Retinal Degenerations

1. Age-Related Macular Degeneration (AMD)

Dry (Non-exudative) AMD

• Begins with accumulation of extracellular deposits called drusen within the RPE basement membrane (Bruch's membrane)
• Drusen appear as discrete yellow lesions clustered in the macula; soft drusen >60 μm are significant
• Lipofuscin accumulates in stressed RPE cells
• Progresses to geographic atrophy — well-defined zones of RPE loss — with slow central visual decline (months to decades)
• Peripheral retina is spared: patients lose face recognition but retain ambulation

Scattered yellow drusen in the macula (dry form) with a crescent of fresh hemorrhage temporal to the fovea from a subretinal neovascular membrane (wet form) — Harrison's Principles of Internal Medicine 22E

Wet (Neovascular/Exudative) AMD

• Occurs when choroidal neovascular (CNV) vessels penetrate Bruch's membrane into the subretinal space
• Leakage causes retinal elevation, metamorphopsia, and blurred vision; hemorrhage can cause sudden visual loss
• Results in disciform (round) macular scar and permanent central vision loss if untreated
• Detected by fluorescein angiography and OCT

Treatment

⚠️ Recent evidence (2024–2025): A network meta-analysis (PMID 39043575) confirmed faricimab's efficacy for neovascular AMD. A 2025 network meta-analysis (PMID 40241463) compared intravitreal anti-VEGF agents comprehensively. OCT biomarkers predicting progression to late AMD have been systematically reviewed (PMID 38154619).

2. Retinitis Pigmentosa (RP)

Genetics

• Over 100 gene loci implicated in non-syndromic RP
• Inheritance patterns: autosomal dominant (AD), autosomal recessive (AR), X-linked, or sporadic
• Most AD-RP: mutations in rhodopsin gene (phototransduction cascade)
• Most X-linked RP (90%): mutations in RPGR gene (connecting cilium protein)
• Pathways affected: phototransduction cascade, retinoid cycle, photoreceptor structure, RPE function
• ~50% of affected individuals have no identified molecular defect
• Cell death mechanism: apoptosis, possibly from accumulation of misfolded proteins

Symptoms

• Nyctalopia (night blindness) — earliest feature; rods affected first
• Progressive peripheral visual field constriction with ring scotoma
• Photopsia
• Central visual acuity loss is a later feature (unless cataract develops earlier)

Classic Triad on Fundoscopy

1. Bone-spicule pigmentation — mid-peripheral intraretinal perivascular pigment deposits
2. Arteriolar attenuation
3. "Waxy" disc pallor (optic nerve head atrophy)

Dense bone-spicule pigmentation throughout the peripheral retina with arteriolar narrowing and "waxy" disc pallor. — Harrison's Principles of Internal Medicine 22E

Investigations

• ERG: reduced or absent scotopic (rod) responses — extinguished in advanced disease; hallmark test
• Fundus autofluorescence (FAF): posterior pole hyperautofluorescent rings
• Visual field testing: peripheral constriction
• OCT: macular changes (CMO, ERM, atrophy)
• Genetic panel testing

Management

• No curative treatment for most forms
• Cystoid macular oedema (CMO): oral acetazolamide or topical carbonic anhydrase inhibitors
• Light protection: amber spectacles (blocking <550 nm) may reduce glare and improve contrast
• Dietary: vitamin A supplementation (effect uncertain, gene-dependent; caution with toxicity)
• Avoid retinotoxic drugs: isotretinoin, phenothiazines, hydroxychloroquine, tamoxifen, vigabatrin
• Gene therapy: Leber congenital amaurosis (LCA) with RPE65 mutations — voretigene neparvovec (Luxturna) approved, with improvement in visual function
• Cataract surgery beneficial when lens opacity limits vision

Syndromic RP (20–30% of cases)

3. Other Hereditary Retinal Dystrophies

Leber Congenital Amaurosis (LCA)

• Severe early-onset retinal dystrophy (~5% of RP); presents at birth or early infancy
• Mutations in RPE65, CEP290, CRB1, GUCY2D, and others
• Gene therapy (voretigene neparvovec) for RPE65-associated LCA is an approved treatment

Stargardt Disease (Fundus Flavimaculatus)

• Most common hereditary macular dystrophy in children/young adults; onset usually <25 years
• AR inheritance; ABCA4 gene mutations
• Features: central visual loss, yellow-white flecks in the posterior pole, bull's-eye maculopathy
• ERG usually normal initially
• No established treatment; avoid excess vitamin A (substrate for toxic bisretinoids)

Cone and Cone-Rod Dystrophies

• Primary cone degeneration (vs. RP's primary rod degeneration)
• Symptoms: photophobia, colour vision loss, central scotoma early; ERG shows absent photopic responses
• May progress to rod involvement (cone-rod dystrophy)

Best Vitelliform Macular Dystrophy

• Second most common macular dystrophy (after Stargardt)
• BEST1 (bestrophin) gene mutations on chromosome 11q13
• Characteristic "egg yolk" macular lesion on fundoscopy

Toxic / Drug-Induced Retinopathy

• Chloroquine/hydroxychloroquine: bull's-eye maculopathy; screening with OCT and visual fields required for long-term users
• Thioridazine (phenothiazine): diffuse retinal pigmentary changes
• Vigabatrin: peripheral visual field constriction

Summary: Distinguishing Features