Ophthalmology – Hydroxychloroquine (Plaquenil) Retinal Toxicity

Basics

Description

Hydroxychloroquine (HCQ; Plaquenil) retinopathy is a potentially irreversible toxic retinopathy caused by long-term exposure to hydroxychloroquine.

Chloroquine can cause a similar retinopathy but is:

• More retinotoxic
• Used much less frequently

HCQ is commonly prescribed for:

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Other connective-tissue and inflammatory disorders

The principal ophthalmic objective is:

Detect toxicity before symptomatic or funduscopically obvious retinal damage develops.

Key Modern Principle

The classic bull’s-eye maculopathy is a late finding.

Modern screening aims to identify toxicity much earlier using:

• Spectral-domain OCT
• Automated visual fields
• Fundus autofluorescence

before major visual acuity loss occurs.

Epidemiology

Retinal toxicity is strongly related to:

• Daily dose
• Duration of therapy

At recommended dosing, risk is:

• Very low during the first 5 years
• Still low during the first 10 years
• Progressively higher with prolonged therapy

Long-term exposure, particularly beyond 15–20 years, substantially increases cumulative risk.

Hydroxychloroquine vs Chloroquine

Hydroxychloroquine is preferred because it has:

Lower retinal toxicity

than chloroquine.

Both drugs can cause a similar pattern of:

• Photoreceptor injury
• RPE degeneration
• Progressive maculopathy

Major Risk Factors

The most important risk factors are:

• High daily dose
• Long duration of use
• Renal impairment
• Concomitant tamoxifen therapy
• Older age at initiation or during long-term exposure
• Preexisting macular disease that complicates screening

Daily Dose

For hydroxychloroquine, the recommended maximum dose is approximately:

≤5 mg/kg/day using actual body weight

This replaced older recommendations based on:

• Ideal body weight
• 6.5 mg/kg/day thresholds

Actual body weight is now preferred for routine HCQ dose calculation.

Chloroquine Dose

For chloroquine, an approximate recommended ceiling is:

≤2.3 mg/kg/day using actual body weight

Chloroquine carries a higher toxicity risk than HCQ.

Important Correction – Obesity

Older teaching recommended calculating HCQ dose using:

Ideal body weight

This is no longer the standard approach.

Modern screening recommendations generally use:

Actual body weight

while avoiding unnecessarily high absolute daily doses in very obese patients.

Duration of Therapy

Duration is one of the strongest predictors of toxicity.

Risk rises substantially after:

5 years of continuous treatment

and continues increasing with cumulative exposure.

Renal Disease

Hydroxychloroquine is partly cleared by the kidneys.

Reduced renal function can increase:

• Drug exposure
• Retinal toxicity risk

Therefore patients with chronic kidney disease may require:

• Dose adjustment
• Earlier and/or more frequent ophthalmic screening

Tamoxifen

Concomitant tamoxifen significantly increases the risk of HCQ retinopathy.

These patients should be considered:

Higher risk

and monitored accordingly.

Liver Disease

Severe hepatic dysfunction may alter drug metabolism, but renal function is a better-established major risk factor in contemporary screening recommendations.

Pathophysiology

The exact mechanism is incompletely understood.

HCQ accumulates within:

• Lysosomes
• RPE
• Retinal tissues

It interferes with:

• Lysosomal function
• Autophagy
• Photoreceptor–RPE metabolism

The earliest clinically detectable damage usually involves:

Outer retinal photoreceptors

particularly the:

• Ellipsoid zone
• Outer nuclear layer
• Photoreceptor outer segments

RPE damage becomes more prominent later.

Distribution of Toxicity

Two major patterns occur:

Parafoveal Pattern

Most common in many non-Asian populations.

Damage forms a ring approximately:

2–6° from fixation

Pericentral Pattern

More common in patients of:

Asian ancestry

Damage occurs farther from the fovea, often along the vascular arcades.

This is critically important when selecting:

• Visual field strategy
• OCT scan width
• FAF imaging area

Clinical Presentation

Early toxicity is usually:

Asymptomatic

This is why screening is essential.

When symptoms occur they may include:

• Difficulty reading
• Paracentral missing areas
• Blurred vision
• Metamorphopsia
• Reduced contrast
• Glare
• Central or paracentral scotoma

Visual Acuity

Central acuity may remain:

Normal until relatively late

because the fovea can remain structurally preserved during early parafoveal disease.

Therefore:

Normal 20/20 acuity does not exclude HCQ toxicity.

Fundus Examination

Early toxicity may show:

• No visible abnormalities

Later disease may show:

• Parafoveal pigmentary changes
• RPE mottling
• RPE atrophy

Advanced disease produces the classic:

Bull’s-eye maculopathy

Bull’s-Eye Maculopathy

The classic appearance consists of:

• Central relative foveal preservation
• Surrounding ring of RPE atrophy
• Outer surrounding pigmentary change

This represents:

Established, relatively advanced toxicity

and should not be the stage at which screening first detects disease.

Advanced Toxicity

Severe disease may eventually produce:

• Diffuse RPE atrophy
• Vascular attenuation
• Peripheral retinal degeneration
• Optic disc pallor

At this stage, vision may be severely and permanently affected.

Screening Principles

The goals of screening are to identify:

Definite early toxicity before irreversible central visual loss

while avoiding unnecessary discontinuation of a systemically valuable drug based on an equivocal test.

Abnormal findings should therefore be:

• Reproducible
• Corroborated by complementary structural or functional testing

before recommending drug cessation whenever possible.

Baseline Examination

A baseline ophthalmic examination should be performed soon after starting long-term HCQ therapy.

The baseline helps identify:

• Preexisting macular disease
• Abnormal visual fields
• Structural abnormalities that may later mimic toxicity

Baseline assessment typically includes:

• Dilated fundus examination
• SD-OCT
• Often FAF and/or visual field testing depending on practice and risk

When to Begin Annual Screening

For patients taking an appropriate dose and without major risk factors:

Annual screening generally begins by 5 years of therapy.

Earlier annual screening is appropriate when major risk factors are present, such as:

• High daily dose
• Renal disease
• Tamoxifen therapy
• Significant preexisting retinal disease

Primary Screening Test – OCT

Spectral-domain OCT is one of the most important modern screening tests.

Early findings include:

• Parafoveal outer nuclear layer thinning
• Ellipsoid-zone disruption
• Photoreceptor outer-segment loss
• Relative central foveal preservation

Flying-Saucer Sign

Advanced parafoveal outer retinal loss with relative foveal preservation may produce the classic OCT:

“Flying saucer” sign

However:

This is not an early sign and should not be required to diagnose toxicity.

Modern screening aims to detect disease before this develops.

OCT in Pericentral Disease

Routine narrow macular OCT scans can miss pericentral toxicity.

In patients at risk for a pericentral phenotype, particularly Asian patients, use:

• Wider OCT scans
• Scans extending beyond the central macula
• Correlation with wide-field FAF

Automated Visual Fields

Visual field testing detects functional loss.

Typical early abnormalities include:

• Paracentral scotomas
• Partial ring scotoma

These can become:

• Complete parafoveal ring scotomas
• Central defects in advanced disease

10-2 Visual Field

For typical parafoveal toxicity:

Humphrey 10-2

is commonly used because it densely samples the central macula.

Wider Visual Fields

When pericentral toxicity is possible, consider:

• 24-2
• 30-2
• Other wider-field strategies

because a 10-2 alone may miss disease occurring farther from fixation.

Visual Field Reliability

Visual fields are subjective and may produce:

• Learning effects
• Fixation artifacts
• False positives

A suspicious field abnormality should usually be:

Repeated and correlated with OCT or another objective test.

Fundus Autofluorescence

FAF is useful for mapping the distribution of RPE stress and damage.

Possible findings include:

Earlier Disease

• Parafoveal or pericentral hyperautofluorescence

Later Disease

• Hypoautofluorescence from established RPE loss

Wide-field FAF is particularly useful for:

Pericentral toxicity

Multifocal ERG

mfERG objectively assesses localized retinal function.

It may demonstrate:

• Reduced parafoveal responses
• Ring-like functional depression

It is particularly useful when:

• Visual fields are unreliable
• OCT and field findings disagree
• Confirmation of suspected toxicity is needed

It is generally a:

Confirmatory rather than universal first-line test.

Full-Field ERG

Full-field ERG is usually:

• Normal in early disease

because early HCQ toxicity is localized to the macula or pericentral retina.

It becomes abnormal mainly in:

Advanced widespread retinopathy

and is not a routine screening test.

Electrooculography

EOG has:

No significant routine role in modern HCQ screening.

Amsler Grid

Amsler grid testing is insufficiently sensitive for early toxicity.

It should not replace modern screening with OCT and automated perimetry.

Color Vision

Color vision testing is:

• Nonspecific
• Usually abnormal only later

It is not a primary modern screening test.

Fundus Photography

Photography may document:

• Pigmentary change
• Bull’s-eye maculopathy

but is relatively insensitive for early toxicity.

Fluorescein Angiography

FA is not routinely useful for early screening.

It may demonstrate:

• Window defects
• RPE atrophy

in established disease.

Diagnostic Pattern

A convincing diagnosis often involves concordant abnormalities such as:

Typical OCT outer retinal loss + matching visual field defect

or:

OCT abnormality + corresponding FAF/mfERG abnormality

Differential Diagnosis

HCQ toxicity may mimic:

• Age-related macular degeneration
• Pattern dystrophy
• Stargardt disease
• Cone dystrophy
• Cone–rod dystrophy
• Macular telangiectasia type 2
• Epiretinal membrane-related field/OCT changes
• High myopia
• Other toxic retinopathies

HCQ Toxicity vs AMD

HCQ toxicity favors:

• Bilateral symmetric parafoveal/pericentral outer retinal loss
• Ring-like distribution
• Relative early foveal preservation

AMD more commonly shows:

• Drusen
• Pigment epithelial detachments
• Sub-RPE deposits
• Geographic atrophy in a different distribution

HCQ Toxicity vs Pattern Dystrophy

Pattern dystrophy may produce:

• Lipofuscin abnormalities
• RPE pigment patterns
• Vitelliform material

but usually lacks the classic symmetric parafoveal outer retinal loss pattern seen in HCQ toxicity.

Treatment

There is:

No proven treatment that reverses established HCQ retinal toxicity.

The key intervention is:

Stopping the offending drug before severe damage occurs.

Drug Discontinuation

When toxicity is considered definite or highly likely:

• Communicate promptly with the prescribing physician
• Discuss discontinuation or substitution

HCQ should not usually be stopped casually on a single questionable screening abnormality because it may be medically important for control of:

• Lupus
• Rheumatoid arthritis
• Other systemic disease

Ophthalmologist–Prescriber Collaboration

The ophthalmologist should communicate:

• Whether toxicity is definite, probable, or uncertain
• Severity
• Structural progression
• Functional involvement

The prescribing physician weighs this against:

• Systemic disease control
• Alternative therapies
• Risk of stopping HCQ

Dose Reduction

If toxicity is not present but the daily dose is excessive, consider discussing:

Dose reduction to ≤5 mg/kg/day actual body weight

with the prescribing clinician.

Progression After Drug Cessation

An important feature is:

HCQ retinopathy may continue to progress after the medication is stopped.

This occurs because:

• Drug persists in tissues
• Established retinal injury may continue biologically

Progression is most likely when toxicity is already:

• Severe
• Associated with RPE damage

Early Toxicity After Cessation

When toxicity is detected before significant RPE loss:

• Progression may be limited
• Central vision may remain good

However, true structural damage generally does not simply regenerate.

Thus the goal is:

Preservation rather than reversal.

Important Correction – “Reversible Premaculopathy”

Older literature suggested that early toxicity might reverse completely after drug cessation.

Modern understanding is more cautious:

Established HCQ retinal toxicity is generally considered irreversible.

Early detection prevents progression to disabling disease rather than reliably restoring damaged photoreceptors.

Follow-Up After Toxicity

Patients with confirmed toxicity should continue ophthalmic monitoring even after stopping HCQ.

Follow with:

• OCT
• Visual fields
• FAF

because progression can continue.

Other Ocular Effects

HCQ and especially chloroquine may cause:

• Corneal epithelial deposits / vortex keratopathy

These deposits are usually:

• Reversible
• Not predictive of retinal toxicity
• Rarely visually significant

Corneal Verticillata

Drug-related corneal deposits can appear as:

Whorl-like epithelial lines

They do not require stopping HCQ unless:

• Symptoms are significant
• Other toxicity is present

Accommodation and Lens Effects

Older chloroquine literature described:

• Accommodation abnormalities
• Lens changes

These are much less clinically important than retinal toxicity with modern HCQ use.

Patient Education

Patients should understand:

• Why screening is needed
• That early toxicity may be asymptomatic
• That retinal damage can be irreversible
• The importance of attending scheduled screening

Patients should report:

• New paracentral missing areas
• Reading difficulty
• Metamorphopsia
• Unexplained visual decline

Prognosis

Prognosis depends mainly on:

Stage at which toxicity is detected

Early Detection

If detected before major RPE damage:

• Central acuity may remain excellent
• Progression after cessation is often limited
• Long-term functional vision can remain good

Advanced Disease

If bull’s-eye maculopathy or extensive RPE loss is already present:

• Visual field loss may progress
• Central vision may eventually decline
• Structural progression can continue despite stopping the drug

Complications

The major complication is:

Permanent bilateral visual impairment

Advanced toxicity may cause:

• Central/paracentral scotomas
• Reading difficulty
• Reduced contrast sensitivity
• Extensive macular atrophy

Ophthalmology Pearls

• Hydroxychloroquine retinal toxicity is dose- and duration-dependent and may be irreversible.
• The modern recommended HCQ dose is approximately ≤5 mg/kg/day using actual body weight, not the older 6.5 mg/kg ideal-body-weight rule.
• Major risk factors are high daily dose, long duration, renal disease, and tamoxifen use.
• Early toxicity is usually asymptomatic with normal visual acuity and a normal-looking fundus.
• Bull’s-eye maculopathy is a late sign, not the goal of screening.
• SD-OCT is a cornerstone of modern screening, looking for parafoveal or pericentral outer retinal damage.
• Use 10-2 fields for typical parafoveal disease, but wider fields such as 24-2/30-2 are important when pericentral toxicity is possible.
• Asian patients are more likely to develop pericentral toxicity, so screening must extend beyond the central macula.
• FAF helps map the topographic extent of disease; mfERG is useful for objective confirmation when results are equivocal.
• Amsler grid, color testing, EOG, and fluorescein angiography are not adequate primary screening tests for early toxicity.
• Patients at standard dose without major risk factors generally begin annual screening by 5 years of therapy; high-risk patients require earlier surveillance.
• Do not stop HCQ solely on one questionable test—confirm toxicity whenever possible and coordinate with the prescribing physician.
• Once true retinopathy is established, retinal damage is generally not reversible and may continue to progress even after HCQ is discontinued.