the latest on the diagnosis and treatment of retinal ... · centre for eye health 1 the latest on...

Centre for Eye Health

1

The latest on the diagnosis and

treatment of retinal dystrophies

Professor Michael Kalloniatis

Centre for Eye Health, and,

School of Optometry and Vision Science

An initiative of Guide Dogs NSW/ACT and The University of New South Wales

Acknowledgements

Some material provided by

– Nayuta Yoshioka

– Michael Yapp

– Agnes Choi

– Erica Fletcher

– Lisa Nivison-Smith

Images collected by other staff at CFEH


Aims of the lecture

Diagnosing retinal dystrophies

– Peripheral reticular pigmentation has some similarities with rod-

cone dystrophies: characteristics and aetiology

Classification of retinal dystrophies

Clinical cases

– Diagnostic criteria and mechanisms

Latest information on intervention measures

– From the laboratory to the patient


A patient presents with this appearance? Female in her mid 60’s; normal VA but reports difficulty with night vision (doesn’t drive at night) and vision loss in the family


OCT


OCT

Kalloniatis et al EER 2015

Retinitis Pigmentosa


2


Peripheral reticular degeneration with macular changes 46yo female with no family history of eye disease

Night vision problems for over 20 yrs; VA 6/6 OU

Full field flash ERG: normal rod and cone responses

– This patient does not have an inherited rod-cone dystrophy

(retinitis pigmentosa)


Peripheral reticular degeneration with macular changes 46yo female with no family history of eye disease

Night vision problems for over 20 yrs; VA 6/6 OU


Peripheral reticular pigmentation

Peripheral reticular pigmentation

associated with various AMD genotypes

Witmer et al 2012

– Found peripheral anomalies identified

through fundus autofluorescence were

common in AMD


AMD

Control

20 mins of dark adaptation (rod function)

Age related macular degeneration:

Is it a rod-cone disease?

Owsley et al 2016 Ophthalmology; Jackson et al IOVS 2014; Dimitrov et al IOVS 2012

rod

cone

rod




Anatomical work

– Curcio’s group: IOVS 1993, 1996

• Aging - rod photoreceptor loss greater than cone loss

• Rod loss followed by cone loss in non-exudative AMD

• Few cones and no rods remain in advanced exudative AMD

Psychophysics (modified visual field apparatus)

– Owsley’s group: IOVS 2000

• Rod sensitivity loss (10dB) compared to cone loss (3dB)

– Eccentricity dependent (greater central)

• Extended well outside macular region (~20 degrees radius)


Would you worry if:

– VA dropped by 3 lines?

• 3dB change in contrast sensitivity (photopic)

– VA dropped by 10 lines?

• 10dB change in contrast sensitivity (scotopic)




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Age related macular degeneration: Do you wander why AMD patients prefer not to drive at night?

Owsley et al 2016 Ophthalmology

Cone threshold plateau

Rod threshold plateau 1.5 log units = 15dB = 15 lines VA chart


Key points #1

Electrophysiological testing is required to confirm inherited

retinal dystrophies

Peripheral reticular pigmentation is more common for

patients with the AMD phenotype (both GA and exudative)

– Fundus autofluorescence reveals:

• reticular hypofluorescence

• patchy hypofluorescence

• granular fluorescent changes

• focal pinpoint hyperfluorescence

AMD is not solely a ‘macular’ disease but rather a rod-cone

degeneration impacting on structure and function throughout

the retina

Classification of

Retinal dystrophies


Retinal Dystrophies

Various disorders in which visual loss is due to photoreceptor degeneration or dysfunction

May be rod or cone dominated

In addition to changes of visual function, degeneration generally associated with:

• patchy atrophy and associated pigmentary changes

• neuronal loss

• net loss of tissue volume

• astrocyte proliferation and cyst development

Many have a genetic component

Environmental (getting old, drug induced, light induced)

Some are relatively ‘stationary’


Basic Division of Retinopathies

Inherited – Retinitis pigmentosa

– CSNB

• (eg Oguchi's disease)

– Achromatopsia

– Leber’s congenital amaurosis (EOSRD – Early Onset Severe

Retinal Dystrophy)

– Juvenile macular degeneration

• Stargardt’s disease/Fundus

flavimaculatus

– Retinoschisis (X-linked)

Acquired

– Diabetic/hypertensive

retinopathy

• Vascular occlusive disease

– Achromatopsia

– Paraneoplastic syndromes

(MAR, CAR)

– Age related macular

degeneration (AMD)

– Central Serous Retinopathy

– Retinal detachment

– Retinoschisis (myopic) An initiative of Guide Dogs NSW/ACT and The University of New South Wales

ON GC

OFF GC

Cone ON BC

Rod ON BC

Cone OFF BC

AII AC

Cone AC

Cones Rods

Müller Cell

RL

OPL

INL

IPL

GCL

HC-CB

NFL

IPC

HC-AT

Cone AC

Cone ON BC

Cone OFF BC

gj

OFF GC

RODS CONES

Retinal anatomy

RPE


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A2E accumulation in AMD and ABCA4 mutations

Cone and Rod

Outer

Segment

Retinal Pigment

Epithelium

(RPE)

Mata et al Retinal Physician 2013

Cone opsin

A2E (cytotoxic bis-retinoid)

X-linked carriers are not ‘normal’


Lyonization

Dr Mary Lyon (Nature, 1961) proposed that in every somatic cell of a female, only one X-chromosome is functioning

• X-chromosome is inactivated during development

• The Lyon hypothesis predicts that every female will have two cell populations: one with normal activity and one with mutant activity

XX


Tan et al (1995) X-inactivated transgenic marker

X*X* X*X XY

On average, 50% paternal and 50% maternal

X-choromosomes are inactivated


Low marker

expression

High marker

expression

Tan et al (1995) X-inactivated transgenic marker


Choroideremia

End-stage choroideremia Female carrier of

choroideremia

Choroideremia: rare X-linked recessive condition

leading to degeneration of the choriocapillaris, loss

of RPE & photoreceptor degeneration.


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Conclusions - what you need to know

about female carriers

Female carriers of X-linked conditions may

display considerable diversity because of the

random nature of X-inactivation, eg RP

• MILD - fundus changes in pre-equatorial region

• OTHERS - abnormal retinal reflex, pigmentary changes,

altered ERG, visual field loss, reduced photopigment

content

Different proportions of expressed mutant X-gene results

in a spectrum of affected individuals (mild severe)

Location of anomaly in retinal dystrophies


. . . . . . . .

. . . . . . . . . .

Cone Photoreceptor

Depolarizing Cone Bipolar

Cell

‘ON’

Hyperpolarising Cone Bipolar Cell

‘OFF’ Depolarizing Rod Bipolar

Cell

‘ON’

RPE dysfunction: Chromophore Delivery or Recycling

Photopigment

Phototransduction

Neurotransmitter

Release

Neurotransmitter Receptor or

Channel (Trpm1)

Rod-cone

dystrophies


Fundus Autofluorescence (FAF)

Based upon autofluorescent properties of lipofuscin

granules in RPE cells

Lipid-containing residues of lysosomal digestion

Lipofuscin accumulates with age and in diseased cells

Normal = isofluorescence

Hyper/Hypo = RPE dysfunction


Retinitis pigmentosa: autofluorescence


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Optomap image 48 yo male RP suspect with 6/7.5 OU and no family

history of eye disease


OCT in this patient

Fundus appearance and other clinical features is consistent with inherited

‘Retinitis Pigmentosa’


Visual Field (48 yo male RP suspect with 6/7.5

OU and no family history of eye disease)


“Typical” visual field progression

Massoff’s work (stimulus dependent):

VF half life ~7.4-8.4yrs and critical age ~22-28 yrs


Full field ERG Waveform

http://webvision.med.utah.edu/book/electrophysiology/the-electroretinogram-clinical-applications/

Time

Vo

lta

ge

←

Hyperp

ola

risation

Depola

risation →

Rod &/or Cone Hyperpolarisation

Photoreceptors

ON bipolar cells

(Müller cells)

ON Bipolar Cell & Müller cell

Depolarisation


Electrophysiology Results:

Flicker: Cone

Light adapt: Cone Only

Dark adapt: Rod Only

Normal Disease


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Electrophysiology Results: Electro-oculogram (EOG)

DT

LP Ratio:11.5/4.5

RE LE


Autosomal Dominant (AD) (Pro-23-His) mutation

Berson et al (Arch Ophthal - 1991)

• All relatives

BLUE WHITE 30Hz

AGE

28

24

25

48

50

NORMAL


Retinal injury and repair in a dog model of RP

– Cideciyan et al PNAS 2005

Routine clinical procedures, ie, photography,

lead to marked increase in retinal degeneration

– Dog model of ADRP (rhodopsin mutation)

Clinical recommendations:

• “judicious to modify clinical examination of patients with rhodopsin mutations”

– Retinal photography should not be standard in these patients

– Short duration and minimum light

– light exposure during ocular surgery should be reduced.

Cone, cone-rod and

other dystrophies


‘Cone’ dystrophies A group of hereditary conditions (AD, X-

linked, AR) that present as cone-rod

dystrophies, eg ABCA4 mutation lead to a spectrum

of diseased referred to as Stargardt’s disease and Fundus

flavimaculatus

Gradual bilateral impairment of central vision

– May be mild impairment to more severe (6/120)

• Typical progressive red-green defect (against the rule): may progress to achromatopsia

• Normal ‘Bull’s eye’ central RPE atrophy and mid-periphery ‘bone spicule’ geographic atrophy

• Arteriolar attenuation and disc pallor


Patients SS/TS/WS

Referred by optometrist for tests only regarding

congenital nystagmus

Saw pediatric ophthalmologist in Melbourne

SS (17yo) TS (13 yo) WS (10 yo)

OD +2.50/-1.00x170 +0.75/-0.50x160 +2.50/-1.25x3

6/12-1 6/20 6/24

OS +2.00/-1.75x35 +1.00/-0.50x15 +2.50/-1.00x3

6/12-2 6/36 6/24


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Fundus Photos OD

SS TS WS


Central macular OCT OD

WS

TS

SS


ERG OU

SS (17yo)

Flicker: Cone Only

Light adapt: Cone Only

Dark adapt: Rod Only

Normal

All three siblings: marked reduction of cone full field

ERG and flicker ERG and normal scotopic responses

Dx: cone dystrophy


63 yo with inherited retinal dystrophy: Case history 63 yo female with history of progressive vision loss

– VA ~6/15 OU with main concern was that she has been told she has a ‘inherited retinal dystrophy’

• Denied electrophysiology testing

• Avoids driving at night

• Was told no point in having genetic testing

– Has always had poor vision in RE (lazy eye: long standing R hypertropia) but now both eyes poor

– Treated for lymphoma in 2002: no tamoxifen used nor has she ever taken plaquenil

• No current medications

– Pseudophake: retinal investigations began after cataract surgery did not improve VA

Acknowledgement: Dr Adrian Bruce and Norm Russo


63 yo with inherited retinal dystrophy: Issues to consider Is history of lymphoma chemotherapy a factor in the retinopathy?

– Confirmed and tamoxifen is not used for lymphoma therapy

– Paraneoplasmic syndrome – Cancer Associated Retinopathy (CAR)?

• Typically associated with small cell carcinoma

Is it possible to have been exposed to plaquenil (Hydroxychloroquine)

– Never left Australia

4 other siblings no history of eye disease

Parents deceased

Is the use of Vitamin A suitable in this patient?

Is genetic testing useful?


Optomap OD


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Optomap OS


Fundus photographs


OCT results

Not AMD as RPE largely intact


Optometrist forwarded correspondence

Ophthalmologist letter

– (3.5 years ago)

What does this mean?

– Likely a late onset cone or cone-rod

dystrophy

– Possible

• ABCA4 and rds/peripherin mutations

An initiative of Guide Dogs NSW/ACT and The University of New South Wales Cideciyan et al (2009)

Different phenotypes: ABCA4 mutations less severe (Stargardt’s) to severe (atypical RP)


Points to consider

Is it useful to know if ABCA4?

– Children may be carriers

– Carriers have increased risk of AMD

• Heterozygous mutations in ABCA4 have been associated with AMD in several studies

(Allikmets et al., 1997a;Allikmets, 2000;Mata et al., 2001;Shroyer et al., 2001;Zhang et al.,

1999; Klevering et al 2005)

– Can provide definitive advice relating to Vitamin A exposure

Mutations in the peripherin/RDS gene are the major cause of multifocal pattern

dystrophy simulating STGD1/fundus flavimaculatus.

– Boon et al BJO 2007 (found 9 diff varieties)

RPE largely intact thus unlikely to be CTRP5 mutation has recently been reported

as the causal gene of late-onset retinal degeneration (L-ORD), an autosomal

dominant disorder with striking clinical and pathological similarity to AMD


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15 yo male with strong family history of male

associated vision loss

-VA 6/38 OD and 6/12 OS; reduced CS OU;

-OD no distortions or missing patches; less distinct

squares OS


15 yo male with strong family history of male

associated vision loss


X-linked retinoschisis

– ERG

• Confirmed normal a-wave

severely depressed b-wave


Key points #2

Look for patterns in family history and always examine siblings and

parents

– X-linked: look for changes in mothers and female siblings

Electrophysiology provides useful insights relating to the site of the

anomaly

– RPE, photoreceptor, post-receptoral

Fundus autofluorescence reflects RPE function/dysfunction

ABCA4 mutation is the most common cause of inherited retinal

dystrophies

– Ranges from early or late onset cone dominated dystrophies to ‘atypical’ RP

The latest in RP

research


Gene therapy

Photoreceptors degenerating (or dysfunctional) Gene therapy

– RPE65: Leber’s Congenital Amaurosis (US, UK and EU groups)

• 4-6 year follow up in some patients

• All show improvement first 12 mths, then declining

• Delivery of gene continues to be an area being targeted for improvement

– Choroideremia gene therapy (UK group)

• RAB escort protein-1 lost: targeting the mutation in a Phase 1 trial

– MERTK-gene causing RCS RP mutation (Saudi Arabia group)

• Few patients have received treatment (subjective improvement)


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Gene therapy

Gene therapy

– Usher’s syndrome (UK)

• Mutation in the MYO7A gene causing Usher 1B (Usher’s 1 phenotype)

• Clinical trail in progress

– Stargardt’s disease (UK group)

• ABCA4 gene targeted in phase 1/II trial

– Achromatopsia (EU group)

• CNGA3 gene therapy (targeting cGMP channel): proof of principle in mice

– Retinoschisis (UK group)

• Proof of principle in animal models

– Optogenetic approach

• Insert photosensitive channel into remaining retinal ganglion cells

• Proof of principle in animal models


Non-genetic targeting

Gene therapy approach may be the wrong way to go in treating RP

DRUGSFORD (EU group)

– Targeting cGMP channel to modulate retinal dystrophy progression

Unoprostone

– This anti-glaucoma medication is now in Phase III clinical trials in Japan

– Mechanism of action is thought to be via neuroprotection

Many anti-VEGF trials underway


Non-genetic targeting Koenekoop et al and 9-cis retinal

RPE65 and LRAT mutations

– Of 14 subjects, only 3 maintained improved Goldmann VF and 4

maintained improved VA, 2 yrs after treatment with 9-cis

vitamin A analog (daily dosage) V4e

V4e and smaller is I4e An initiative of Guide Dogs NSW/ACT and The University of New South Wales

Strategies in slowing down or

restoring vision

Are replacement cells suitable?

– Human Embryonic Stem Cells

• Clinical trials using replace cells (stem cells) have begun

in humans suffering from

– Stargardt’s disease (N=9)

– Age related macular degeneration (N=9)

» Only ~1 year follow up

– iPS (induced pluripotent stem cells)

• One patient in Japan: vision now stable 6 mths into trial


End stage retinal dystrophy

No photoreceptors left – Prosthetic device (bionic eye)

• Subretinal or Epiretinal implant

ARGUS II (second sight, USA)

– Over 150 patients implanted with a 60 electrode array

– Expanding into Europe....and maybe Australia


Subretinal implant

Acknowledgement: Professor Erica Fletcher


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What will people see?

16 Phosphenes


64 Phosphenes



1000 Phosphenes



Original Picture


Optometry as a health

care profession

CFEH is here to help!


Optometry and duty of care to detect disease

Glaucoma: most deprived present with worse vision

(Index of Multiple Deprivation)

Yip et al Public Health 2015; Sharma et al BJO 2014


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Optometry and duty of care to detect disease

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2015

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