Ocular side effect of systemic drugs

Systemic steroids

➢ Uses:
• Systemic steroids are used in wide variety of diseases for long term period.
• They are mainly used as
(1) Anti-inflammatory
(2) Immuno-modulator or
(3) Steroid replacement therapy
• They are used in conditions like Bronchial asthma, Interstitial lung disease (ILD), Sarcoidosis. Collagen or auto-immune diseases of skin and joint like Rheumatoid arthritis, systemic lupus erythematosus, and replacement therapy Addison’s diseases. 

➢ Ocular side effects:
The most common ocular side effects due to steroids are
1. Formation of lens opacities (cataract)

2. Steroid-induced glaucoma. 

1. Steroid cataract: both systemic and topical are cataractogenic.
• Incidence:
▪ The exact relationship between the total daily dose and duration of steroid administration and the risk of cataract formation is not clear.There is no clear cut safe dose or duration limit.
▪ Patients receiving maintenance dose of less than l0 mg/day of prednisone (or equivalent) or treated for less than 4yrs may be consider immune.Patients on alternate day therapy have relatively lesser risk.

 
• Clinical features:
▪ Steroid-induced lens changes start in the posterior subcapsular part as vacuoles which turn into opacities.
▪ Opacities then develop in the anterior subcapsular region. (lens opacities are initially posterior subcapsular and later anterior subcapuslar region affected.)
▪ If steroid therapy is continued, the entire lens may become opaque and the pupil white (mature cataract). 

• Management:
▪ If possible, steroid therapy should be reduced to minimum possible dose or changed to alternate-day therapy.
▪ Regression of early opacities may occur when the drug is stopped or reduced, although progression may occur despite withdrawal.
▪ Patients with mature cataract need surgery.
▪ The results of surgery are excellent in the absence of other serious eye pathology 

2. Steroid-induced glaucoma:
▪ The prolonged use of strong topical steroids (e.g. dexamethasone, betamethasone) causes an elevation of intraocular pressure in about 30% of the general population while the incidence is relatively less with systemic steroids.
▪ It necessary for patients on systemic steroids to have their intraocular pressures measured by an ophthalmologist periodically or if they are symptomatic.

Chloroquine, Hydroxychloroquine:

➢ Uses 

• Prophylaxis and Treatment of malaria.
• As well as in the treatment of certain Rheumatological diseases like : Rheumatoid arthritis, Juvenile chronic arthritis, Systemic lupus erythematosus.
• Dermatological diseases like: Discoid lupus
• Sarcoidosis: for control calcium abnormalities 

➢ Ocular side effects
▪ The most common ocular side effects due to chloroquine are:
    1. Maculopathy 

    2. Keratopathy 

Antimalarials are excreted from the body very slowly. 

They are melanotropic drugs that become concentrated in melanin-containing structures of the eye, such as RPE & choroid.
; a cumulative dose of less than 100 g or treatment duration under 1 year is rarely associated with retinal damage. The risk of toxicity increases significantly when the cumulative dose exceeds 300 g (i.e. 250 mg daily for 3 years). 

1. Maculopathy
▪ Incidence 

- The incidence of retinal damage is dose related. The normal daily dose is 250 mg 

- Chloroquine retinotoxicity is related to the total cumulative dose. 

- A cumulative dose of less than 100 gm of chloroquine or a duration of treatment of less than 1 year is rarely associated with retinal damage. 

- The risk of toxicity increases significantly when the dose exceeds 300 gm (i.e. 250mg daily for 3 years). 

- Hydroxychloroquine appears to be safer than chlorquine as the incidence of retinal toxicity is lower and, it is usually mild and non-progressive.

Clinical features: Ocular manifestations: 

Vortex Keratopathy (cornea verticillata)
-Chloroquine keratopathy is due to the deposition of the drug in the corneal epithelium, but unlike chloroquine maculopathy, it is not dose related. 

-Vortex keratopathy (cornea verticillata) is characterized by whorl-like corneal epithelial deposits.

-Bilateral, fine greyish or golden-brown opacities in the inferior corneal epithelium.

-A whorl-like pattern which originates from a point below the pupil and swirls outwards, sparing the limbus.

-In the vast majority of cases the keratopathy is innocuous. 

-Rarely it may cause symptoms of haloes and slight visual impairment.

-The changes are usually reversible on cessation of therapy. 

The corneal changes consist of bilateral and symmetrical greyish or golden deposits in the superficial corneal epithelium that appear in a vortex fashion from a point below the pupil and swirl outwards therefore also called vortex keratopathy or cornea verticillata.

Chloroquine retinopathy can be divided into following stages:

1. Premaculopathy:
Characterized by normal visual acuity, and 

a scotoma to a red target located between 4° and 9° of fixation. 

Color vision defect – both mild blue green and proton red-green defect. ( most sensitive test)

The visual function usually return to normal if the drug is stopped.

2. Established maculopathy: next stage.
Characterized by slightly reduced visual acuity, (6/9 to 6/12) 

Fundus : loss of the foveolar reflex and a subtle parafoveal halo RPE pallor. (retinal pigment epithelial) These changes are usually non-progressive if the drug is stopped. 

3. Bull's eye maculopathy:
Characterized by moderately reduced visual acuity ( 6/18 – 6/24) 

Bull’s eye macular lesion: central foveolar island of hyperpigmentation surrounded by depigmented zone of RPE atrophy, which encircled by a hyperpigmented ring. 

FFA: shows RPE window defect due to RPE atrophy. 

This stage may progress even if the drug is stopped.

4. Severe maculopathy:
Characterizedby marked reduction of visual acuity (6/36- 6/60) 

with widespread retinal pigment epithelial RPE atrophy surrounding fovea.

5. End-stage maculopathy:
Characterized by severe reduction of visual acuity and 

marked atrophy of the retinal pigment epithelium with unmasking of the larger choroidal blood vessels. The retinal arterioles may also become attenuated and 

pigment clumps develop in the peripheral retina. 

These changes are irreversible. 

▪ Screening Test: At present there is no single test that is sufficiently reliable to rule out early maculopathy. Recording of visual acuity and ophthalmoscopy are routinely done to detect early maculopathy.

Ethambutol

➢ Uses
• Ethambutol is used in combination with isoniazid or rifampicin in the treatment o f tuberculosis.
• The normal dose is 25 mg/kg per day for the first 2 months and 15 mg/kg per day thereafter. 

➢ Ocular side effects:
1. Optic Neuropathy (optic neuritis) 

2. Visual field defects 

3. Colour vision abnormalities.

Toxicity is dose and duration dependent 

Optic neuropathy develops in about 1% cases with a dose of 15 mg/kg per day and 

in about 6% cases with a dose of 25 mg/kg per day. 

Toxicity typically occurs within 3-6 months of starting treatment. 

The risk is increased with higher doses, particularly in patients with impaired renal function.

Ocular manifestation: 

Presentation of optic neritis is with abrupt visual impairment.
• Visual loss is usually sudden and dramatic with impairment of Colour perception especially to red/green.

Sign: The optic disc may either be normal or there may be oedema and splinter-shaped haemorrhages.
• Although a variety of visual field defects may occur the most common is a temporal defect.

Visual field defects are of two types : 

- Central type involves the maculopapular bundle and results in
    - decreased visual acuity, 

    - central or centrocaecal scotomas 

    - and impairment of blue-yellow colour vision. 

- Peripheral type causes peripheral visual field constriction and red-green dyschromatopsia.

Prognosis is good following cessation of treatment. Although it may take upto 12 months.
▪ Recovery is the rule once the drug is stopped, although this is frequently very slow and may take up to 12 months. 

Screening
▪ Repeated at every 4-weekly intervals, if the dose is more than 15 mg/kg.
▪ Particularly in patients with impaired renal function.
▪ The patient should be advised to stop taking the drug immediately on development of visual symptoms.
▪ Unfortunately, there is no test that can identify patients who will develop optic neuropathy.
▪ If the daily dose exceeds 15 mg/kg, a baseline ophthalmic examination should be performed before starting treatment.