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DRUG INDUCED MACULOPATHY: A quick Look

 

Dr. Jay Chhablani, MS, DNB, FMRF
Correspondance: 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
 and retinal pigment epithelium

Vascular damage

Retinal folds

Phenoithiazine
Qunine sulfate
Thioridazine
Clofazimine
Cholopromazine
Deferoxamine
Chloroquine derivatives
Corticosteroid
Chloroquine
Cisplatin& carmustine
Hydroxychloroquine

Cisplatin & carmustine
Qunine sulfate
Aminogycoside
Interferon
Ergot derivatives
Talc
Phenylpropanolamine
Oral contraceptives
Cystoid macular edema
Epinephrine
Latanoprost
Nicotinic acid

Sulfa derivatives
Hydroxychlorothiazide
Acetazolamide
Triamterene
Metronidazole
Chlorthalidone

 

Crystalline retinopathy

Uveitis

Tamoxifen
Talc
Canthaxanthine
Nitrofurantoin
Methoxyflurane

Rifabutin
Cidofovir

Miscellaneous

Digoxin
Methanol

 

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.

  1. Loss of RPE pigmentation

  2. Accumulation of pigment laden cells in outer retinal laures

  3. 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 –

Work up

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 –

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

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.

TAMOXIFEN 

It’s a nonsteroidal estrogen antagonist used in treatment of advanced breast carcinoma & as adjuvant therapy after surgical resection of early disease.

Risk factors for retinopathy
Toxic doses – 60-100mg/day
Total dosage > 100g
Recent studies has shown that chronic low dosage (10-20mg/day) with as little as 7.7g total dose can also ocular toxicity.
Symptoms – decreased VA & color vision

Ocular signs
Anterior segment - vortex keratopathy 
Fundus – bilateral multiple, yellow, crystalline, ring like deposits in the maculae. These persists even on cessation of treatment
                macular edema
                punctuate retinal pigmentary changes

Work up

Histopathology – intraretinal deposits in the nerve fiber layer & inner plexiform layer
More numerous in the paramacular areas.
Visual function & edema improve after discontinuation of the drug, but the refractile deposits remain.

Differential diagnosis – juxtafoveal telangiectasia – FFA to rule out
In a confirmed case of tamoxifen toxicity with visual complaints, the drug must be stopped.

Since maculopathy is rare , routine screening is not needed with current loe dose therapy ( 10-20mg/day).

CANTHAXANTHINE

It is a naturally occurring carotenoid used as a tanning agent. It is also used as a food coloring agent, for skin pigmentation in vitiligo & treatment of photosensitivity in psoriasis & erythrocytic porphyrias.

Histopathology – lipid soluble crystals are found pathologically in the entire inner retina
& ciliary body.

Risk factors for retinopathy
dose related ( >19gms over 2 yrs)

Symptoms - most of the patients are asymptomatic.
Fundus – bilateral ring-shaped deposition of yellow orange crystals in the superficial retina arranged in a doughnet shape at the posterior poles surrounding the fovea.

Work up
FFA – normal

With discontinuation of treatment, deposits may slowly clear over many years.

METHOXYFLURANE

It is a inhalational anesthetic agent.

Mechanism
It is metabolized to oxalic acid which combines with calcium to form insoluble calcium oxalte salt. This is deposited in various body tissues & the RPE & inner retina in the eye.

Ocular signs
Fundus – numerous yellow-white punctuate lesions in the posterior pole & periarterially.

CLOFAZIMINE
Used to treat dapsone resistant leprosy, pyoderma gangrenosum, discoid lupus.
Symptoms
Visual acuity mildly affected, with reduced scotopic, photopic and flicker ERG amplitudes
Ocular signs – crystals may accumulate in the cornea
Bull’s eye maculopathy with pigmentary retinopathy
Cessation of treatment may result in clearence but does not appear to affect the retinopathy.

CISPLATIN & CARMUSTINE
Used for treatment of malignant glioma & metastatic breast cancer
Three types of retinal toxicity

  1. Pigmentry maculopathy with marked decreased VA, and abnormal electrophysiologic testing.

  2.  Cotton wool spots, intraretinal hemorrhages, macular exudates & optic neuropathy with disc swelling

  3. Vascular retinopathy or optic retinopathy include arterial occlusion, vasculitis & papillitis.

Other effects – orbital pain, chemosis, secondary glaucoma, internal ophthalmoplegia and cavernous sinus syndrome
Visual loss is usually progressive.


TALC
Usually occurs in intravenous abusers.
Mechanism - oral medications like methylphenidate hydrochloride (Ritalin) or methadone contains talc as inert filler material. Intravenous drug abusers crush these medications and create an aqueous suspension by adding water and heating the mixture. This solution is subsequently drawn up into syringe and injected intravenously. The talc particles embolize to the pulmonary vasculature and get trapped. After repeated injections, collateral vasculature develops, allowing the particles to enter the systemic circulation and embolizes to other organs, including the eye.
Ocular signs
Due to embolic phenomenon on retinal vasculature, a characteristic picture of an ischemic retinopathy begins to develop. Capillary nonperfusion, microaneurysm formation, cotton wool spots and venous loops.
Severe cases may develop optic disc & peripheral new vessels and vitreous hemorrhage.
Treatment - laser photocoagulation for new vessels and vitrectomy for hemorrhage.

ORAL CONTEACEPTIVE
CRVO, CRAO, Cilioretinal artery occlusion have been reported.

AMINOGYCOSIDE
Intravitreal injection for bacterial endophthalmitis, prophylactic intravitreal injection after pars plana vitrectomy, prophylactic subconjunctival injections after ocular surgery, and with the use of small amounts in the infusion fluid during cataract extraction.
Preservatives add to the toxicity.
Occurs after the inadvertent injection of massive doses.
Gentamicin is the most toxic aminogycoside followed by tobramycin and amicacin.
Mechanism
Affects the retinal vasculature.
Formation of abnormal lamellar lysosomal inclusions in the RPE.
Necrosis of outer then inner segments.

Histopathologic changes - vascular occlusion by granuocytes
Risk factors for retinopathy
Injection directed towards posterior pole with the bevel toward the retina
Increased rate off injection

Ocular signs
Superficial & intraretinal hemorrhages, retinal edema, cotton wool spots, arteriolar narrowing & venous beading
Rubeiosis iridis, neovascular glaucoma, pigmentary retinopathy and optic atrophy in late stages.
Work up
FFA – severe vascular nonperfusion in the acute stages.
Prevention by inadvertent use
If inadvertent use occurs, immediate pars plana vitrectomy with posterior segment lavage

INTERFERON
Mechanism
 Immune complex deposition & activated complement C5a with leucocyte infilteration.

Risk factors for retinopathy
More frequent in diabetic & Hypertensive patients
Changes noted within 4-8 weeks of therapy
Ocular signs
Multiple cotton wool spots with retinal hemorrhages.
Optic disc edema, BRAO, BRVO, CME
EPINEPHRINE
Macular edema in aphakic eyes.
CME indistinguishable from clinically & angiographically from postoperative ahakic CME.
CME resolves with cessation of epinephrine.
Should be avoided in the tratment of the glaucomatous aphalic and pseudophakic eye.

NICOTINIC ACID
Niacin used in high doses to reduce serum lipid & cholestrol levels.
Blurred vision & paracentral scotoma.
FFA – typical CME
With cessation of drug cme resolves, vision returns to normal.

LATANOPROST
2-5% patients develops CME , which resolves after discontinuation.

SULFA DERIVATIVES
Ciliary body swelling leads to anterior chamber shallowing.
Retinal folds as a result of vitreous traction on the macula that is caused by the forward shift of the lens & iris.
CORTICOSTEROID PREPARAEATION
 Intravitreal injections have been shown to cause retinal necrosis. Corticosteroid themselves probably have minimal toxic effects on the retina but the vehicles causes the retinal necrosis.

NITROFURANTOIN
 May cause crystalline retinopathy.
RIFABUTIN
 Used for Mycobacterium avium complex in AIDS patients
Toxic dose –……….. mg/day
Causes anterior uveitis, posterior vitritis and retinal vasculitis

CIDOFOVIR
Used I treatment of CMV retinitis
Cause anterior uveitis, hypotony and visual loss.
Fewer side effects on retina.

CARDIAC GLYCOSIDES

Direct toxicity on photoreceptors
Blurred vision, scintillating scotomas& xanthopsia.
Reversible with discontinuation of drug

METHANOL
Occasionally ingested by alcoholics
Toxicity – caused by formic acid
Visual blurring and field deficits within 18 hrs
Early fundus changes – optic nerve hyperemia & retinal edema
Late – optic atrophy
Treatment – early haemodialysis is effective in removing methanol from the body, but if visual recovery is not evident by 6 days, it often remains permanently decreased.