Retinitis Pigmentosa: An Overview

Retinitis Pigmentosa (RP) Overview

• RP is a group of pigmentary retinopathies leading to photoreceptor loss and retinal pigment deposits.
• Primarily affects rods, causing peripheral vision loss while sparing macular function until later stages.
• Rod photoreceptor degeneration is the primary issue, leading to secondary cone degeneration.
• Rod outer segments contain membrane discs for phototransduction, phagocytosed by RPE and replenished.
• mRNA, protein synthesis, and protein trafficking support disc renewal.
• Initially rods are affected, followed by cones, termed rod-cone dystrophy.
• Prevalence is about 1 in 5000, making it the most common hereditary retinal dystrophy.

Classification of RP

• Based on retinal involvement distribution: central, pericentral, sector, peripheral.
• Roughly half of RP cases are sporadic (simplex), the rest have a family history.
  • Autosomal dominant (AD) accounts for 15-35%, typically a milder form.
  • Autosomal recessive (AR) is about 60%, usually the most severe.
  • X-linked (5-18%) is the least common but progresses rapidly and severely.
• RP genes can be inherited through mitochondrial DNA from the mother.
• Mitochondrial DNA defects cause varying presentations.
• Syndromic versus non-syndromic classification exists. Most RP patients are non-syndromic.
• Classified by photoreceptor involvement: rod, rod/cone, or cone-rod dystrophy (inverse RP).

Syndromic Conditions Associated with RP

• Usher Syndrome is the most common syndromic form, RP associated with neurosensory deafness, ~14% of RP cases.
• Autosomal recessive ciliopathy with hearing loss, RP, and sometimes vestibular dysfunction.
  • Type 1: mutations in CDH23, MYO7A, PCDH15, USH1C, and USH1G genes
    • Profound congenital hearing loss, severe balance issues, and difficulty walking early in life.
    • Ocular symptoms begin before age 10 (night blindness), progressing to severe vision loss, nystagmus, keratoconus, and optic atrophy.
  • Type 2: mutations in USH2A, GPR98, and DFNB31 genes
    • Moderate to severe hearing loss at birth, normal balance.
    • Hearing impairment worsens, but individuals can generally communicate verbally and benefit from hearing aids
    • Ophthalmological signs, particularly retinitis pigmentosa, usually emerge in late adolescence.
  • Type 3: mutations in the CLRN1 gene
    • Normal hearing at birth, followed by progressive hearing loss during adolescence
    • Ophthalmological symptoms, such as night blindness, also typically begin in adolescence.
    • Blind spots start to appear in the late teens to early twenties, and legal blindness often occurs by midlife. Legal Blindness: visual acuity of 20/200 or worse in the better eye with best correction, or visual field restriction to 20 degrees or less.

Other Syndromes:

• Bassen-Kornzweig Syndrome (abetalipoproteinemia)
  • Mutations in MTTP gene disrupt lipoprotein assembly.
  • Autosomal recessive.
  • Systemic symptoms include diarrhea, vomiting, steatorrhea, delayed growth, and impaired bone development.
  • Ocular signs: Issues with vision in low-light conditions, constriction of the visual field, pigmentary retinopathy, angioid streaks, nystagmus, anisocoria, ptosis, eye muscle paralysis, ophthalmoplegia, and cataracts.
• Refsum disease
  • Classic Refsum Disease: accumulation of phytanic acid due to mutations in PHYH/PAHX or PEX7 genes.
    • Autosomal recessive.
    • Systemic symptoms: anosmia, deafness, skin abnormalities.
    • Ocular sign is RP.
  • Infantile Refsum Disease: mutations in PEX1, PEX2, PEX26, PHYH, or PEX7 genes.
    • Autosomal recessive.
    • Systemic signs: ataxia, polyneuropathy, hypotonia, mild facial dysmorphism, and cardiomyopathy
    • Ocular signs: RP, typically beginning in infancy.
• Laurence-Moon Syndrome: obesity, atypical RP, mental deficiency, genital dystrophy, polydactylism and familial occurrence.
  • Anomalies: genu valgum, coxa vara, scoliosis, deafness, strabismus, nystagmus and congenital heart disease.
• Bardet-Biedl Syndrome
• Neuronal Ceroid lipofuscinosis (Batten Disease)
  • CLN3 gene mutation affects lysosomes and synapses.
  • Primarily autosomal recessive.
  • Infantile, late infantile, juvenile, and adult forms exist, varying by onset age.
    • Systemic Symptoms: ataxia, mental retardation, seizures, and acute spasms
    • Ocular signs: macular involvement, cherry-red spots, progressive degeneration, retinal dystrophy, and blindness.
• Alström disease
  • Mutations in the ALMS1 gene.
  • Autosomal recessive.
  • Diagnostic criteria: hearing loss, obesity, diabetes mellitus (DM), acanthosis nigricans, and retinitis pigmentosa (RP).
  • Systemic Symptoms: cardiovascular conditions, cardiovascular conditions, acanthosis nigricans, gout, hypothyroidism, kyphoscoliosis, and chronic nephropathy.
  • Ocular signs: nystagmus, photophobia, strabismus, and cone–rod dystrophy.
• Kearns-Sayre Syndrome
  • Sporadic deletions in mitochondrial DNA, or mutations in mtDNA or nuclear genes (RRM2B).
  • Mitochondrial or autosomal recessive inheritance.
  • Systemic symptoms: sensorineural deafness, cerebellar ataxia, dysarthria, skeletal muscle myopathy, intellectual disability, gastrointestinal disorders, cardiomyopathy, cardiac conduction defects, heart block, endocrine issues, delayed puberty, and hypoparathyroidism.
  • Ocular signs: progressive external ophthalmoplegia, ptosis, night blindness, and pigmentary retinopathy.

Clinical Features of RP

• Bilateral involvement.
• Presentation often during the first to third decade.
  • AR: presents in early adolescence
  • AD: late 20s-30s
• 75% of patients have symptoms by age 30.
• Deterioration primarily of rod function
• Progressive visual field loss from mid-peripheral scotomas to ring scotoma; central vision lost last.
• VA in typical RP: good central vision preserved until later stages.
  • adRP patients more likely to retain good acuity beyond 60 years.
  • XLRP patients usually legally blind (20/200 or worse) by younger age.
  • Atypical RP (inverse RP) may have earlier central visual impairment.
• Associated factors like CME, cataracts, or ERM can lead to earlier vision decrease.

Fundus Findings in RP

• Requires bilateral presentation to be termed RP
• Bone spicules.
• Arteriolar narrowing.
• Attenuated vessels.
• Waxy pallor of the optic nerve.
• Initial stages can lack visible fundus changes with abnormal ERG only.

Symptoms of RP

• Night blindness and dark adaptation difficulties.
• Loss of peripheral vision.
• Reduced central vision at later stages.
• Photopsias.
• Color vision loss.
• Photophobia.

RP Triad

• Bone-spicule pigmentation.
• Attenuation vessel.
• Disc pallor, waxy.

Other RP types:

• Retinitis pigmentosa inversus: macula and posterior pole are affected.
• Retinitis pigmentosa sine pigmento: symptoms of RP without pigmentary fundus changes, up to 20% of cases.
• Retinitis punctata albescens: multiple, punctate white spots in mid periphery, attenuated vessels and bone spicules.
• Sector retinitis pigmentosa: pigmentary changes limited to one retinal area.

Additional Signs & Symptoms of RP

• Open-angle glaucoma.
• ONH-drusen (stagnated axoplasmic).
• Yellow balls in ON.
• Vitreous pigment cells ("dusting").
• CME (70%).
• ERM (1.4-51%).
• PSC (20-39%).
• Myopia (more common in XL type).

Testing for RP

• ERG: initial reduction of rod function response.
  • Abnormal ERG findings may be seen even with a normal fundus.
  • Early stages: reduced amplitude with prolonged implicit time in scotopic ERG.
  • Later stages: reduced amplitudes with delayed responses in photopic ERG and 30-Hz flicker.
• EOG is subnormal.
• mfERG is normal but abnormal when cone loss affects central retina.
• OCT: Identifies CME, ERM.
• Fundus Autofluorescence (FAF).
• Visual Fields (VF).
• Genetic testing via My Retina Tracker Genetic Testing Program (351-gene panel).

Therapy for RP

• Vitamin A Palmitate (15,000 IU/day) for adults with common RP forms under medical supervision.
  • Avoid in ABCA4 mutation cases.
• Topical and oral CAI; topical, oral, periocular, and intravitreal steroid injections for CME.
• Voretigene neparvovec (Luxturna) for biallelic RPE65 mutations with sufficient remaining cells.
• Correct refractive errors.
• Low vision aids.
• Blue-light screen filters and UV-protected sunglasses.
• Monitoring and treating associated complications (CMO and cataract).
• Healthy diet with fresh fruits and green leafy vegetables; avoid high doses of Vitamin E.
• Co-manage with PCP for systemic issues.
• Multidisciplinary approach.
• Electronic retinal implant Argus II for advanced RP with bare to no light perception.

RP Differentials

• Syphilis: salt and pepper fundus.
• Rubella.
• Trauma: RPE hyperplasia.
• Pigmentary paravenous retino-choroidal atrophy: RPE along the veins.
  • Non-progressive/slowly progressive and no treatment.
• Retinitis Punctata Albescens (RPA): AR (RLBP1 mutation).
  • Slower progression than RP.
  • Uniform white dots in mid periphery.
  • Symptoms: Nyctalopia, progressive VF loss, late central vision loss, photophobia.
  • ERG: early depression of scotopic, abnormal in late stages.

Retinitis Punctata Albescens Differentials

• Fundus Albipunctatus: stationary form of congenital stationary night blindness (CSNB).
  • Born with it, doesn't progress.
  • AR mutation in RDH5 gene.
  • White dots concentrated in mid-periphery and perimacular area, no RPE degeneration, normal arteries and ONH.
  • Good VA and CV.
  • Normal rod sensitivity after prolonged dark adaptation.

Congenital Stationary Night Blindness (CSNB)

• AD, AR, or X-linked.
• Non-progressive, infantile onset, nyctalopia.
• Fundus normal or abnormal.
• Myopia (X-linked), nystagmus (severe forms).
• ERG:
  • Type 1 W/ normal fundus: Abnormal dim scotopic ERGs but the bright flash ERG maintains oscillatory potentials
  • Type 2 W/ normal fundus: Electronegative wave!
• Retina Signs: Oguchi’s disease: golden fundus coloration reversed with long dark adaptation (Mizuo’s Sign, 2-3 hours). Arrestin gene mutation. Type 2 ERG pattern without retinal signs

Enhanced S-cone Syndrome (ESCS)/Goldmann-Favre Syndrome

• Progressive macular disease resulting in blurred vision
• AR via a mutation in nuclear receptor gene NR2E3
• ERG with significant cone and rod depression, except for S-cone responses.
• Foveal schisis, night blindness, severely abnormal ERG
• hyperopia at young age frequently with peripheral retinal degeneration
• Management: Gene testing and monitor schisis

X-Linked Retinoschisis (XLRS)

• Juvenile retinoschisis, affects males.
• Mutation of the retinoschisin 1 (RS1) gene.
• ERG: Normal a-wave but electronegative scotopic mixed response.

Cone Dystrophies

• Inherited: Cone photoreceptor or post-receptor problems.
• Major clinical features: Photophobia, reduced VA, abnormal color vision.
• Mostly stationary, some progressive.
• ERG: Reduced or absent cone responses.

Types of Cone Dystrophies:

• Stationary Cone Dystrophy:
  • Rod monochromatism (complete achromatopsia):
    • AR.
    • Only rod vision (brightness, no colors).
    • Mutations in cyclic-nucleotide channel genes (CNGA3, CNGB3).
    • Clinical signs: Nystagmus, photophobia, reduced acuity (20/200), and a normal fundus.
    • ERG: cone responses are absent; rod responses are normal or subnormal
    • Central scotoma, absent CV.
    • The Flynn Phenomenon
    • OCT: foveal cavitation sign due to the absence of the ellipsoid zone.
    • Management: Genetic testing, low vision aids, tinted dark sunglasses (red).
• Progressive Macular Dystrophies:
  • Progressive Cone Dystrophy (PCD):
    • AD, AR, or XL.
    • Gradual and bilateral.
    • Central vision affected, photophobia, decreased color vision.
    • Fundus exam: Bull’s eye maculopathy, peripheral atrophy, and later ONH pallor.
    • ERG: Flat or subnormal cone response, rod preserved until later age.
    • OCT: fovea cavitation sign.
    • Management: Genetic testing, tinted glasses, low vision.
  • Stargardt Disease:
    • Most common form of juvenile macular dystrophy. -AR trait caused by mutations in the ABCA4 gene
    • Accumulation of lipofuscin within the RPE.
    • Symptoms usually begin in the first two decades of life.
    • Linked to a mutation in the ABCA4 gene.
    • FA is considered the gold standard diagnostic test for Stargardt disease (Dark / Silent choroid)
    • OCT Outer retinal foveal atrophy
    • Counselling/ gene therapy may be needed
  • Fundus Flavimaculatus:
    • Adult onset, asymptomatic.
    • Bilateral, ill-defined, yellow-white deep retinal lesions (flecks).
    • ERG & EOG as in Stargardt.
    • Observation as management.
  • Best Vitelliform Dystrophy (BVD):
    • Autosomal-dominant
    • Mutations in the gene, BEST1 (VMD2) (11q13 locus)
    • Bilateral yolk-like yellow lesion first: infancy or early childhood (pseudohypopyon)
    • In OCT, will see accumulation of the material Accumulation in Bruch membrane and RPE detachment
    • EOG: abnormal: HALLMARK OF THIS DISEASE!
    • Genetic counselling/ monitor for CNVM