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Chloroquine/Hydroxychloroquine Toxicity

CHRONIC — Retina

Symptoms

  • Often asymptomatic in early stages (detected only on screening).
  • Decreased central vision and abnormal color vision (late-stage).
  • Reported paracentral scotomas.
  • Reduced dark adaptation.

Clinical Findings

Bull's-eye maculopathy (late-stage)

  • Annular ring of parafoveal RPE atrophy surrounding a preserved foveal island.
  • Represents end-stage, irreversible anatomic injury and photoreceptor loss.

Structural signs (sd-OCT & faf)

  • "Flying-saucer sign": Parafoveal loss of the ellipsoid zone (EZ) with preservation beneath the fovea, making the central EZ look like a hovering saucer.
  • Outer nuclear layer thinning typically precedes EZ loss.
  • Fundus Autofluorescence (FAF): Early perifoveal hyperautofluorescence (RPE stress) progressing to hypoautofluorescence (atrophy).

Functional signs (vf & mferg)

  • 10-2 Humphrey Visual Field: Earliest detectable finding is a reproducible paracentral scotoma (2°–8° from fixation).
  • Multifocal ERG (mfERG): Depressed central/paracentral responses; often abnormal before VF or OCT changes.

Ethnicity-dependent patterns

  • White/European patients: Toxicity concentrates in the parafovea (2°–8° ring).
  • Asian patients: Toxicity often affects the pericentral/mid-peripheral retina (8°–15° ring).
  • Clinical note: 10-2 VF may miss Asian-pattern toxicity; use 24-2 or 30-2 and wider-field OCT.

Corneal verticillata (vortex keratopathy)

  • Golden-brown intraepithelial whorls radiating from below the pupillary axis.
  • Marker of drug exposure only; non-sight-threatening and reversible upon cessation.

Risk factors

  • Duration of use >5 years.
  • Dose >5 mg/kg of real (not ideal) body weight per day.
  • Renal insufficiency (decreased drug clearance).
  • Concomitant Tamoxifen use (synergistic toxicity).
  • Pre-existing macular or retinal disease.

Etiology

Mechanism

  • Chronic use of hydroxychloroquine (Plaquenil) or chloroquine.
  • Drug binds to melanin in the RPE, causing chronic lysosomal dysfunction and eventual photoreceptor damage.

Progression

  • Damage is not reversible and may continue to progress after drug discontinuation due to slow release from RPE melanin.

Red Flags

  • Parafoveal EZ thinning or disruption on OCT: Indicates early toxicity.
  • Reproducible paracentral scotoma on 10-2 VF: Toxicity present even if fundus looks normal.
  • Daily dose >5 mg/kg real body weight: Significantly increases toxicity risk.
  • Renal failure: Requires more frequent screening and lower dosing.

Investigations

Baseline evaluation (within 1 year of start)

  • BCVA and dilated fundus exam.
  • Baseline 10-2 VF (24-2 for Asians) and SD-OCT.
  • Fundus photography for longitudinal comparison.

Annual screening (begin at year 5)

  • Primary tests: Automated 10-2 VF and SD-OCT.
  • Asian patients: Use 24-2 or 30-2 VF and wide-angle OCT scans.
  • Adjuncts: mfERG (most sensitive functional test) and FAF.
  • Protocol: Confirm any abnormality with a second test/modality before diagnosing toxicity.

Treatment

Medication management

  • Discontinue the offending drug in coordination with rheumatology.
  • Switch to an alternative disease-modifying agent.

Dose optimization (prevention)

  • Maintain dose ≤5 mg/kg real body weight/day.
  • Adjust for renal impairment and avoid Tamoxifen if possible.

Supportive care

  • Counsel patient that vision may continue to decline slightly after stopping the drug.
  • Provide low-vision rehabilitation for advanced cases.

Clinical Pearl

Toxicity is dose- and duration-dependent. Always dose by real body weight (≤5 mg/kg). The screening goal is to catch outer-retinal changes on OCT or VF long before the classic "bull's-eye" becomes visible on exam.

Differential Diagnosis

  • Cone dystrophy
  • Stargardt disease
  • Batten disease
  • Spielmeyer-Vogt syndrome

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