OCULAR MANIFESTATIONS OF TB

INFECTION

MD SHAHID MANZOOR

INTRODUCTION

Tuberculosis is a chronic infection caused by Mycobacterium

tuberculosis that is characterized by the formation of

necrotizing granulomas.

Tuberculos is primarily involves the lung. Other organs

including the eye may be involved secondarily. Tuberculosis

may affect any part of the eye with variable clinical features.

Ocular TB incidence ranges from 1.4 - 5.74%.

INTRODUCTION

Ocular tuberculosis is an extrapulmonary form.

Primary infection of the eye is rare.

Secondary ocular tuberculosis is the ocular involvement

as a result of haematogenous spread from a distant site or

a direct invasion from adjacent areas like skin, sinus

or cranial cavity or, as hypersensitivity response to

distant infection.

The disease is usually chronic and insidious with

exacerbations & remissions.

INTRODUCTION

Infection

1. The number and virulence of the organisms,

2. Immunity of the host.

The clinical presentation.

Direct infection by TB.

Hypersensitivity reactions to tubercular proteins.

PATHOPHYSIOLOGY

Tuberculosis is caused by M. tuberculosis, which is an

obligate aerobic, slow growing, nonspore forming,

nonmotile bacterium.

Humans are the only natural host.

It is primarily spread as an airborne aerosol which gains

access to susceptible hosts through the lung and results in

a latent or dormant infection in hosts with normally

functioning immune systems.

Usually, between 5 and 200 inhaled bacilli are needed to

cause infection in humans.

PATHOPHYSIOLOGY

Infect end organs typically having high regional oxygen

tension (apices of the lungs, kidneys, bones, meninges,

eye, and choroid).

M.tuberculosis tends to grow successfully in the choroid

and ciliary body where the oxygen tension is high

compared with other ocular structures.

The hallmark of extra-pulmonary TB is caseating

granuloma and necrosis

CLINICAL PRESENTATION

A ) ADNEXAL MANIFESTATIONS

B) ANTERIOR SEGMENT MANIFESTATION

C) POSTERIOR SEGMENT MANIFESTATIONS

D) NEURO-OPHTHALMIC MANIFESTATIONS

E) DRUG-RELATED OCULAR TOXICITY IN TB-

INFECTED PATIENTS

A) ADNEXAL MANIFESTATIONS

1) Lupus Vulgaris

2) Eyelid Tuberculous Granuloma

1) LUPUS VULGARIS

Unilateral , insidious

Manifests begins as painless , soft ,

reddish-brown nodules which

slowly enlarge to form irregularly

shaped red plaque and later

ulceration and scarring occurred

(painful ).

Often accompanied by lymphadenopathy.

Complications - squamous cell carcinoma

1) LUPUS VULGARIS

1) LUPUS VULGARIS

On diascopy, it shows characteristic "apple-jelly" color.

Biopsy will reveal tuberculoid granuloma with few

AF bacilli.

Mantoux test is positive.

Treatment includes ATT.

2) EYELID TUBERCULOUS GRANULOMA

Unilateral , insidious

Manifests with a violet-brown ,

non-tender, mobile nodule.

Often accompanied by

lymphadenopathy.

The nodule may ulcerate after some time and spread locally

in an irregular fashion and it is often accompanied by pain

and discharge.

Complications include trichiasis and entropion formation. .

2) EYELID TUBERCULOUS GRANULOMA

2) EYELID TUBERCULOUS GRANULOMA

The diagnosis can be difficult and it may require

biopsy in which acid fast bacilli (AFB) and the

characteristic histopathology may be seen.

The growth of Mycobacterium tuberculosis from such a

specimen remains the gold standard for the diagnosis of

TB. PCR based tests of the pathological specimens have

been proven to be useful.

B) ANTERIOR SEGMENT INVOLVEMENT

1) Tuberculous conjunctivitis.

2) Conjunctival granuloma.

3) Phlyctenular keratoconjunctivitis.

4) Tuberculous Scleritis

5) Interstitial keratitis

6) Iridocyclitis

1) TUBERCULOUS CONJUNCTIVITIS

1. Primary – Unilateral

2. Secondary – Bilateral

Mucoid discharge, Edema of lids

chemosis

Large follicles which ulcerate

Small, painless, and indolent ulcer, nodule on the tarsal

conjunctiva and fornix.

Parinaud oculoglandular syndrome.

Preauricular lymphadenopathy is seen in these cases.

1) TUBERCULOUS CONJUNCTIVITIS

Diagnosis

Isolation of organism from conjunctival secretions or scrapings.

Treatment

Primary focus – Excision of conjunctiva

Topical antibiotics

Topical steroid

ATT

2) CONJUNCTIVAL GRANULOMAS

It is a Type IV Hypersensitivity reaction,

presents as an inflammatory mass on

the conjunctiva.

It is usually occurs due to tuberculosis

but can be associated with Staphylococcus aureus .

Complications include keratitis ,scleritis, corneal ulcer

Subsequent calcification of granulomas can impede vision,

and inflammation can cause irreversible damage to ocular

tissue.

3) PHYLYCTENULAR KERATOCONJUNCTIVITIS

Presents with photophobia, tearing and

blepharospasm .

Mainifests as slightly raised,

small, pinkish white or yellow nodules

surrounded by dilated vessels located

on conjunctiva near the limbus or

on peripheral cornea.

Classically, there is no clear zone between the limbus and the

lesion.

3) PHYLYCTENULAR KERATOCONJUNCTIVITIS

3) PHYLYCTENULAR KERATOCONJUNCTIVITIS

After a few days, the superficial part of the raised nodule

becomes gray and soft; the center of the lesion then

ulcerates, sloughs, and clears without scarring.

Delayed hypersensitivity reaction to mycobacterial antigens

More commonly in children, bilateral.

Responds promptly to topical application of

corticosteroids.

These ulcers are associated with neovascularization and

can go on to perforate.

4) TUBERCULOUS SCLERITIS

Mostly it presents as an anterior

scleritis while posterior scleritis

is rare .

Localized focal elevated nodules

of the sclera or Necrotizing.

The sclera may be infected by direct spread from a local

conjunctival or choroidal lesion, or more commonly by

haematogenous spread.

4) TUBERCULOUS SCLERITIS

This may undergo necrosis and may lead to scleromalacia

It does not respond to topical steroids and requires

antituberculous therapy

5) INTERSTITIAL KERATITIS

an inflammation of the corneal stroma

without primary involvement of the

epithelium or endothelium.

In most cases, the inflammation is

an immune-mediated process

triggered by an appropriate antigen.

Treatment- systemic antitubercular drugs, topical steroids

and cycloplegics

6) ANTERIOR UVEITIS

unilateral or bilateral chronic granulomatous disease

which presents with large, mutton

fat keratic precipitates,

posterior synechiae, and iris

or angle granulomas..

In severe cases, hypopyon

Iris nodules may be present near the pupillary border

(Koeppe) or on the iris surface (Bussaca).

6) ANTERIOR UVEITIS

6) ANTERIOR UVEITIS

Anterior uveitis is often accompanied by vitritis

an insidious onset and runs a chroniccourse, inevitably complicated by the development of cataract and posterior synechiae.

Administration of antituberculosis treatment can help in reducing the number of recurrences in these eyes.

INTERMEDIATE UVEITIS

Chronic, low-grade, vitritis with

snowball opacities, snow banking,

peripheral vascular sheathing,

and peripheral granuloma.

In a North Indian population, TB was found to be an

unusually common etiology of intermediate uveitis

(46.7%).

The most frequent complications related to Tb uveitis

included cystoid macular edema (40%) and cataract

(38.9%).

Other less common complications - epiretinal

membrane, raised intraocular pressure, optic disc pallor,

peripheral neovascularization, retinal

detachment and vitreous hemorrhage.

In eyes with media opacity, ultrasound biomicroscopy can

assist in detecting the presence of a granuloma in the ciliary

body region.

C) POSTERIOR SEGMENT MANIFESTATIONS

The ocular changes can be divided into four groups:

Choroidal tubercles,

Choroidal tuberculoma,

Serpiginous like choroiditis and

Subretinal abscess.

1) CHOROIDAL TUBERCLES

Most common manifestation

of intra-ocular tuberculosis and

result from hematogenous spread.

less than 5, upto 50 in number,

Unilateral or bilateral,

grayish white to yellow in color

with indistinct borders,

are located mostly in the posterior pole.

1) CHOROIDAL TUBERCLES

1) CHOROIDAL TUBERCLES

are seen in military tuberculosis and central nervous

system tuberculosis (meningitis)

On fluorescein angiography, they are hypofluorescent

during dye transit with late hyperfluorescence.

Active Choroidal tubercles usually respond well to ATT

and generally take up to 3 to 4 months to heal. On

healing, the tubercles result in pigmented and atrophic

scars.

2) CHOROIDAL TUBERCULOMA

Choroidal tubercle continues to

grow, it forms a solitary mass known as

tuberculoma

Present as a solitary, yellowish,

subretinal mass with surrounding

exudative retinal detachment ,

mimicking a choroidal tumor.

May be located anywhere

Measure from 4 to 14 mm in size and generally

2) CHOROIDAL TUBERCULOMA

May occur in immunocompetent patients and in

patients with disseminated tuberculosis, may have

overlying hemorrhages, retinal folds, and surrounding

exudative retinal detachment

On ultrasonography, these lesions are solid, elevated

masses with moderate to low internal reflectivity.

respond well to antituberculosis treatment

3) SERPIGINOUS LIKE CHOROIDITIS

It is a bilateral, chronic, progressive

and recurrent inflammation that primarily

involves the choroid and choriocapillaris

and progresses to involve the retina .

These lesions begin in the peri papillary area and spread

centrifugally.

Multifocal form where the lesions are discrete and noncontiguous

initially but later in the course may form a diffuse, contiguous

pattern.

3) SERPIGINOUS LIKE CHOROIDITIS

3) SERPIGINOUS LIKE CHOROIDITIS

It may represent an immune-mediated hypersensitivity reaction

with relentless progression despite administration of systemic

corticosteroids and immunosuppressive agents.

Antituberculosis treatment in conjunction with oral

corticosteroids/immunosuppressive agents may reduce the number

of recurrences.

The healing of such lesions may lead to peripapillary

retinochoroiditis scar.

The retinochoroiditis may become extensive and may involve the

ciliary body causing cyclitis with hypotony and phthisis bulbi.

4. SUB-RETINAL ABSCESSES

Multiplication of the bacilli in the

caseous material of the granulomas

can lead to liquefaction necrosis and

abscess formation and form yellowish

subretinal mass lesions accompanied

by exudative retinal detachment.

Patients with disseminated tuberculosis.

4. SUB-RETINAL ABSCESSES

4. SUB-RETINAL ABSCESSES

Rarely, these lesions can rupture into the vitreous cavity

and may lead to endophthalmitis or panophthalmitis

usually heal with ATT and healed lesions may show

pigmentation and atrophy with chances of good visual

recovery .

Sub-retinal neo-vascularization may develop within the

scar

RETINAL VASCULITIS

in patients with tuberculosis involve

the veins or, rarely, the arteries.

The characteristic features include

bilateral, vitreous infiltrates

(vitritis), perivascular cuffing,

infiltrates, retinal haemorrhages,

perivascular choroiditis scars, neo-

vascularization and neuro-retinitis.

On FFA, extensive peripheral

capillary nonperfusion areas that lead to retinal/optic

disc neovascularization characterize

TB retinal vasculitis.

It has been long speculated that

patients of idiopathic retinal vasculitis, the so called Eales'

disease, may indeed be tuberculous retinal vasculitis.

presence of MTB DNA was demonstrated in

epiretinal membranes of patients with Eales' disease who

underwent vitreous surgery.

EALES’ DISEASE

Bilateral, idiopathic, occlusive, peripheral periphlebitis and

neovascularization.

Recurrent attacks of diminution of vision in young males –

recurrent vitreous hemorrhage

The disease is characterized by three overlapping stages:

(a) periphlebitis,

(b) occlusion and

(c) retinal neovascularization.

Mild uveitis is common

EALES’ DISEASE

(A) Peripheral vascular sheathing

and occlusion in the

superotemporal quadrant.

(A) (B) peripheral neovascularization;

(B) (C) haemorrhage from new vessels

EALES’ DISEASE

Complications include tractional retinal detachment,

rubeosis iridis, glaucoma and cataract.

.The treatment includes systemic corticosteroids,

antituberculosis treatment, laser photocoagulation of the

ischemic retina, and pars plana vitrectomy in cases of no

resolving vitreous hemorrhage or tractional retinal

detachment.

The visual prognosis is good in the majority of cases.

D) NEURO-OPHTHALMIC MANIFESTATIONS

The optic neuropathy develops either from direct

infection induced by the mycobacteria or from a

hypersensitivity to the infectious agent.

The involvement may manifest as an optic nerve

tubercle, papillitis, papilledema, optic neuritis,

retrobulbar neuritis, neuroretinitis.

• Clinical features

1. Sudden painful loss of vision

2. Vitreous haze

3. Hyperemia of the disc

4. blurring of disc margins

5. optic atrophy

• Treatment

– Systemic steroids: methyl prednisolone 1g IV

– ATT

E) DRUG-RELATED OCULAR TOXICITY IN TB-

INFECTED PATIENTS

1 )Ethambutol.

Ocular toxic effects include optic neuritis, colour vision

abnormalities and visual field defects.

Toxicity is dose- and duration-dependent; the incidence is

up to 6% at a daily dose of 25 mg/kg and rare with a daily

dose not exceeding 15 mg/kg.

Toxicity typically occurs within 3–6 months of starting

treatment.

2) Rifampicin - orange-red discoloration of tears

3) Isoniazid

Optic neuritis

Steven Johnson syndrome involving lids and

conjunctiva

4) Rifabutin used for the treatment of pulmonary

tuberculosis may in itself cause anterior uveitis .

COMPLICATIONS OF OCULAR TB

Cataract

Glaucoma

Cystoid

Macular edema

Retinal detachment

Corneal Scarring

DIFFERENTIAL DIAGNOSIS OF OCULAR TB

Infectious Disorders Noninfectious Disorders

Syphilis

Toxoplasmosis

Toxocariasis

Candidiasis

Brucellosis

Leprosy

Nocardiasis

Coccidiomycosis

Leptospirosis

Cat scratch disease

Lyme disease

Sarcoidosis

Behçet's disease

Metastasis

Tumors

Autoimmune vasculitis

DIAGNOSIS

Confirmation of the diagnosis is a challenge since

intraocular tissue or fluids are examined rarely. The

diagnosis of ocular tuberculosis has thus remained largely

presumptive and dependent on associated systemic

infection. Owing to large variations in the clinical spectrum,

it is difficult to diagnose the disease based on clinical

findings alone.

The diagnosis is typically made based on the clinical

presentation in conjunction with corroborative evidence,

direct evidence, and therapeutic response

DIAGNOSIS

I. Clinical signs

II. Ocular investigations

III. Systemic investigations

IV. Exclusion of other uveitis entities

V. Therapeutic test

VI. New diagnostic assays

I. CLINICAL SIGNS

Presence of features of any one of the following: uveitis,

cyclitis ,choroiditis retinitis ,retinal vasculitis, neuro-

retinitis ,optic neuropathy, endophthalmitis and pan-

ophthalmitis

An intractable disease course with multiple recurrences

on nonspecific treatment (corticosteroids) is a clue

suggesting a possible tubercular etiology.

II. OCULAR INVESTIGATIONS

a. Demonstration of AFB by microscope or culture

of M tuberculosis from the intraocular

fluid/tissue-media.

b. Positive polymerase chain reaction from

intraocular fluids for IS 6110 or other

conserved sequences in M.tuberculosis genome.

III. SYSTEMIC INVESTIGATIONS

a. Positive Mantoux reaction

b. Evidence of healed or active tubercular lesion on

radiography of the chest.

c. Evidence of confirmed active extrapulmonary

tuberculosis (either by microscopic examination or by

culture of the affected tissue for M tuberculosis).

IV. EXCLUSION OF OTHER UVEITIS ENTITIES

Other causes of uveitis must be excluded by various

laboratory investigations including serology for syphilis,

toxoplasmosis, sarcoidosis, and others.

V. THERAPEUTIC TEST

A positive response to 4-drug ATT (isoniazid, rifampicin,

ethambutol, and pyrazinamide) over a period of 4 to 6

weeks can be diagnostic.

Therapeutic trial with single drug isoniazid should be

avoided due to risk of development of resistance.

NEW DIAGNOSTIC ASSAYS

Interferon-g release assays (IGRA)

It based on the in vitro assays that measure interferon-g released

by sensitized T cells after stimulation by Mycobacterium

tuberculosis antigens.

Two kits are available commercially:

TSPOT. TB test (Oxford Immunotec Ltd, Oxford, UK) and the

QuantiFERON —TB GOLD (QFTG: Cellestis Ltd, Carnegie, Australia)

TREATMENT

The treatment of tuberculosis is complex ,high levels of

patient adherence are required.

Inappropriate management can result in life-threatening

consequences as well as drug resistance.

A multiple drug regimen is recommended to avoid

resistance.

Addition of ATT to corticosteroids in uveitis patients with

latent/manifest TB also leads to significant reduction in

recurrences of uveitis (Bansal et al 2008).

Systemic corticosteroids used for the first 4–6 weeks,

together with ATT, may limit damage to ocular tissues caused

from delayed type hypersensitivity.

However, one should avoid using corticosteroids alone

without concomitant ATT as the corticosteroids may promote

multiplication of bacilli, leading to panophthalmitis or they

may cause a flare-up of systemic tuberculosis by activating a

latent infection.

SYSTEMIC SIDE EFFECTS OF ATT

Close follow-up and monitoring of the liver function tests

and renal function are also mandatory.

ISONIAZID

Hepatotoxicity

Elderly, slow acetylators more prone

Polyneuropathy

Prevented by concurrent pyridoxine

Rashes, acne

Heamatological –haemolytic anaemia in G6PD deficiency

RIFAMPICIN

Mild elevation of liver enzymes – common

Rashes, hepatotoxicity, thrombocytopenia

Orange discoloration of urine, sweat, tears

Potent CYP-P450 inducer- reduce the serum level of

drugs warfarin, oestrogen but can potentiate the action

of neuromuscular blocking agents

PYRAZINAMIDE

GI disturbances

Hepatotoxicity

Hyperuricaemia – gout

Arthralgia

SUMMARY

Incidence of ocular tuberculosis – 1.4%

• Involves all the ocular structures except lens

• Most common manifestation

Chroiditis, Anterior Uveitis, sclerokeratitis.

• Consider the diagnosis of TB especially in patients presenting with

occlusive retinal vasculitis & choroiditis.

• All patients on ATT should be screened for ocular toxicity