Drug induced maculopathy

From EyeWiki


Patterns of retinal toxicity

Patterns of retinal toxicity
Disruption of the retina and retinal pigment epithelium
Vascular damage Vascular damage Crystalline retinopathy Uveitis

Phenothiazine
Quinine sulfate
Thioridazine
Clofazimine
Cholopromazine
Deferoxamine
Chloroquine derivatives
Corticosteroid
Chloroquine
Cisplatin & carmustine

Hydroxychloroquine

Aminogycoside
Interferon
Ergot derivatives
Talc
Phenylpropanolamine
Oral contraceptives
Cystoid macular edema
Epinephrine
Latanoprost
Nicotinic acid
Sulfa derivatives
Hydroxychlorothiazide
Acetazolamide
Triamterene
Metronidazole
Chlorthalidone

Tamoxifen
Talc
Canthaxanthine
Nitrofurantoin
Methoxyflurane


Rifabutin
Cidofovir



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 retinal pigment epithelium (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 layers 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

Updated recommendation for screening

American Academy of Ophthalmology (https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h)

  • Pattern of Retinopathy: Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage.
  • Dose: We recommend a maximum daily HCQ use of 5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using 2.3 mg/kg real weight.
  • Risk of Toxicity: The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year.
  • Major Risk Factors: High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen.
  • Screening Schedule: A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors.
  • Screening Tests: The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus.
  • Toxicity: Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication.
  • Counseling: Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

Symptoms

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.

Signs

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.

lens - white flake-like posterior lens opacity

uvea - decreased accommodation due to its effects on ciliary body

Bull's - eye maculopathy stages –

  1. Premaculopathy- normal Visual acuity (VA). i. loss of foveal reflex ii. fine granular changes at the macula, seen better with red green filter iii. may be associated with small scotomas to a red target or amsler’s grid iv. reversible
  2. 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
  3. Established maculopathy - moderate reduction VA (6/18-6/24), Bull’s eye lesion in the macula
  4. Severe maculopathy - marked reduction VA (6/36-6/60), widespread RPE atrophy surrounding the fovea
  5. 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

Diagnostic procedures

  • Amsler’s Grid –
    • Red amsler may detect 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

Major risk factors for chloroquine retinopathy

Reused, with permission, from American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy, Revised 2016. The Ophthalmic News and Education Network, American Academy of Ophthalmology. https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h. Accessed December 17, 2018.

Screening frequency

Reused, with permission, from American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy, Revised 2016. The Ophthalmic News and Education Network, American Academy of Ophthalmology. https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h. Accessed December 17, 2018.

Recommended screening tests for chloroquine retinopathy

Reused, with permission, from American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy, Revised 2016. The Ophthalmic News and Education Network, American Academy of Ophthalmology. https://www.aao.org/clinical-statement/revised-recommendations-on-screening-chloroquine-h. Accessed December 17, 2018.

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 –

  1. Early stage – normal or mild granular pigment stippling, posterior to the equator
  2. Intermediate – salt & pepper pigmentry disturbance in the mid periphery & posterior pole. Focal loss of RPE & choriocapillaris
  3. 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

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, punctate retinal pigmentary changes

Work up

  • FFA – late focal staining in the macula consistent with CME.
  • ERG – decreased photopic & scotopic a & b wave amplitude.


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 low 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 punctate 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 contraceptive

CRVO, CRAO, Cilioretinal artery occlusion have been reported.

Aminoglycoside

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 granulocytes

Risk factors for retinopathy- Injection directed towards posterior pole with the bevel toward the retina, Increased rate of 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/macular infarct.

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 aphakic and pseudophakic eye.

Nicotinic acid

Niacin used in high doses to reduce serum lipid & cholestrol levels. Blurred vision & paracentral scotoma. FFA – the CME may not leak

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 prepararation

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

Causes anterior uveitis, posterior vitritis and retinal vasculitis

Cidofovir

Used in the 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.

References

  1. Albert & Jakobiec's Principles & Practice of Ophthalmology, 3rd Edition
  2. The Retina - Stephen Ryan , 3rd Edition
  3. Drug-induced ocular disorders. Drug Saf. 2008;31(2):127-41.
  4. Drug-induced maculopathy, Int Ophthalmol Clin. 1999 Fall;39(4):67-82.