Inherited Retinal Disease

flash ERG

• mass retinal test

• abnormal: ≥ 20% affected

multifocal ERG

test for small areas (100um) of retinal dysfunction

cones/rods

what does the a wave show on an ERG?

muller cells & bipolar cell region

what does the b wave show on ERG?

rod

____ response: stimulating dark-adapted eye

cone

____ response: stimulating light-adapted eye, w/ flickering light (30Hz)

no (not beneficial unless the condition is treatable)

do you repeat an ERG?

cones

waveform: photopic A

retinal component: _______

cone dystrophies

in what type of disorders is the photopic A waveform altered in?

rods

waveform: scotopic A

retinal component: _______

inner nuclear layer (cones)

waveform: photopic B

retinal component: _______

inner nuclear layer (rods)

waveform: scotopic B

retinal component: _______

cones

waveform: flicker ERG

retinal component: _______

macula

waveform: multifocal ERG

retinal component: _______

rod dystrophies

in what type of disorders is the scotopic A waveform altered in?

retinoschisis

in what type of disorders is the photopic B waveform altered in?

retinoschisis

in what type of disorders is the scotopic B waveform altered in?

cone dystrophies

in what type of disorders is the flicker ERG waveform altered in?

maculopathy

in what type of disorders is the multifocal ERG waveform altered in?

EOG

measures electrical potential generated by RPE/photoreceptor complex, produces square waves

positive

the cornea is electro ___

negative

the posterior pole is electro ____

light peak / dark trough

what is the arden ratio?

>1.80

what is a normal arden ratio?

dark adaptation

• night blindness test: ability of retina & pupil to react to decreased illumination

• Goldmann-Weekers adaptometer

• cones: initial segment

• rods: 2nd slower segment

• rod-cone break @ 7min

autosomal dominant

• every generation affected

• males = females

• transmission only by affected person

• 50% risk to offspring

• variable expression

• s/sx:

  • milder

  • later onset

autosomal recessive

• same generation affected

• transmission by asymptomatic

• probability:

  • 50% carrier

  • 25% affected

  • 25% neither carrier nor affected

• every child of an affected person is a carrier

• both members of the chromosome pair must be affected for expression of the trait

• males = females

• less variable expression

• s/sx:

  • more severe than AD

  • earlier onset than AD

X-linked recessive

• only males are affected

• trait transmitted through mother (carrier) w/ abnormal gene on 1 of her X chromosomes

• probability:

  • transmission from mother to daughter (carrier) or son (affected): 50%

  • transmission from affected father to daughter: 100%

  • transmission from affected father to son: 0%

• less variable in expression than AD

• s/sx:

  • more severe

  • earlier onset than AD

lyonization

• random inactivation of 1 X-chromosome in every cell

• carrier manifests s/sx depending on degree of predetermined inactivation

1. RP

2. CSNB

3. Best’s

4. dominant drusen

5. aniridia

6. Duane’s

7. Marfan’s

8. ptosis

9. neurofibromatosis

list AD diseases

1. RP

2. CSNB

3. Usher’s

4. gyrate atrophy

5. Stargardt’s

6. fundus flavimaculatus

7. rod monochromat

8. Sjogren’s

list AR diseases

1. RP

2. CSNB

3. choroideremia

4. ocular albinism

5. R-G color defects

6. Fabry’s

list X-linked diseases

1. RP

2. congenital stationary night blindness

3. fundus albipunctatus

4. choroideremia

5. gyrate atrophy of choroid & retina

list diseases that affect peripheral & night vision

1. Stargardt’s disease/FF

2. Best’s vitelliform dystrophy

3. pattern dystrophies of RPE

4. dominant drusen

5. central areolar choroidal dystrophy

6. rod monochromatism

7. progressive cone dystrophy

8. albinism

list diseases that affect central & color vision

bilateral, symmetrical

almost all hereditary disorders are ______(bilateral/unilateral) & ________(asymmetrical/symmetrical)

RP

• group of heredofamilial diseases characterized by progressive VF loss, night blindness, & abnormal/non-recordable EG

• primarily affects photoreceptors & RPE function

• prevalence: ~2million worldwide

• age of onset: 9-19yo

• bilateral, symmetric, progressive but variable

• history: age of onset of sx, FHx, associated systemic issues

• hereditary pattern: >100 gene loci have been mapped or identified

• PSC, PCO, & CME more common

early phase RP

• nyctalopia & photophobia

• spreading ring scotomas: 30-50deg

• RPE grey-green discoloration

• diffuse RPE depigmentation & migration of pigment into sensory retina

• reduced ERG (scotopic moreso than photopic)

• ERM

• PVD

• vitreous condensation by 10yo

mid phase RP

• moth-eaten RPE loss mid-periphery

• bone spicule pigmentation

• arteriolar attenuation

• waxy pallor of ONH

• PSC

• CME

• vitreous opacities & cells (free melanin pigment granules, uveal melanocytes, macrophage-like cells) evenly distributed throughout vitreous

late phase RP

• choroidal vessels yellow-white w/ RPE loss

• optic nerve pallor

• VF reduction to small central & temporal island

• non-recordable ERG

• FA: diffuse hyperfluorescence due to RPE defects, hypofluorescence due to pigment clumping & choriocapillaris/RPE atrophy

focal degeneration

describe the histopathology of rods & cones w/ RP

depigmentation, atrophy, proliferation w/ pigment clumping & migration around vessels, accumulation of degraded phagosomal material

describe the histopathology of the RPE w/ RP

total loss of all retinal neurons, replaced w/ glial tissue

describe the histopathology of inner retina w/ RP

ERM, gliosis of optic disc, hyalinization/thickening of vessel wall

describe the histopathology of RP besides rods/cones/RPE/inner retina changes

1. scotopic ERG diminished to absent

2. abnormal/absence of light rise

3. dark adaptation: increased R-C thresholds

4. photopic gradual reduction to absent

5. 30Hz flicker cone responses last to be reduced

6. less amplitude variability than dark or light-adapted flash stimuli

what are the ERG/EOG changes associated with RP?

1. genetic counseling

2. low vision & spectacle tints

3. cataract extraction

4. vitamin A + lutein, DHA may delay disease progression

5. avoid vitamin E

6. gene therapy, stem cell therapy, transplantation, artificial vision

what are the tx/management strategies for RP?

luxturna

• approved for tx of confirmed biallelic RPE65 mutation-associated retinal dystrophy (Leber’s Congenital Amaurosis & some RP)

• delivers normal copy of RPE65 gene directly to retinal cells

• cells then produce normal protein that converts light to an electrical signal in retina to restore pt’s vision loss

• subretinal injection

• given w/ oral prednisone to limit potential immune rxn

1. retinitis sine pigmento

2. unilateral RP

3. sector RP

4. retinitis punctata albescens

5. Leber’s congenital amaurosis

what are the atypical RPs?

retinitis sine pigmento

• AD, AR

• onset: 1st-2nd decades

• probable variation of RP

• less severe s/sx

  • slight attenuation

  • waxy pallor

  • ERM

• monitor x5y for dx

unilateral RP

• rare

• onset: 3rd-4th decades

• prognosis similar to RP

• carefully ddx (blunt trauma, resolved RD, IOFB, choroidal vascular occlusions, inflammation)

sector RP

• AD

• onset: <20yo

• bilateral & symmetrical

• inferior or inferior nasal

  • attenuated arterioles

  • RPE changes

  • corresponding VF defect

• slow progression

• DDx: retinal trauma, inflammation, RD

retinitis punctata albescens

• AR

• onset: 1st decade

• fundus:

  • discrete whitish dots w/ subsequent bone spicules

  • vessel attenuation

  • ONH pallor

• abnormal ERG

  • may improve w/ dark adaptation but will not normalize

• slow progression

• DDx: other white dot syndromes

Leber’s congenital amaurosis

• congenital RP

• AR form onset: 1st yr

• AD form onset: 1st decade

• s/sx:

  • profound visual impairment at birth

  • searching nystagmus

  • photophobia

  • oculo-digital sign

  • sluggish pupillary rxn

  • cataracts (50%)

  • keratoconus

  • glaucoma

  • extinguished ERG

• fundus

  • progressive chorioretinal degeneration w/ optic atrophy

  • arteriolar attenuation

• poor prognosis

• tx: genetic testing, Luxturna for RPE65

loss of outer segments of PR w/ progressive degeneration of all retinal layers & RPE

describe the pathology of Leber’s Congenital Amaurosis

Usher’s Syndrome

• AR

• 10% of all RP pts

• congenital non-progressive deafness

1. Usher’s Syndrome

2. Bardet-Biedl Syndrome

3. Refsum’s Syndrome

4. Bassen-Kornzweig Syndrome

5. Batten’s Disease

what are some RP-associated systemic diseases?

congenital stationary night blindness

• X-linked > AR > AD

• s/sx:

  • night blindness

  • possible VA reduction

  • high myopia

  • essentially normal retina but may have loss of foveal reflex

  • VF constricted in mesopic conditions but normal in photopic

  • dark adaptation abnormal

• etiology:

  • defect in light-activated enzymatic process involved in normal rod functioning

  • defect in synaptic transfer of message

• complete or incomplete

1. severe nightblindness

2. scotopic normal a-wave, severely reduced/absent b-wave

3. EOG normal

what are the s/sx of complete CSNB?

1. do not uniformly report severe nightblindness

2. scotopic a & b waves reduced but measurable

3. EOG abnormal

what are the s/sx of CSNB?

fundus albipunctatus

• CSNB variant

• AR, AD

• s/sx:

  • dull white dots midperiphery & perimacular

  • normalization w/ prolonged dark adaptation

  • slow adaptation of cones & rods

  • ERG is abnormal but normal after 3hrs of dark adaptation

choroideremia

• X-linked

  • mutation in Rab escort protein 1 → degeneration of RPE then choroid & PR

• onset: 1st-2nd decades

• s/sx:

  • night blindness

  • peripheral VF constriction

  • eventual loss of central vision

  • ERG: photopic severely reduced, scotopic non-recordable

  • EOG abnormal

• fundus

  • initial midperipheral RPE stippling

  • confluent areas of atrophy of RPE & choriocapillaris, vessel attenuation

  • preserved large choroidal vessels

• OCT: thinning of RPE w/ attenuation of interdigitation zone

• FA: early diffuse hyperfluorescence then later stages have hypofluorescence secondary to choroidal atrophy

• prognosis: poor, slowly progressive

1. onset in 2nd decade

2. asymptomatic but some individuals have night blindness, chorioretinal degeneration, patchy granularity of RPE, decreased VA to 20/32

describe the appearance of chorioideremia in a female carrier

gyrate atrophy

• AR

  • deficient OAT activity → increased ornithine levels in plasma/urine/CSF/aqueous

• onset: 1st-2nd grade

• s/sx:

  • myopia

  • night blindness

  • peripheral VF constriction

  • PSC

  • ERG: severely abnormal to non-recordable

  • abnormal EOG

  • systemic: seizure disorders, intellectual disability, muscle weakness

• fundus:

  • mid-peripheral geographic RPE & choroidal atrophy coalesce to form scalloped borders w/ progression

  • macular degeneration

  • optic atrophy

  • vessel attenuation

• poor prognosis w/o tx

  • tx: reduce serum ornithine levels when young, supplement w/ B6

Stargardt’s disease

• AR (rarely AD)

  • enlargement of RPE cells in zones of flecks w/ total disappearance of cones, rods, & RPE in circumfoveal zone

• s/sx:

  • bilateral

  • color vision loss

  • reduced VA

  • central scotoma

  • peripheral vision remains intact

  • normal-abnormal ERG/EOG

  • FA: hypofluorescence but becomes hyper as atrophy progresses

• fundus

  • initial loss of FLR

  • RPE granularity

  • Bull’s eye maculopathy: zone of normal retina at macula, surrounded by grayish yellow depigmentation, pigment stippling

  • beaten-bronze, metallic appearance

fundus flavimaculatus

• AR (rarely AD)

  • enlargement of RPE cells in zones of flecks w/ total disappearance of cones, rods, & RPE in circumfoveal zone

• s/sx:

  • bilateral

  • color vision loss

  • reduced VA

  • central scotoma

  • peripheral vision remains intact

  • normal-abnormal ERG/EOG

  • FA: hypofluorescence but becomes hyper as atrophy progresses

• fundus:

  • midperipheral yellowish-white flecks progressing toward macula

regions of RPE cells engorged w/ abnormal lipofuscin-like material

what are the flecks that appear in Stargardt’s & fundus flavimaculatus?

Best’s vitelliform dystrophy

• AD

  • abnormal accumulation of materials in RPE resulting in dysfunction, atrophy, & eventual loss of PR function

• onset: 4-10yo

• bilateral, asymmetrical

• s/sx:

  • initially slight VA reduction

  • later on, severe VA loss, color vision loss, central scotoma

  • normal ERG

  • abnormal EOG, even prior to fundus change

• fundus:

  • macular egg yolk 0.5-2DD in size

  • progress to scrambled egg & VA loss

  • adult form: polymorphic

• FA: hypofluorescent egg yolk followed by hyperfluorescence w/ RPE breakdown

0: normal macula, abnormal EOG

1: pre-vitelliform

2: vitelliform

3: pseudohypopyon

4: vitelliruptive

5: atrophy & fibrotic scar tissue

6: choroidal neovascularization

list the stages of Best’s vitelliform macular dystrophy

dominant drusen

• AD

  • inherited malfunction of metabolic process in RPE

• onset: w/in first 3 decades

• s/sx:

  • metamorphopsia

  • VA loss

  • color vision loss

  • central scotomas

  • normal to minimally abnormal ERG

  • subnormal EOG in late stages

• fundus:

  • macular drusen

  • confluent

  • eventual calcification

  • RPE atrophy

• low risk of CNVM

• FA: early hyperfluorescence of RPE & late staining

• management: PRP/anti-VEGF for CNVM, low vision aids

1. retinitis punctata albescens

2. fundus albipunctatus

3. fundus flavimaculatas

4. Stargardt’s disease

5. dominant drusen

6. talc retinopathy

7. tamoxifen retinopathy

what are the white-dot syndromes?

central areolar choroidal dystrophy

• AD, AR

  • choriocapillaris atrophy w/ subsequent loss of RPE & sensory retina

• onset: after age 40

• s/sx:

  • slowly progressive VA loss to <20/200

  • color vision loss

  • central scotoma

  • normal to minimally abnormal ERG/EOG

• fundus:

  • initial macular RPE stippling

  • progressing to RPE & choriocapillaris atrophy w/ sharply defined borders

• FA: early hyperfluorescence w/ eventual loss of choriocapillaris flow

• poor prognosis w/ VA loss but peripheral vision intact

complete rod monochromatism

• AR

  • congenital absence of cones

• s/sx:

  • severe photophobia

  • pendular nystagmus

  • decreased vision, <20/200

  • color vision absent

  • ERG: photopic non-recordable, scotopic normal

• fundus:

  • normal

  • loss of FLR

incomplete rod monochromatism

• AR

  • congenital marked deficiency of cones

• s/sx:

  • less severe photophobia

  • less severe pendular nystagmus

  • decreased vision, 20/40-20/100

  • color vision subnormal

  • ERG: minimal photopic waveform, scotopic normal

• fundus:

  • normal

  • loss of FLR

progressive cone dystrophy

• AD (possibly AR & X-linked)

• onset: 1st-2nd decade

• s/sx:

  • VA 20/60-20/200

  • photophobia

  • color vision loss

  • fine nystagmus

  • central scotoma

• fundus:

  • bulls eye zone of RPE mottling & atrophy

  • diffuse pigment stippling, loss of foveal reflex & VA

  • RPE/choriocapillaris atrophy, optic atrophy, attenuated vessels

• FA: bulls eye hyperfluorescent ring w/ fine areas of leakage

• ERG: photopic abnormal to non-recordable, scotopic normal

• EOG: usually normal

• poor prognosis

1. Stargardt’s disease

2. progressive cone dystrophy

3. plaquenil toxicity

4. thioridazine/mellaril toxicity

what are the bull’s eye maculopathies?

1. usage >5y

2. cumulative dose of HCQ>1000g or CQ>460g

3. daily dose of HCQ>400mg/day or CQ>250mg/day

4. older age

5. kidney or liver dysfunction

6. retinal disease or maculopathy

what are the factors increasing the risk of CQ or HCQ retinopathy?

oculocutaneous albinism

• AR, AD

  • congenital hypopigmentation of skin & eyes

• s/sx:

  • nystagmus

  • photo-refractive error

  • reduced VA

  • strabismus

  • normal color vision

• fundus:

  • foveal hypoplasia

  • retinal hypopigmentation

  • iris transillumination

• ERG/EOG: supernormal due to light scatter

• nystagmus & VA may improve w/ age

• management: spec tints, UV protection

negative

the complete form of oculocutaneous albinism is tyrosinase _____, the pt is incapable of synthesizing melanin

positive

the incomplete form of oculocutaneous albinism is tyrosinase _____, the pt synthesizes variable amounts of melanin & varies in complexion, iris, & fundus pigmentation

ocular albinism

• X-linked, AR

• hypopigmentation limited to ocular structures

1. iris transillumination

2. scattered fundus depigmentation & granularity

what are the signs that asymptomatic female carriers of ocular albinism can show?

early phase RP

early phase RP

mid-phase RP

mid-phase RP

RP

RP

RP

late phase RP

late phase RP

sector RP

retinitis punctata albescens

retinitis punctata albescens

fundus albipunctatus

choroideremia

choroideremia

choroideremia

choroideremia

choroideremia

choroideremia

gyrate atrophy