroid- induced ocular hypertension were seen in 8 eyes, out of the 60

eyes(13.3%), which is an unusually high percentage of steroid response. This

outlines the presence of a high number of steroid responders in the South

Indian community, which was hitherto unreported.

Out of these 8 eyes, 6 belonged to the 0.5 ml group. One patient even

developed steroid induced glaucoma, with irreversible cupping. This can be

compared with only 2 eyes developing steroid induced ocular hypertension in

the 0.25 ml group. Thus, it becomes evident that 0.25 ml is the obvious safe

choice of dosage in a community with high rate of steroid responders. All eyes

with steroid induced ocular hypertension were brought to normal levels of IOP

within a month with appropriate anti-glaucoma medication.

Posterior sub capsular cataract was observed in 2 eyes, one injected with

0.5 ml and the other 0.25 ml. Both eyes belonged to the same patient. This

complication has also not been reported in the supra-tarsal form of steroid

before.

SUMMARY

1. The mean age of eligible participants was 17.5 years.

2. As expected , there was a male preponderance (90%)

3. 74% received supratarsal injection in one eye while 26% received

sequential injections in both eyes.

4. The pan / mixed form was most comely encountered 81.7%.

5. The disease was seasonal in 78.3%.

6. 8.3% of eyes had associated keratoconus.

7. Itching was the predominant symptom 95%.

8. Shield ulcers were present in 11 eyes 18%.

9. Steroid response was observed in 8 eyes (13.33%), indicting a high level

of steroid responders in the South Indian community.

10. One eye in the 0.5ml group developed steroid induced glaucoma.

11. There was one treatment failure who belonged to the 0.5ml group.

12. Posterior subcapsular cataract was observed in 3.3 % ( 2 eyes ) , one

injected with 0.5 ml and the other with 0.25ml. Both eyes belonged to

the same patient.

CONCLUSION

Refractory Vernal kerato-conjunctivitis is a chronic debilitating disease,

that requires a treatment modality that promises long-term efficacy and safety.

Supra-tarsal injection of triamcinolone acetate shows promising results to

control the disease for a significant period of time. Despite earlier recurrences,

0.25 ml of triamcinolone acetate shows an efficacy pattern that matches the 0.5

ml and a safety profile that is much more reliable than the 0.5 ml, considering

the high rate of steroid responders in the South Indian community.

From my study, 0.25 ml of triamcinolone acetate is the recommended

dosage for all cases of severe or refractory VKC. However, in cases of severe

VKC with presence of shield ulcer, it is recommended to use the 0.5 ml

dosage.

The results of my study become crucial, considering the chronicity of the

disease and the repeated number of steroid injections and topical steroids

required to control this disease. Thus, my study has proven that a little can go a

long way in treating this illness and improving the quality of life in these

patients.

HISTOPATHOLOGY

Source - Elsevier science (USA)

MATERIALS REQUIRED FOR SUPRATARSAL TRIAMCINOLONE INJECTION

COBBLESTONE PAPILLAE

Source - cehjournal.org

HORNER – TRANTAS DOTS

Source - pacificu.edu

PRE PROCEDURE

POST PROCEDURE

Resolution of papillae and limbal hyperplasia

PRE PROCEDURE

POST PROCEDURE

Resolution of papillae and shield ulcer

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PROFORMA Assessment form for supratarsal injection of triamcinolone

for VKC study Name : Evaluating Doctor : Study no.: Group: [1or 2] Hospital no.: Date of assessment: / / Age: years Sex: [1-Male,2-Female] Valid contact no.: Affected eye: [1-Right, 2-Left] Visual Acuity Visual Acuity of other eye: Seasonal -1,Perennial-2,First episode-3 Years of affection_______________________________ Associations: Ocular: Keratoconus: [0-Nil,1-Present2-Others] Others,please specify:_____________________________________________________

Systemic: History of Atopy: [0-Nil,1-Bronchial asthma,2-Eczema,3-Allergy,3-Family

history of allergy,4-Others] If others,please specify,_______________________________________________________________________ Associated systemic illness: [0-Nil,1-Diabetes,2-Hypertension,3-Cardiac,4-Others] If others,please specify_______________________________________________________________________ Diagnosis of VKC: [1-Tarsal,2-Limbal,3-Pan] HIV test(if adult): [0-Negative,1-Positive,2-Not Done] Treatment history:

Systemic: Informed consent: [0-Not taken,1-Taken].

Ocular examination:

Drug Dosage Duration If stopped,how long ago?

Subjective symptoms: [0-Nil,1-Mild,2-Moderate,3-Severe] 1. Itching

2. Tearing

3. Discharge

4. Redness

5. Foreign body sensation

6. Pain

7. Photophobia

If other symptoms,please specify_______________________________________________________________ Objective signs: Lids: Lid edema: [0-Nil,1-Mild,2-Moderate,3-Severe] Conjunctiva: Papillae: [0-Nil,1-Micro,2-Macro,3-Giant] Hyperaemia: [0-Nil,1-Mild,2-Moderate,3-Severe] Discharge: [0-Nil,1-Mild,2-Moderate,3-Severe] Chemosis: [0-Nil,1-Mild,2-Moderate,3-Severe] Limbus: Limbal thickening: [0-Nil,1-Present] ___________________ [clock hours] Tranta’s dots: [0-Nil,1-Present] Cornea: Shield’s ulcer: [0-Nil,1-Present] ________ Size _________________ location Epithelial keratitis: [0-Nil,1-Present] Pannus: [0-Nil,1-Present] Any other sign,kindly specify:_______________________________________________ Anterior chamber: Lens status: [1-Phakic,2-Aphakic,2-Pseudophakic,4-cataractous] Pupil: Fundus: Ocular movements: Intraocular pressure: mmHg(by non contact tonometry) digital(if no acquisition) Picture taken: [0-No,1-Yes] Overall Status: [1-Normal,2-Mild,3-Moderate,4-Severe]

Procedure: Anaesthesia: [1-Local,2-General] If general,why?_________________________________________ Immediate post procedure/intra procedural adverse events: [0-Nil,1-Present] If yes,specify the adverse event and management__________________________________________________ Post-procedure advice: Study eye medication : Addnl. Drugs for study eye ,if any : Other eye medications : To review after : 3 weeks Date of Prescribed Review :

FOLLOW UP EVALUATION Name: Evaluating doctor: Date of Prescribed Review: Study no: Hospital no: Date of Actual Review: If picture taken previously,kindly take follow up photo. Follow-up photo: [0-Not taken,1-Taken] Subjective symptoms: [0-Nil,1-Mild,2-Moderate,3-Severe]

1. Itching

2. Tearing

3. Discharge

4. Redness

5. Foreign body sensation

6. Pain

7. Photophobia

Drug

Dosage

Duration

Cromal forte

eyedrops

bd

2 months

If other symptoms,please specify_______________________________________________________________ Objective signs: Lids: Lid edema: [0-Nil,1-Mild,2-Moderate,3-Severe] Conjunctiva: Papillae: [0-Nil,1-Micro,2-Macro,3-Giant] Hyperaemia: [0-Nil,1-Mild,2-Moderate,3-Severe] Discharge: [0-Nil,1-Mild,2-Moderate,3-Severe] Chemosis: [0-Nil,1-Mild,2-Moderate,3-Severe] Limbus: Limbal thickening: [0-Nil,1-Present] ___________________ [clock hours] Tranta’s dots: [0-Nil,1-Present] Cornea: Shield’s ulcer: [0-Nil,1-Present] ________ Size _________________ location Epithelial keratitis: [0-Nil,1-Present] Pannus: [0-Nil,1-Present] Any other sign,kindly specify:_______________________________________________ Anterior chamber: Lens status: [1-Phakic,2-Aphakic,2-Pseudophakic,4-Cataractous] Pupil: Fundus: Ocular movements: Intraocular pressure: mmHg (by non contact tonometry) digital(if no acquisition) Overall Status: [1-Normal,2-Mild,3-Moderate,4-Severe]

Drug

Dosage

Duration

Cromal forte

eyedrops

bd

2 months

Any intervention done: Advice: Study eye medication : Addnl. Drugs for study eye ,if any : Other eye medications : To review after : 2 months 1 week Prescribed date of review: