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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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
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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
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OCT
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OCT
Kalloniatis et al EER 2015
Retinitis Pigmentosa
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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)
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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
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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
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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
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Age related macular degeneration:
Is it a rod-cone disease?
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)
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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)
Age related macular degeneration:
Is it a rod-cone disease?
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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
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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
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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’
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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’
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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
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Tan et al (1995) X-inactivated transgenic marker
X*X* X*X XY
On average, 50% paternal and 50% maternal
X-choromosomes are inactivated
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Low marker
expression
High marker
expression
Tan et al (1995) X-inactivated transgenic marker
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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
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. . . . . . . .
. . . . . . . . . .
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
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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
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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
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OCT in this patient
Fundus appearance and other clinical features is consistent with inherited
‘Retinitis Pigmentosa’
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Visual Field (48 yo male RP suspect with 6/7.5
OU and no family history of eye disease)
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“Typical” visual field progression
Massoff’s work (stimulus dependent):
VF half life ~7.4-8.4yrs and critical age ~22-28 yrs
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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
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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
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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
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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
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‘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
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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
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Central macular OCT OD
WS
TS
SS
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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
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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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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?
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Optomap OD
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Optomap OS
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Fundus photographs
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OCT results
Not AMD as RPE largely intact
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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
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Different phenotypes: ABCA4 mutations less severe (Stargardt’s) to severe (atypical RP)
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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
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15 yo male with strong family history of male
associated vision loss
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X-linked retinoschisis
– ERG
• Confirmed normal a-wave
severely depressed b-wave
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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
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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
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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
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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
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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
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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
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Subretinal implant
Acknowledgement: Professor Erica Fletcher
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What will people see?
16 Phosphenes
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64 Phosphenes
What will people see?
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1000 Phosphenes
What will people see?
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Original Picture
What will people see?
Optometry as a health
care profession
CFEH is here to help!
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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