DRUG INDUCED MACULOPATHY: A quick Look
Dr. Jay Chhablani, MS, DNB, FMRF
Consultant, Smt Kanuri Santhamma Retina Vitreous Centre
Generally all the drugs are likely to have some side effects.For ophthalmologists,it is essential to know the drugs which affects the vision or involves the eye as a part of their sideeffects.This is a summary of the drugs causing damage to posterior segment of the eye.
Patterns of retinal toxicity:
Disruption of the retina |
Vascular damage |
Retinal folds |
Crystalline retinopathy |
Uveitis |
Phenoithiazine |
Cisplatin & carmustine |
Sulfa derivatives |
Tamoxifen |
Rifabutin |
Miscellaneous |
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Digoxin |
CHLOROQUINE AND HYDROXYCHLOROQUINE
Chloroquine and its derivative, hydroxychloroquine sulfate, which have been useful in treating malaria and in larger doses, collagen-vascular disease, cause a cumulative dose-related pigmentary retinopathy.
Mechanism - Inhibition of critical enzymes & interference with the metabolic functions of RPE & photoreceptors. Both drugs apparently have a selective affinity for melanin, so it gets concentrated in RPE & uveal tissue & is retained for long periods, even after its usage is stopped.
Histopathologic changes - earliest histopathologic change, even before RPE damage, appears to be membranous cytoplasmic bodies in ganglion cells and degenerative changes in photoreceptor outer segments.
- Loss of RPE pigmentation
- Accumulation of pigment laden cells in outer retinal laures
- Damage & reduction of photoreceptors
Incidence – It increases with daily dose & duration & varies from 1-28% without any predilection for any particular age, sex or race.
Risk factors for retinopathy
Chloroquine :
Daily dose > 3.5 mg/kg/day or > 250mg/day
Cumulative dose > 100gms
Duration of treatment >1yr
Evidence of renal & hepatic insufficiency
Hypdroxychloroquine :
Daily dose > 6.5 mg/kg/day or > 400 mg/day
Duration of treatment >1yr
Evidence of renal & hepatic insufficiency
Daily dose is the most important factor
Symptoms: can be asymptomatic.Earliest symptoms - difficulty in reading/ fine tasks due to central / paracentral scotomas.Gradually these enlarge & involve fixation, reducing visual acuity later.Other symptoms- metamorphopsia, red-green haloes, cycloplegia, amblyopia, photophobia, flickering of yellow lights.
Ocular signs
Cornea - Vortex Keratopathy:consists of grayish or golden brown corneal epithelial deposits. They are innocuous, completely reversible & not related to dose or duration. 50% patients may have decreased corneal sensation. They start at a point below the pupil & gradually swirl outwards sparing limbus.
poliosis
Lens - white flake-like posterior lens opacity
Uvea - decreased accommodation due to its effects on ciliary body
Bull's - eye maculopathy
Stages –
- Premaculopathy- normal VA
- loss of foveal reflex
- fine granular changes at the macula, seen better with red green filter
- may be associated with small scotomas to a red target or amsler’s grid
- reversible
- Early maculopathy – modest reduction VA (6/9-6/12)
- central foveal pigmentation surrounded by concentric depigmented zone of RPE atrophy, horizontally oval & more prominent inferior to the fovea. This is in turn encircled by a hyperpigmented ring.
- On FFA – window defect due to RPE atrophy
- Irreversible
- Established maculopathy - moderate reduction VA (6/18-6/24),Bull’s eye lesion in the macula
- Severe maculopathy - marked reduction VA (6/36-6/60), widespread RPE atrophy surrounding the fovea
- End stages - severe reduction VA ,marked RPE atrophy with unmasking of choroidal vessels
peripheral pigment irregularity with bone spicule formation, vascular attenuation & optic disc pallor.
Work up
- Amsler’s Grid – excellent screening tool
- Red amsler is a sensitive method for detecting an early paracentral scotoma
- Weekly self monitoring
- Perimetry – static perimetry with a red target – best
- threshold static perimetric examination reveals pericentral defects in the superior vertical meridian.
- scotoma is usually a subtle & located within 10 degree of fixation
- FFA – changes seen only after the development of positive scotomas, pigment changes & loss of visual acuity.
- Early hyperfluorecence – RPE atrophy
- It should be done on all patients with preexisting macular diseases
- Dilated fundus photography- every visit
- Electrophysiologic tests – Multifocal ERG may detect toxicity at its earliest stages. There is also variability in dark-adaptometric, ERG, and electro-oculographic results. The ERG may have a reduced b wave, but in general the latter three tests reflect later, more widespread retinopathy.
- Color vision – not a very sensitive tool, may be normal in early stages. Detected at very late stages
Screening – The American academy of ophthalmology guidelines for screening:
Baseline examination- dilated fundus, amsler’s grid (weekly monitoring at home), measurement of central VF, fundus photographs.
Protocol – first five years – routine examinations (the interval determined by the patient’s age)
Annually - if patient is obese, has renal or hepatic dysfunction, has concomitant macular disease or is >60yrs of age
After 5 yrs of therapy – at least annually for all patients
Overall, hydroxychloroquine appears to be the safer drug, and should be considered if this class of medication is required for treatment.
PHENOTHIAZINES
THIORIDAZINE
This is an antipsychotic drug used in schizophrenia & related psychoes.
Risk factors for retinopathy
normal daily doses range 150 – 600mg.
toxic dose >800mg/day
Symptoms – blurred vision, dyschromatopsia (reddish or brownish discoloration of vision) & nyctalopia.
Mechanism – not known
most likely mechanism may be inhibition of oxidative phosphorylation with subsequent abnormalities in rhodopsin synthesis & its effect on dopamine receptors in retina.
Maculopathy –
- Early stage – normal or mild granular pigment stippling, posterior to the equator
- Intermediate – salt & pepper pigmentry disturbance in the mid periphery & posterior pole. Focal loss of RPE & choriocapillaris
- Late- diffuse loss of RPE & choriocapillaris, coarse pigment plaques, vascular attenuation, optic atrophy
Histopathologic examination - suggests that the initial site of damage is in the outer segment of the photoreceptors, which is then followed by degeneration of the RPE and choriocapillaries.
Work up
- Perimetry – non specific, most characteristic – paracentral or ring scotoma
- FFA – loss of RPE & choriocapillaris within the areas of depigmentation
Current recommendation for minimal effective doses – 300mg/day or less with an absolute maximum of 800mg/day for very short period of time. Toxicity is more dependent on total daily dose than on cumulative dose.If the drug is stopped early after the onset of symptoms, the patients usually report improvement in vision. However the fundus changes progress despite discontinuation of therapy.
CHLORPROMAZINE
This is a piperazine similar to thioridazine but lacks the pipedyl side chain & thus less toxic.
Risk factors for retinopathy
normal daily doses range 75-300mg
toxicity has been reported with doses of 1200 to 2400 mg/day for 1 to 2 years.
Mechanism - Inhibition of retinal enzymes and phototoxicity have been suggested as possible causes of the retinal degeneration.
Ocular signs
Anterior segment – yellowish brown pigmentary deposition in the corneal epithelium, descemet's membrane and the anterior surface of the lens.
Oculogyric crisis, miosis & blurred vision due to paralysis of accommodation .
Fundus - pigmentry changes, vascular attenuation & optic disc pallor
Toxicity is more dependent on total daily dose than on cumulative dose
