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 An initiative of Guide Dogs NSW/ACT and The University of New South Wales 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 An initiative of Guide Dogs NSW/ACT and The University of New South Wales OCT An initiative of Guide Dogs NSW/ACT and The University of New South Wales OCT Kalloniatis et al EER 2015 Retinitis Pigmentosa
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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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
OCT
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
OCT
Kalloniatis et al EER 2015
Retinitis Pigmentosa
Centre for Eye Health
2
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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)
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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)
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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?
Centre for Eye Health
3
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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’
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
Centre for Eye Health
4
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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’
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
Tan et al (1995) X-inactivated transgenic marker
X*X* X*X XY
On average, 50% paternal and 50% maternal
X-choromosomes are inactivated
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
Low marker
expression
High marker
expression
Tan et al (1995) X-inactivated transgenic marker
An initiative of Guide Dogs NSW/ACT and The University of New South Wales
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.
Centre for Eye Health
5
An initiative of Guide Dogs NSW/ACT and The University of New South Wales