Ocular Findings in Hydroxychloroquine (HCQ) Toxicity

Background

Pharmacokinetics Relevant to Toxicity

Ocular Findings

1. Corneal Changes (Cornea Verticillata / Keratopathy)

• Vortex keratopathy (cornea verticillata): Whorl-like, golden-brown/grey epithelial deposits in the cornea, arranged in a swirling pattern from a point below the pupil.
• Location: Inferior corneal epithelium (Bowman's layer level).
• Symptom: Mild glare or haloes; often asymptomatic.
• Important distinction: Does NOT cause visual impairment and does NOT predict retinal toxicity. (Kanski; Khurana)
• Reversible on stopping the drug.
• Similar pattern seen with amiodarone, chlorpromazine, and indomethacin.

2. Lenticular Changes

• Fine, whitish, granular deposits on the anterior lens capsule.
• Clinically insignificant and rarely cause visual symptoms. (Zia; Khurana)

3. Retinal Toxicity (Most Clinically Significant)

A. Pre-maculopathy (Earliest / Reversible Stage)

• No visible fundus changes on clinical examination.
• Detected only by functional tests (Amsler grid, central visual fields, colour vision).
• Subtle paracentral scotoma on Humphrey visual field (10-2 protocol).
• Reversible if drug stopped at this stage — most critical detection point. (Kanski, Khurana)

B. Early Maculopathy

• Subtle macular pigmentary changes — fine, stippled RPE irregularity in the foveal/parafoveal region.
• Loss of the foveal reflex.
• Mild decrease in visual acuity.

C. Bull's Eye Maculopathy (Established Toxicity — Pathognomonic)

• Pathognomonic pattern: Central zone of relative foveal sparing (or hyperpigmentation) surrounded by a concentric ring of RPE depigmentation/atrophy, further encircled by an outer ring of hyperpigmentation.
• Resembles a "bull's eye" or "target lesion" at the macula.
• Associated with significant, often irreversible visual loss.
• The distinctive ring-like EPR degeneration is clearly visible on fundus photography (as shown below).

D. Advanced / End-Stage

• Widespread RPE and photoreceptor atrophy extending beyond the macula.
• Pattern resembles retinitis pigmentosa (bone-spicule pigmentation, arteriolar attenuation, waxy disc pallor). (Harrison's, p. 975)
• Severe, irreversible visual loss; may progress even after drug withdrawal due to continued tissue binding.

4. Summary Table: Retinal Changes by Stage

5. Other Posterior Segment Findings

• Macular oedema (rare, early)
• Abnormal EOG and ERG — reduced Arden ratio on EOG; reduced photopic/scotopic responses on ERG reflect widespread RPE and photoreceptor dysfunction. (Kanski)
• Reduced contrast sensitivity and colour vision (especially red-green axis)

Ocular Symptoms Reported by Patients

• Difficulty reading, blurred central vision
• Paracentral scotoma (patients may describe a "missing spot" near centre of vision)
• Photophobia, glare, haloes (from keratopathy)
• In advanced disease: tunnel vision, night blindness

Screening Protocol (Kanski / AAO Guidelines)

• SD-OCT: Shows thinning/loss of the ellipsoid zone (photoreceptor layer) in parafoveal region — earliest structural sign.
• Fundus autofluorescence (FAF): Parafoveal hyper- or hypo-autofluorescence before visible fundus changes.
• Humphrey 10-2 visual field: Detects paracentral scotoma.
• mfERG (multifocal ERG): Objective functional test detecting parafoveal dysfunction. (Kanski)
• Amsler grid: Simple, patient-administered; detects metamorphopsia/scotoma but insensitive for early changes.

Key Points (Zia / Khurana)

1. Corneal verticillata is common but benign and does not predict retinal damage.
2. Bull's eye maculopathy is pathognomonic but represents advanced, irreversible disease — the goal of screening is detection at the pre-maculopathy stage.
3. Toxicity can progress even after stopping HCQ due to the drug's long tissue half-life.
4. Chloroquine is more toxic than hydroxychloroquine at equivalent doses.
5. Regular annual ophthalmological review is mandatory for all patients on long-term HCQ therapy. (Harrison's, p. 9991)