Retinitis Pigmentosa - Detailed Overview

Definition

Epidemiology

• Most common hereditary retinal degeneration worldwide
• Prevalence: approximately 1 in 3,000 to 1 in 5,000 individuals
• Bilateral and roughly symmetrical in presentation
• Age of onset, rate of progression, and extent of visual loss are often related to the inheritance pattern

Fundoscopic Appearance

Genetics and Molecular Basis

• RHO (rhodopsin): Most cases of AD-RP; encodes the rod photopigment central to phototransduction
• RPGR (retinitis pigmentosa GTPase regulator): ~90% of X-linked RP; encodes a protein localised in the connecting cilium of rod photoreceptors
• Peripherin: A glycoprotein in photoreceptor outer segments
• USH2A, EYS: AR forms
• Over 100 gene loci are implicated in non-syndromic RP; despite this, approximately half of affected individuals have no identified molecular genetic abnormality

1. Defects in the phototransduction cascade (e.g., rhodopsin mutations)
2. Defects in the retinoid cycle
3. Defects in photoreceptor structure
4. Other biological functions of the photoreceptor and RPE

Pathophysiology

• Rod photoreceptors die via apoptosis as the primary pathological event
• Cone cell death is partly mediated through activation of RIP kinase
• Loss of rods leads to progressive night blindness and peripheral visual field loss
• As cones are subsequently lost, central visual acuity deteriorates
• Retinal atrophy leads to:
  • Constriction of retinal arterioles
  • Optic nerve head atrophy ("waxy pallor" of the optic disc)
  • Accumulation of retinal pigment around blood vessels - producing the "bone-spicule" pattern that gives the disease its name

Clinical Features

Symptoms (in order of typical appearance)

1. Nyctalopia (night blindness) - usually the first and most prominent symptom; also dark adaptation difficulties
2. Peripheral visual field loss - gradual constriction; patients may bump into objects
3. Ring scotoma - characteristic mid-peripheral ring of visual loss
4. Photopsia - not uncommon (flashes of light)
5. Reduced central vision - typically a later feature, unless a cataract develops early

Signs

1. Bone-spicule retinal pigmentation - bilateral mid-peripheral intraretinal perivascular "bone-spicule" pigmentary changes and RPE atrophy; may be absent early
2. Arteriolar attenuation - narrowing of retinal blood vessels
3. Waxy (pale) optic disc - optic nerve pallor with a distinctive waxy quality

• Visual acuity may be normal initially (contrast sensitivity affected earlier)
• Progressive visual field loss, typically a ring scotoma that progresses to a small central tunnel
• Vitreous cells (most consistent sign per Wills Eye Manual)
• Areas of RPE depigmentation or atrophy
• Posterior subcapsular cataract (common association)
• Cystoid macular edema (CME)
• Epiretinal membrane (ERM)

Investigations

• Electroretinogram (ERG): Usually markedly reduced or extinguished - shows no electrical evidence of retinal function in advanced disease; the most important functional test
• Visual fields (perimetry): Ring scotoma progressing to tunnel vision
• Dark adaptometry: Impaired dark adaptation
• Optical coherence tomography (OCT): Detects retinal thinning, CME, or ERM
• Genetic testing: Identifies specific mutations (RHO, RPGR, etc.); guides prognosis and gene therapy eligibility
• Family pedigree: Should be prepared; important for genetic counselling

Syndromic RP (20-30% of cases)

Drug-Induced Mimics

• Chloroquine / Hydroxychloroquine - produces a characteristic "bull's-eye maculopathy"; patients on long-term hydroxychloroquine need regular OCT screening
• Thioridazine (and other phenothiazines)

Management

Pharmacological

• Vitamin A palmitate (15,000 IU/day): Some evidence supports slowing of midperipheral visual field loss in nonsmokers; if initiated, monitor liver function tests and vitamin A levels (Goldman-Cecil, Harrison's, Wills Eye)
• Lutein (12 mg/day): Combined with vitamin A, may have some benefit; literature remains inconclusive
• Low phytanic acid diet (in Refsum disease) and vitamin supplementation + low-fat diet (in Bassen-Kornzweig) can retard progression

Optical and Low Vision Aids

• Tinted glasses for photophobia
• Magnification devices, electronic low-vision aids
• Orientation and mobility training

Surgical / Device-Based

• Retinal implants (prostheses): Both epiretinal and subretinal microchip implants have been used with some success to improve light perception in very advanced RP (e.g., Argus II epiretinal prosthesis)
• Cataract extraction for posterior subcapsular cataracts when visually significant
• Intravitreal anti-VEGF or acetazolamide for cystoid macular edema

Gene Therapy (Emerging)

• RPE65 replacement (voretigene neparvovec / Luxturna): Approved for Leber congenital amaurosis and RPE65-associated RP; demonstrated improvement in visual function
• RPGR gene therapy (X-linked RP): A 2026 systematic review and meta-analysis (PMID: 41773775) evaluated the efficacy and safety of gene therapy for RPGR-associated X-linked RP - representing the frontier of treatment for this form
• Multiple clinical trials ongoing across various genetic subtypes

Prognosis

• Highly variable depending on inheritance pattern and specific gene mutation
• Autosomal dominant forms are typically milder and progress more slowly; patients may retain useful vision into middle or late adult life
• Autosomal recessive and X-linked forms tend to be more severe with earlier vision loss
• Most patients eventually develop tunnel vision (preserved central field only); total blindness can occur but is not universal
• Legal blindness occurs in a significant proportion, typically between the 5th and 7th decades

Summary Table