ELECTRORETINOGRAM

I.

ERG RESPONSES A. Definition Mass response evoked from entire retina by a brief flash of light Measures panretinal response i.e. does not necessarily correlate with VA Occurs secondary to transretinal movement of ions induced by the light stimulus B. ISCEV Standard ERG (5 different responses allow interpretation) 1. Scotopic: Dark adapted (30 mins) Rod response (scotopic) Maximal combined response Oscillatory potentials 2. Photopic: Light adapted (10 mins) Single flash cone response (photopic) 30-Hz flicker responses

II.

ERG CHARACTERISTICS A. Normal ERG is biphasic a-wave: photoreceptor response (initial, fast, negative waveform) b-wave: Muller and BPC (next, slower, positive waveform) i. directly dependent on functional photoreceptors ii. magnitude = photoreceptor integrity Duration: usually less than 150 msec B. Amplitude (mV): Proportional to the area of functioning retina stimulated Abnormal only when large areas or retina impaired a-wave: baseline a-wave trough b-wave: a-wave trough b-wave peak iii. b-1: both rod and cone activity iv. b-2: mainly cone activity Implicit time (latency in msec): time to reach a peak (onset of stimulus to trough of a-wave or peak of b-wave)

C.

D. Technique Use of corneal CL electrode gives most accurate and reproducible results Alternative is to use skin just below lower eyelid margin Reference electrode placed on the forehead Pupils should be dilated and light flashes presented full-field (Ganzfeld) by bowl perimeter

III.

Scotopic ERG (Dark-adapted testing) A. Rod response 1000 more sensitive to light than cones Dark adaptation for at least 20 mins Dim white or blue flash below cone threshold Waveform: prominent b-wave but almost no detectable a-wave

B.

Maximal combined rod and cone response Bright flash in dark adapted state Maximally stimulates both cones and rods Waveform: large a- and b-wave with oscillatory potentials superimposed on ascending b-wave Oscillatory potentials Isolated by filtering out slower ERG components Result of feedback interactions between Amacrine and interplexiform cells Reflects primarily cone function Reduced in ischaemic states and some forms of CSNB

C.

IV.

PHOTOPHIC ERG (LIGHT-ADAPTED) A. Single flash cone response Obtained by maintaining patient in light-adapted state Stimulus: bright white flash Rods suppressed by light adaptation and do not contribute to waveform Results in an a-wae and b-wave with small oscillations B. 30-Hz flicker responses Rods can respond to stimulus up to 20 Hz (8Hz clinical situations) Stimulus: 30 Hz measures cone response only Normally shows a b-wave implicit time of less than 32 msec Allows easy assessment of ERG timing Elicited up to 50 Hz after which individual responses not recordable (critical flicker fusion)

V.

ERG INTERPRETATION A. Cone density ERG does not distinguish between macular and peripheral lesions on the basis of cone and rod signals Although cones are more populous in fovea, 90% lie beyond macula a. Large atrophic macular scar: cone (photopic) b-wave amplitude would be reduced by 10% only b. Macular lesion with reduced photophic ERG: diffuse cone degeneration beyond macula B. Amplitude dependent on Stimulus intensity Pupil size Area of retina stimulated Refractive error a. ERG relatively insensitive to refractive error b. High myopia: reduced signals but not to extent of hereditary degeneration Age c. Elderly show reduced amplitude vv. younger d. Newborn: small ERG signal but rises rapidly in first few months Optic nerve lesions e. Debate as to whether occasionally enhance the ERG (interrupted centrifugal inhibitory signals)

VI.

OTHER ERG TYPES A. Early receptor potentials and c-wave 1. ERP Small response occurring with no detectable latency before the a-wave Evoked by an intense flash Correlated with electrical charge in cell membrane during conversion of lumirhodopsin to metarhodopsin 60-80% of amplitude generated by cones Used primarily in research to measure visual pigment bleaching and regeneration 2. C-wave Late response occurring 2-4 seconds after stimulus in dark adapted eye Generated by RPE B. Focal (Foveal) ERG Stimulate only foveal or parafoveal cones Suppress rods and prevent interference with bright light Rapidly flickering stimulus used so that several hundred small ERG responses can be summated Used primarily when clinical findings do not correlate with patients VA Provides objective information on the presence/absence of macular disease Multifocal ERG

C.

Topographic map of the retina o Cone-generated responses that subtend 25 radially from fixation Can determine macular dysfunction in patients with stable and accurate fixation e.g. early detection of hydroxychloroquine toxicity Evaluate or compare treatment responses in various macular conditions Further transformation showing differences between recorded and reference (normal subjects) mfERG can highlight areas of visual loss

D. Bright flash ERG Flash stimulus brighter than usual e.g. high intensity photographic strobe Judges retinal function in eyes with opaque media prior to vitrectomy for e.g. retinal trauma An unrecordable ERG indicates poor prognosis due to widespread retinal damage A moderate signal e.g. 50V suggests salvageable retina Gives no direct information about VA or possible ON damage E. Pattern ERG Objective assessment of central retinal function Elicited by an alternating checkerboard stimulus Responses to several hundred stimuli (alternations) averaged Recorded with a conductive fibre or foil electrode touching cornea Localised to RGC (although generated by RGC, normal functional retinal cells distally are required also) Diagnose or monitor glaucoma, OHT, ON, OA and amblyopia Difficult reproducibility Confounding factors e.g. cataract and maculopathy Components a. P50: positive, prominent, 50ms (macular photoreceptors) b. N95: negative, larger, 95ms (RGC)

VII.

APPLICATIONS A. Diagnosing and following generalised retinal dystrophies 1. Evaluation of macular disease peripheral involvement a. RP b. Retinitis punctate albescens c. Lebers congenital amaurosis d. Choroideraemia e. Gyrate atrophy f. Achromatopsia g. CSNB h. Cone dystrophies i. Goldman-Favre syndrome j. XL Juvenile Retinoschisis k. Disorders mimicking RP 2. Distinguish diffuse disease vs focal disease a. Diffuse: hereditary dystrophy, drug toxicity i. Reduced amplitude and cause delayed and abnormal waveforms (reflects gross malfunction) b. Focal: BVO, regional uveitic damage i. Reduced amplitude in proportion to area of damage with normal waveform and timing B. Assess family members for known hereditary disease 1. X-Linked conditions e.g. choroideremia a. Female carriers show mosaic pattern b. ERG shows subtle abnormalities 2. Children a. Reveal abnormalities prior to symptoms or signs b. Can be performed without GA, although oral sedation may be required Assess decreased vision and nystagmus present at birth

C.

D. Chronic ischaemic damage from vascular disease 1. Retinal capillary loss or vascular insufficiency 2. Abnormal b-wave and oscillatory potentials e.g. delayed implicit time reduced amplitude 3. Inversion of b:a-wave ratio or delay in 30 Hz flicker is an ominous sign in CRVO E. Asssess retinal function in the presence of opaque ocular media 1. Reasonable signal behind opaque media indicates attached functional retina 2. Differentiate traumatic from toxic effects of FB e.g. siderosis 3. Drug toxicity e.g. thioridazine, chloroquine Evaluate functional visual loss

F. VIII.

CAUTIONS A. Normal values vary with recording technique and should be provided by each laboratory B. Variations in lightning and recording conditions (flash intensity, light and dark adaptation) can all greatly affect test results C. Difficult to dark adapt children for 30 mins: dim light (mesopic) conditions used to evoke predominantly rod-mediated responses D. Interpretation difficult in first few months of life before adult waveforms developed E. Anaesthesia can depress ERG responses

F.

Cataract or corneal opacity may act as a diffuser of light occasionally resulting in supernormal ERG

Interpreting ERG results Nonrecordable/Extinguished ERG (Reduced a and b waves) LCA Retinal aplasia RP TRD OAO TRD Metallosis Diffuse unilateral subacute neuroretinitis (DUSN) Drugs (phenothiazines, chloroquine) Cancer and Metastatic associated retinopathy Negative wave form (normal a wave, reduced b wave) CSNB XL Retinoschisis CRVO/CRAO Myotonic Dystrophy Duchenne Muscular Dystrophy Oguchis disease Quinine Toxicity Enhanced S-cone (Goldmann-Favre) Some auto-immune retinopathies OA or CRAO (transynaptic degeneration from RGC to BPC) Abnormal cone and rod b-wave amplitudes Abnormal/Nonrecordable Photopic ERG

Often mild rod ERG abnormality

Cone degenerations Achromatopsia XL blue-cone monochromatism XL cone dystrophy with tapetal-like sheen

Abnormal/Nonrecordable Scotopic ERG Abnormal photopic b-wave ERG Rod-cone degenerations (RP) LCA Choroideraemia Chorioretinitis (variable) Secondary RP (storage disease) Progressive retinitis punctate albescens Non recordable rod ERG Abnormal dark-adapted FERG Normal to near-normal photopic ERG CSNB Early RP (rare) which is progressive Reduced oscillatory potentials Increased risk of developing severe PDR Non-specific Metallic FB Chorioretinitis (acute or old) Early pan-retinal degeneration Partial RVO Low serum taurine Vasculitis/DR

Cones more affected than rods

Cone-rod degenerations/dystrophies (AD, AR, XR) Post-inflammatory degenerations

ELECTRO-OCULOGRAM

I.

PRINCIPLES A. Standing potential 1. Positive voltage at cornea (6-10mV) 2. Generated across RPE cell 3. Activation of PR leads to changes in ionic composition of subretinal space 4. Exposure of steady light to dark-adapted eye leads to slow increase in standing potential across RPE 5. Light response reaches peak 5-10 mins after onset a. Affected by movement artefact and electrical drift B. Electro-oculography 1. Indirectly measures the standing potential 2. Electrodes placed on skin at canthi o 3. Voltage between them recoded as patient looks left to right over 30 4. Amplitude a. Dominated by the rod system (mass response) b. Proportional to the actual voltage across the eye 5. International standard technique a. Placement b. Time of adaptation c. Light intensity (=pupil dilation) Arden (Light-Dark) ratio 1. Light peak/Dark trough x 100 a. Normal: 1.85 or 185% (considerable variation) b. Subnormal: 1.65 c. Severe: 1.30

C.

II.

INDICATIONS AND LIMITATIONS A. Indications 1. Best vitelliform dystrophy a. Most specific test for RPE involvement with normal retina: diagnosis, early detection and screening b. Evaluate any manifestation e.g. yellow lesions, macular scars 2. Aid diagnosis of CSNB and XLR a. Abnormal ERG (BPC region); EOG normal (normal rods) 3. ? Early chloroquine toxicity a. Serial testing may show progressive changes B. Limitations 1. Origin and meaning of electrical response is not well understood 2. Depends on integrity of both RPE and PR inner retina 3. Does not correlate with RPE pigmentary changes or visual function a. Diffuse fundus flavimaculatus or pattern dystrophy: RPE primarily involved but EOG is normal or mildly subnormal b. Rubella retinopathy: RPE diffusely altered but EOG is normal c. Best disease: normal retina but severely reduced EOG

III.

OTHER RPE TESTS A. ERG c-wave 1. Cornea-positive wave 2. Appears 1-5 secs after onset of light stimulus + 3. Represents hyperpolarisation of apical RPE in response to decrease in subretinal K 4. Difficult to record (too fast for EOG, too slow to avoid artefact) 5. Correlates clinically with EOG B. Fast oscillation 1. Cornea-negative wave 2. Appears 1-2 mins after light stimulus + 3. Represents delayed effect from K changes in subretinal space 4. Generated across basal RPE membrane 5. Probably involves chloride conductance pathways 6. Does not always mirror EOG in disease 7. May show changes in cystic fibrosis Non-photic responses 1. Changes in standing potential induced by chemicals 2. IV hyperosmolar solution, acetazolamide or sodium bicarbonate 3. Lead to depolarisation of basal RPE membrane 4. Provide information independent of photoreceptor activity

C.

VISUALLY EVOKED POTENTIALS

I.

PRINCIPLES A. Visually evoked cortical potential 1. Generated by the occipital visual cortex 2. Stimulated by light flashes or patterned stimuli (alternating checkerboard or stripes on TV monitor) 3. Response to many alternations or flashes is recorded and averaged 4. Use of checkerboard stimulus preferable when eye is optically correctable a. Cortex very sensitive to sharp edges and contrast b. Relatively insensitive to diffuse light 5. Determines macular function 6. Minimal peripheral retinal input 7. Reflects visual endpoint i.e. any abnormality between retina and cortex B. Normal pattern-evoked VECP 1. Recorded with electroencephalogram electrodes 2. Often the inion (back of occiput) is compared to locations to right and left 3. Characterised by 2 negative (N75 and N135) and 2 positive (P100) peaks 4. Amplitude and implicit times depend on check size, contrast and alternation frequency 5. Absolute amplitudes: difficult due to variability among normal individuals 6. Implicit times: less variable and more reliable 7. P100 latency is most useful clinical indicator Interpretation 1. Optic nerve dysfunction: decreased amplitude, increased P100 latency 2. Delays also common in macular dysfunction i.e. delayed VEP ON disease

C.

II.

INDICATIONS A. B. C. D. E. F. G. Confirm diagnosis of optic neuropathy and other demyelinating disease Assess misprojection of optic nerve fibres e.g. albinism VEP acuity in infants and nonverbal children: increased VA = response to decreased stimuli Detect and locate VF defects e.g. comparing response to stimuli in different locations Evaluate potential for reasonable VA in pts with media opacities Amblyopia Detection of malingering

III.

ELECTRICALLY EVOKED POTENTIALS A. B. C. D. E. F. G. Evoked by mechanical and electrical stimuli Brief electric current (0.5 mA) passed through eye Generates neural signal transmitted to visual cortex Causes a sensation of light (phosphene) Cortical response recorded similarly to VECP Indicator of retinal integrity and subsequent visual pathway Evaluate condition and salvageability of traumatised eyes with hge and possible RD in which even bright-flash ERG is unrecordable

PSYCHOPHYSICAL TESTING

I.

PRINCIPLES A. Electrophysiological testing 1. Objectively measures cell layers and cell types 2. Does not always allow testing of localised responses 3. May not be sensitive to small degrees of visual dysfunction B. Pyschophysical tests 1. Types a. VA b. VF c. Dark adaptation d. Colour vision e. Contrast sensitivity 2. Advantages a. Exceedingly sensitive b. Always subjective c. Usually not tissue specific

II.

DARK ADAPTATION A. Principles 1. Measures the absolute thresholds of cone and rod sensitivity a. Human eye sensitive to range of 10-11 log units b. Complementary or more sensitive to ERG i.e. focal test 2. Most often tested on instrument e.g. Goldmann-Weekers adaptometer a. Light adapted to bright background light sufficient to bleach 25% of rhodopsin o b. Light extinguished followed by series of dim light targets 11 below fixation c. Light intensity controlled by neutral density filters d. Minimally perceived threshold plotted against time 3. Dark adaptation curve shows 2 plateaus (bipartite plot) a. Cone threshold: cone sensitivity rapidly improves (reached in 5-10 mins) b. Rod-cone break: cones achieve maximum sensitivity (7-10 mins) c. Rod threshold: reached after 30 mins i. If clinical interest is only rod sensitivity in the dark, test can be shortened by eliminating first step of adaptation to bright light B. Indications 1. Night blindness (nyctalopia) 2. Cone dysfunction syndromes 3. Drugs affecting dark adaptation e.g. vitamin A analogues (isoretinoin) 4. Malingering

III.

COLOUR VISION A. Colour perception 1. Response to electromagnetic energy at wavelengths 400-700 nm 2. Absorbed by cone outer segment visual pigments 3. Each cone contains 1 of 3 types of photolabile pigments 4. Initiators of colour vision

a. Tritan: Blue-sensitive (short; 414-424nm) b. Deuteran: Green-sensitive (middle; 522-539nm) c. Protan: Red-sensitive (long; 549-570nm) 5. Integrative cells (retina, higher visual centres) organised primarily to recognise contrasts between light or colours B. Classification 1. Red-green colour deficiency 2. Blue-yellow colour deficiency Tests 1. Anomaloscope a. Most accurate instrument for classifying congenital red-green deficiency b. Not widely used c. Patient views split screen i. Match yellow appearance of one half by mixing varying proportions of red and green light in the other half ii. Abnormal proportions used to make the match 2. Pseudoisochromatic plates a. Ishihara i. Coloured numbers or figures standing out from background of coloured dots ii. Defects result in either no pattern or alternative pattern seen based on brightness rather than hue iii. Can be done quickly iv. Sensitive for screening congenital protan and deuteran defects v. Not effective in classifying the deficiency vi. Require blue-white light (mimics sunlight) b. Hardy-Rand-Rittler i. More sensitive as can detect all 3 congenital colour defects 3. City University test a. 10 plates each containing a central colour and 4 peripheral colours b. Subject selects peripheral colour closely matching central one 4. Panel tests a. Farnsorth-Munsell 100-hue test i. Consists of 85 hue caps divided into 4 racks ii. Difference in hues approximates the minimum difference observed normally (1-4 nm) iii. Each of the 3 forms of dichromatism characterised by filure in a specific meridian of the chart iv. Very sensitive v. Time consuming and fatiguing b. Farnsorth Panel D-15 i. Single box of 15 coloured tablets ii. Hues are much more saturated and cover spectrum so that patients will confuse colours for which they have deficient perception iii. Speed and accuracy make it useful iv. Not very sensitive and may miss mildly affected individuals v. Discriminates well between congenital and acquired defects Congenital: precise protan or deutan pattern Acquired: irregular pattern of errors B-Y: preferentially affected in acquired retinal diseases

C.

DIFFUSE PHOTORECEPTOR DYSTROPHIES

I.

RETINITIS PIGMENTOSA A. Aetiology 1. Definition Clinically and diverse group of diffuse retinal (RPE and NSR) dystrophies TRIAD: nyctalopia, progressive VF loss and abnormal ERG Rod-cone dystrophy: initially predominantly affects rods then cones Prevalence: 1 in 5,000 (most common hereditary retinal dystrophy) Gene mutation: rhodopsin gene

B. Inheritance 1. AR (20%) Most common, severely reduced VA and night blindness occur early Incidence increased if including families with several affected siblings (multiplex RP) or parent consanguinity 17 genetic types identified: 12 cloned 2. AD (10-20%) Least severe, gradual onset of RP, typically adult life with variable penetrance Late onset cataract, less severe VA loss 16 genetic types identified: 14 cloned Rhodopsin gene mutations: mild e.g. a form of CSNB is associated with codon 90 mutations; severe e.g. mutations interfering with attachment of vitamin A to rhodopsin protein 3. XLR (10% USA, 25% England) Rarest, most severe, onset similar to AR rd th Severe VA loss (complete blindness by 3 to 4 decade) Female carriers often have salt-and-pepper fundus and/or golden-metallic (tapetal) reflex at macula 6 genetic types identified: 2 cloned 4. Rare

Sporadic: isolated; more favourable prognosis similar to AR Mitochondrial XLD

GENES INVOLVED IN RP AD Rhodopsin Peripherin-RDS NRL RP1 FSCN2 PRPC8 AR PDEB PDEA CNCG Rhodopsin RLB1 TULP1 ABCR4 RPE65 RP12 USH2A XL RPGR RP2 DIGENIC RDS and ROM1

CRB1

C.

Clinical features 1. Symptoms TRIAD: Bilateral involvement (may be asymmetric), peripheral VF loss and nyctalopia Night vision: decreased, often night blindness Peripheral vision: decreased Central vision: decreased, early or late Colour vision: intact until late Signs

2.

TRIAD: bone-spicule pigmentation, arteriolar attenuation (earliest sign) and waxy optic disc pallor (least reliable) Peripheral pigment clumps: perivascular, often bone-spicule (may be absent) RPE: depigmentation, atrophy, unmasking of choroidal vessels Macula: TRIAD of Atrophy, ERM and CMO

DIFFERENTIAL DIAGNOSIS (DISC) Drug toxicity Quinine/hydroxychloroquine Phenothiazine Infective Syphillis Congenital rubella Measles Inherited Bietti crystalline dystrophy Pigmented paravenous retino-choroidal atrophy Ocular Albinism carrier Vascular OAO CRAO Scarring Chronic CSR Laser PRP scars Toxaemia of pregnancy RD Severe blunt trauma (spontaneous resolved RD) Harada disease Paraneoplastic syndromes CAR/MAR

D. Associated ocular features 1. Anterior segment (TRIAD) Posterior subcapsular cataracts: common in all forms of RP; surgery often beneficial OAG: 3% of cases Keratoconus: uncommon 2. Posterior segment (TRIAD) Optic disc: drusen Myopia degenerative changes including PVD, intermediate uveitis Coats-like disease: lipid deposition in periphery; occasional exudative RD

Atypical RP Cone-rod dystrophy (central/pericentral RP) Cones affected earlier and more severely Presentation with impaired central vision not nyctalopia

Macular signs peripheral changes RP sine pigmento Absence or paucity of pigment accumulation Retinitis punctate albescens AR variant; whitish-yellow spots, mostly at equator Usually sparing macula and associated with arteriolar attenuation More radial pattern vs. fundus albipunctatus Sector RP AD variant; generally symmetric involvement of 1-2 sectors e.g. inferior quadrants Slow progression; many stationary Unilateral RP Rare; usually sporadic; Diagnosis requires normal ERG in fellow eye

E.

Management 1. Investigations Fundus photographs ERG: early - reduced scotopic (rod and combined) response; late reduced photophic response and eventually extinguished ERG (not diagnostic); female carrier mild reduction or delay in b-wave response EOG: subnormal (absent light rise) DA: prolonged useful in early cases when diagnosis uncertain; female carriers of XL disease often have abnormal results VF: progressive loss, usually ring scotoma, progresses to small central field

KINETIC VF TESTING Rod-cone RP Contracted fields, with smaller isopters showing higher thresholds of sensitivity Large spaces between smaller and larger isopters Partial to full ring scotomata are common in mid-equatorial region Eventually melt into peripheral isopters leaving central island Cone-rod RP Isopters contract over time but tend to be close to each other Ring scotomata are closer to fixation Primary cone dystrophy and non-RP cone dystrophy Maintain full isopters Central scotomata are common

2. Treatment Genetic counselling Tinted lenses: comfort outdoors, better contrast sensitivity LVA, vocational rehabilitation and mobility training 0 Blind registration: VF < 20 Vitamin A palmitate (15,000 IU): slows reduction of ERG by 20% but no visual benefit a. Unknown risk of long-term SE: liver toxicity b. Teratogenic: avoid in pregrancy Cataract surgery

Acetazolamide PO: CME Future: gene replacement therapy, retinal cell transplantation, humoral factors

II.

ASSOCIATED SYSTEMIC DISEASE (SECONDARY RP) A. Refsum disease (Phytanoyl-COA Hydroxylase deficiency) AR TRIAD: Increased serum Phytanic acid, Peripheral neuropathy, Palpitations Investigation: elevated fasting serum phytanic acid or reduced phytanic acid oxidase activity in cultured fibroblasts RP: often without bone spicules, nyctalopia, reduced ERG Infantile: dysmorphic facies, mental handicap, hepatomegaly and deafness Adult: cerebellar ataxia, polyneuropathy, deafness, anosmia, cardiopathy and ichthyosis Treatment: low-phytanic acid, low-phytol diet (minimise milk products, animal fats and green leafy vegetables) B. Bassen-Kornzweig syndrome (Hereditary Abetalipoproteinaemia) AR (usually without bone spicules) TRIAD: Abetalipoproteinaemia, Acanthocytosis, Ataxia Abetalipoprotein not synthesised: fat malabsorptioon and fat-soluble vitamin (AEK) deficiency GI symptoms: failure to thrive, fat intolerance, steathorrhea Neurological: spinocerebellar ataxia Ocular: nyctalopia, progressive restriction of EOM, ptosis, strabismus, nystagmus Investigations a. Vitamin A deficiency: diagnostic b. Serum cholesterol and triglycerides: reduced c. Serum protein electrophoresis: lipoprotein deficiency d. Peripheral blood smears: acanthocytosis (crenated thorny RBC) Treatment a. Vitamin supplements (AEK) zinc b. Restrict dietary fat to 15% caloric intake c. Biannual serum levels of vitamins A and E, yearly ERG and DA C. Kearns-Sayre syndrome Mitochondrial inheritance TRIAD: CPEO, atypical RP, heart block Onset usually before age 10 Mitochondrial myopathy: abnormally shaped mitochondria and increased in number, ragged-red fibres on muscle biopsy, includes CPEO Salt-and-pepper degeneration with normal arterioles Ocular: CPEO without diplopia, ptosis (usually < 20 years) Short stature and cardiac defects (death from complete heart block) Treatment: refer cardiology for sequential ECG, may need pacemaker

D. Bardet-Biedl syndrome Previously classified AR but many are multigenic (12 genes identified) Proteins: mediate and regulate microtubule-based intracellular transport 15% show retinopathy by 10 years of age; 80% are blind by 20 years Retina: severe RP, macular pigment mottling (Bulls eye maculopathy), peripheral retinal atrophy, usually without bone-spicule pigment clumping

Systemic TRIAD: Obesity (truncal), Polydactyly, Hypogonadism; puffy hands with indistinct knuckles, renal anomalies (urethral reflux with pyelonephritis and kidney damage), Learning disability (special education support)

Differential Diagnosis of RP and Renal disease Alport syndrome

Alstrom syndrome Familial juvenile nephronophthisis (AR) Senior-Loken syndrome (AR) Type II membranoproliferative glomerulonephritis

E.

Usher syndrome Accounts for 5% of profound deafness in children and 50% of combined deafblindness Prevalence: 3 per 100,000 Inheritance: AR (type 1 and 2); 11 types with known chromosome location (9 cloned genes) Protein: present in hair cells of inner ear and photoreceptor cells Fundus: salt and pepper pigmentation, OA Ocular: miosis, cataract, orbital fat atrophy Systemic: premature ageing beginning in infancy, dwarfism, skeletal abnormalities, deafness, photosensitivity, mental disability and early death

Classification Type 1 Type 2 Type 3

Incidence 75% 23% 2%

Onset 1 decade 2 decade Late

nd st

Deafness Congenital, profound, vestibular dysfunction Congenital, partial, normal vestibular function Progressive hearing loss and vestibular dysfunction

Differential Diagnosis of Ocular Associations and Hearing Loss Systemic disease and RP Alport syndrome Uveitis Congenital syphilis Congenital rubella VKH Other Cogans interstitial keratitis DIDMOAD

Alstrom syndrome Cockayne syndrome Dysplasia spondyloepiphysaria congenital Hurler syndrome Refsum disease

F.

Batten disease (Neuronal Ceroid Lipofuscinosis AR: 7 genes identified Accumulation of waxy lipopigments (ceroid and lipofuscin) within lysosomes of neurons and other cells Accumulation activates cellular dysfunction and apoptosis Characteristics: progressive dementia, seizures and visual loss with RP Diagnosis: clinical and characteristic inclusions (curvilinear, fingerprint or granular) on EM of a peripheral blood smear or tissue biopsy (including conjunctiva) Infantile NCL: OA, macular pigmentation, peripheral mottling, low or absent ERG Late infantile and juvenile NCL: macular granularity or Bulls eye maculopathy, variable RP, vessel attenuation and OA Adult NCL: no ocular manifestations

G. Cystinosis (Amino acid disorders) Accumulation of intralysosomal cystine due to defective export AR, 3 types: nephropathic, late-onset (intermediate) and benign Cornea and conjunctiva: all 3 types RP: nephropathic only; patchy RPE depigmentation alternating with irregularly distributed pigment clumps

Systemic: asymptomatic till age 8-15 months; progressive renal failure, growth retardation, renal rickets and hypothyroidism Treatment: cysteamine (reacts with cysteine to form a mixed disulphide that can leave the lysosome) may be beneficial

III.

LEBER CONGENITAL AMAUROSIS A. Aetiology 1. Definition Infantile to early childhood form of RP Commonest genetic cause of visual impairment in infants and children Severe mutations result in LCA i.e. rod-cone dystrophy; mild mutations lead to later-onset cone-rod dystrophy Primary LCA: 9 known monogenic forms Complicated LCA: systemic disease resulting in severe LCA (seizures, CNS and mental detioration, usually with an obvious decline in school performance) Prognosis: very poor 2. Inheritance Usually AR Genetically very heterogenous: 14 gene loci identified a. CEP290: 15% b. GUCY2D: 12% c. CRB1: 10% Involved genes code for critical proteins in visual transduction cycles Mutations cannot be identified in approx. 30% Genetic testing: confirm diagnosis, predict prognosis and counselling Histology: diffuse absence of photoreceptors B. Clinical 1. Symptoms VA range: 6/60 to NPL at birth Roving eye movements or wandering nystagmus Oculodigital syndrome: results in enophthalmos from orbital fat atrophy Photoaversion 2. Signs 3. ERG Usually non-recordable or severely impaired even with normal appearing fundi

Pupil reflexes: absent or diminished Fundi: normal initially apart from mild arteriolar narrowing Retina: mild peripheral RP, salt-and-pepper changes, yellow flecks (less frequently), white dots (similar to retinitis punctate albescens) Macula: severe pigmentation or coloboma-like atrophy OD: OA (later childhood), disc oedema (uncommon)

Differentiates LCA from dystrophic disease (reduced ERG with age) Requires repeating at a later stage as there is maturation of the normal ERG response in the first year of life e.g. delay ERG till 6 months or repeat after this time

C.

Associations 1. Ocular

High refractive errors: usually hyperopia Strabismus Keratoconus Keratoglobus Cataract

2. Systemic Mental disability (most children have normal intelligence) Deafness Epilepsy and CNS anomalies Renal anomalies Skeletal malformations Endocrine dysfunction

DIFFERENTIAL DIAGNOSIS Ocular Albinism Achromatopsia CSNB Optic nerve hypoplasia Systemic disorders Alstrom syndrome Batten disease (Neuronal ceroid lipofuscinosis) Joubert syndrome Peroxisomal disorders Zellweger syndrome (cerebrohepatorenal) Neonatal Adrenoleukodystrophy Refsum disease Senior-Loken syndrome

IV.

CONE DYSTROPHIES A. Aetiology 1. Definition No evidence of rod dysfunction or predominant progressive cone deficiency (cone-rod dystrophy) 2. Inheritance Sporadic: most common Mutations described in 12 genes: AD usually or XL less often AD: a. GUCA1A (guanylate cyclase activator 1A) calcium-binding protein defect expressed in photoreceptor OS (6p21.1) b. GUCY2D (17p13.1) XLR: a. Adult-onset b. Tapetal retinal reflex: bright green or golden fundus reflex c. Mizuo-Nakamura phenomenon: fundus appearance changes with DA B. Clinical 1. Symptoms nd th Bilateral gradual reduced central and colour vision in 2 -4 decade Often associated hemeralopia (day blindness) and photophobia (light intolerance) Prognosis: poor with severe central VA loss (6/60 or CF) 2. Signs

Macula: normal, non-specific pigmentary changes Tapetal retinal reflex (golden sheen) particularly in XL Bulls eye maculopathy: classic but not always RPE atrophy: progressive with eventual GA OA: temporal (mild to severe) Nystagmus

3. Investigation ERG: subnormal or non-recordable cone response (reduced single-flash and flicker fusion); preserved rod-response till late EOG: normal or sub-normal DA: abnormal cone segment; normal to sub-normal rod segment CV: severe deuteran-tritan defect out of proportion to VA VF: peripheral remain normal (differentiate from RP patterns) FFA: bulls eye maculopathy round hyperfluorescent window defect with hypofluorescent centre
DIFFERENTIAL DIAGNOSIS OF BULLS EYE MACULOPATHY Children Adults

Bardet-Biedl syndrome Hallervorden-Spatz syndrome LCA Batten disease (Neuronal Ceroid Lipofuscinosis) AD olivopntocerebellar ataxia

Stargardt disease (advanced) Cone and cone-rod dystrophy Fenestrated sheen macular dystrophy Central areolar choroidal dystrophy Toxic retinopathy (chloroquine, clofazimine)

C.

Cone-Rod Dystrophies 1. Definition Cones affected proportionately more than rods and both are abnormal Depends on mutation severity: severe mutations result in LCA whilst less severe result in cone-rod dystrophy
Associated Genes ABCA4: Stargardt ALMS1: Alstrom SCA7: AD spinocerebellar ataxia GUCY2D: LCA CRX: RP or LCA

2. Clinical D. Treatment

Expanding central scotomata Progressive severe VA loss Nyctalopia and dyschromatopsia Late: bone-spicule hyperpigmentation and fundus atrophy

1. Tinted glasses or contact lenses 2. Miotic drops 3. Genetic counselling 4. LVA

MACULAR DYSTROPHIES

I.

STARGARDT DISEASE (JUVENILE MACULAR DEGENERATION) A. Aetiology Definition Most common hereditary macular dystrophy (7% of all retina dystrophies) Common cause of central VA loss < 50 years Bilateral, symmetric, progressive condition Triad: macular atrophy, flecks and dark choroid Fundus flavimaculatus: variant of same disease a. Often presents in adulthood, may be an incidental finding, vision may not be impaired b. Flecks: widely scattered throughout fundus Inheritance AR: most common AD pedigrees reported Gene mutations: a. ABCA4: 1p21-22; encodes retina specific ATP-binding cassette (ABC) transporter protein expressed by rod OS b. STGD4 c. ELOVL4: AD; 6q; photoreceptor-specific component of FA elongation d. RDS/peripherin

B. Clinical Symptoms VA: reduced in childhood or young adulthood; typically deteriorates between ages 8 and 15 years Decrease in VA out of proportion to fundus appearance (vs. malingering) Signs

Fundus: relatively normal appearance except for heavily pigmented RPE i.e. may be detectable on AF (patient may be considered functional) Loss of foveal reflex Flecks: bilateral, yellow or yellow-white, usually in pisciform (fish-tail) configuration at level of RPE, at posterior pole or extending to midperiphery Macula: Bulls eye maculopathy, oval snail-slime orbeaten-bronze appearance, pigment clumping or marked GA

Differential Diagnosis Bulls eye maculopathy Drusen Fundus albipunctatus Retinitis punctate albescens Progressive cone-rod dystrophy Non-physiological

C.

Management Investigations AF: may be present OCT: characteristic thinning of PR layer FFA: dark choroid or midnight fundus (blockage of choroidal fluorescence secondary to increased lipofuscin in RPE) present in 80% ICG: hypofluorescent spots ERG: typically normal in early stages; normal to sub-normal photopic; normal scotopic EOG: subnormal in advanced Prognosis Maculopathy: poor VA loss: rapid progression beyond 6/12; stabilizes at 6/60 CNV: uncommon

II.

VITELLIFORM DEGENERATIONS A. Best disease (Juvenile-onset vitelliform macular dystrophy) Definition Second most common macular dystrophy EOG is always abnormal but the retina may initially appear normal Inheritance AD: variable penetrance and expression BEST1 (VMD2) gene (11q13): encodes besotrophin located in RPE basolateral plasma membrane functioning as chloride channel Carriers: normal fundi but abnormal EOG Symptoms VA: decreased or asymptomatic Onset at birth but may not be detected until years later Amsler changes: if CNV
Stages 1 Pre-vitelliform Asymptomatic Fundus: normal EOG: subnormal Asymptomatic Infancy or early childhood: ages 4-10 years Egg yolk: yellow, round, subretinal cystic lesion (lipofuscin) Typically bilateral: 10% multiple and extrafoveal May occur at puberty Cystic rupture and partial resorption Central VA remains good: 6/12 Scrambled egg: cystic lesion becomes granular Scarring or atrophy

Vitelliform

Pseudo-hypopyon

Vitelliruptive

End-Stage

Serous detachment

Other Signs CNV: 20% of patients Subretinal haemorrhage Hyperopia esophoria/esotropia Investigations EOG: always abnormal showing a severe loss of light response during all stages; typically < 1.5 and often near 1.1; abnormal in carriers ERG: normal OCT: material within RPE FFA: corresponding hypofluorescence due to blockage; hyperfluorescence if CNV Treatment No effective treatment th Prognosis: good until 5 decade; VA loss due to CNV, scarring or GA CNV: PDT, Anti-VEGF, laser

B. Adult-onset Definition Most common adult-onset vitelliform disorder Belongs to pattern dystrophy group Foveal lesions: smaller, do not show similar evolutionary changes th th Onset: 4 to 6 decade Inheritance RDS/peripherin gene (6p): most common BEST1 gene AD recognised in some families Symptoms VA loss: asymptomatic, mild to moderate Metamorphopsia Signs

Vitelliform lesions: bilateral, symmetrical, round or oval, yellowish subfoveal deposits, typically 1/3 DD, often central pigmented spot Drusen: occasional Vitelliform exudative macular detachment: basal laminar (cuticular) drusen Drusenoid RPE detachment: large central coalescence of drusen

Investigations FFA: central hypofluorescence surrounded by a small irregular hyperfluorescent ring EOG: normal or mildly subnormal

III.

PATTERN DYSTROPHIES A. Aetiology

 Definition Generic term including several retinal dystrophies Exhibit various morphological yellow, orange or grey macular deposits Lesions associated with accumulation of lipofuscin at RPE level Clinical pattern can vary among affected family members or even between the 2 eyes of one patient and can evolve from one pattern to another Inheritance Usually present in isolation; typically in midlife Described in association with a. Myotonic dystrophy b. Kjellin syndrome: spastic paraplegia and dementia c. Pseudoxanthoma elasticum

Common Characteristics AD inheritance: mostly associated with RDS/peripherin gene mutations Variable expression Bilateral symmetrical involvement Relatively benign course: small risk of CNV Normal ERG Occasionally abnormal EOG: consistent with diffuse RPE disorder

4 Major Patterns Adult-onset vitelliform dystrophy Butterfly-shaped macular dystrophy nd rd Presentation: 2 -3 decade Asymptomatic or mild central VA loss Triradiate patterned yellow pigment; peripheral pigmentary stippling; atrophic maculopathy FA: non-fluorescent lesions with hyperfluorescent outline Reticular dystrophy Presentation: early childhood Initial pigment granules at fovea; reticular pigmentation spreading to periphery FA: enhances characteristic macular changes Fundus pulverulentus th Presentation: 4 decade; mild central VA loss Simulates fundus flavimaculatus FA: Hyper flecks but NOT dark choroid

IV.

FAMILIAL (DOMINANT) DRUSEN A. Aetiology Definition Early-onset variant of AMD rd Not uncommon for affected patients to develop drusen in 3 decade Inheritance Never established in vast majority AD with full penetrance but variable expressivity in pedigrees EFEMP1 on chromosome 2p16-21: EGF-containing, fibrillin-like, ECM protein (abnormal BM at RPE level) a. Doyne honeycombed dystrophy b. Malattia leventinese

B. Clinical Symptoms Central vision is good if drusen are discrete and extrafoveal Increased risk of AMD Signs

Drusen nd a. Radiating pattern: yellow-white, elongated (2 decade), often confluent b. Typically extend beyond vascular arcade and nasal to the disc c. Honeycomb pattern develops th th RPE degeneration, GA and occasional CNV (4 -5 decade)

Investigations FA: hyperfluorescent (more numerous than seen clinically) ERG: normal EOG: subnormal (advanced disease)

V.

SORSBY (PSEUDOINFLAMMATORY) MACULAR DYSTROPHY A. Aetiology Definition Also known as hereditary haemorrhagic macular dystrophy th Very rare condition; bilateral VA loss in 5 decade from subfoveal CNV Inheritance AD with full penetrance but variable expressivity TIMP3 on chromosome 22q12.13: tissue inhibitor of metalloproteinase (ECM remodelling) B. Clinical Symptoms rd 3 decade: nyctalopia th 5 decade: sudden VA loss due to exudative maculopathy th 7 decade: loss of ambulatory vision from GA Signs

Drusen-like deposits: numerous, fine, yellow-white, confluent, along arcades, nasal to disc and mid-periphery CNV: exudative maculopathy and subretinal scarring GA: pronounced black pigment clumps around central atrophic zones (pseudo-inflammatory appearance)

Investigations ERG: initially normal; subnormal in late disease

OTHER MACULAR DYSTROPHIES Benign concentric annular MD AD; mild VA loss in adult Bulls eye maculopathy Paracentral ring scotoma Annular window defect on FA Dominant CMO AD; gene locus on 7p st nd 1 -2 decade with gradual VA loss Bilateral CMO (INL) Flower-petal leakage on FA Unresponsive to systemic CAI Sjogren-Larsson syndrome Neurocutaneous disorder: congenital ichthyosis, spasticity, convulsions, mental disability, early death AR: 7p11; fatty aldehyde dehydrogenase defiency Bilateral glistening yellow-white crystalline macular deposits (?pathognomonic) Cataract, colobomatous microphthalmos, RP VEP: abnormal Familial ILM dystrophy rd th AD; presentation in 3 -4 decade Glistening inner retinal surface ERG: reduced b-wave

CHOROIDAL DYSTROPHIES

I.

DIFFUSE DYSTROPHY A. Choroideraemia 1. Definition Progressive, diffuse degeneration of choroid, RPE and PR Underlying defect probably in rod photoreceptors 2. Inheritance XLR with locus on Xq21.2 (CHM gene): stop mutation prevents normal production of Rab escort protein (REP-1) localised to RPE Female carriers: 50% of sons develop choroideraemia; 50% of daughters are carriers 3. Symptoms nd rd Nyctalopia: 2 -3 decade Constricted VF Female carrier: VA, peripheral VF and ERG are usually normal 4. Signs

Mid-peripheral RPE abnormalities (may mimic RP) RPE atrophy: central and peripheral spread (foveal sparing till late) End-stage: choroidal vessels over bare sclera, vascular attenuation and OA Female carrier: mild, patchy moth-eaten peripheral RPE atrophy and mottling Retinal vessels and optic disc relatively preserved Other: PSC, early vitreous degeneration

5. Investigations ERG: scotopic non-recordable; photopic severely subnormal; prolonged bwave implicit time; generally extinguished by midlife; usually normal in female carriers FA: filling of retinal and large choroidal vessels but NOT choriocapillaris; foveal window defect (Hypo fovea surrounded by Hyper)

Differential Diagnosis Gyrate atrophy High myopia Generalised choroidal dystrophy Thioridazine hydrochloride (Melleril) toxicity Bietti crystalline dsystrophy

B. Gyrate Atrophy 1. Definition Metabolic disorder: ornithine aminotransferase (OAT) gene mutation B6 cofactor: catalyses conversion of ornithine to glutamic--semialdehyde to proline

Enzyme deficiency: ten-fold elevation of ornithine levels in plasma, urine, CSF and aqueous humour which is toxic to RPE and choroid 2 clinical subtypes: a. Pyridoxine (vitamin B6) responsive: less sever and more slowly progressive clinical course b. Pyridoxine non-responsive

2. Inheritance AR with gene locus on 10q26 More common in Finland 3. Symptoms st nd Myopia and nyctalopia: 1 -2 decade 4. Signs

Mid-peripheral depigmented spots associated with diffuse pigmentary mottling Generalised hyperpigmentationof remaining RPE differentiates it from choroideraemia Characteristic scalloped and sharply demarcated circular/oval areas of CR atrophy numerous crystals at posterior pole Coalescence of atrophic areas with peripheral and central spread (foveal sparing till late) Vascular attenuation and vitreous degeneration, Other: myopia, astigmatism, early-onset cataracts (PSC), CMO or ERM

5. Investigations FA: sharp demarcation between CR atrophy and normal filling of choriocapillaris ERG: subnormal (early) or extinguished (late) Ornithine levels: serum or plasma OAT gene mutational analysis 6. Treatment Arginine-restricted diet: reduce ornithine levels Pyridoxine may normalize plasma and urinary ornithine levels

C.

Generalised Choroidal dystrophy AD; nyctalopia or central VA loss in 4 -5 decade Macula: pigment mottling, RPE atrophy (poor prognosis) Periphery: severe CR atrophy involving entire fundus ERG: subnormal
th th

II.

REGIONAL AND CENTRAL DYSTROPHY

Common Characteristics

Demarcated macular atrophy of RPE and choriocapillaris Normal full-field ERG reponse Differences in onset and progression Differentiated from toxoplasmosis, AMD or Bulls eye maculopathy

A. Central Areolar Choroidal Dystrophy (CACD) AD with gene locus on 17p RDS/peripherin gene mutations affecting arginine residue rd th Gradual central VA loss: 3 -4 decade th th Prognosis: poor with SVL by 6 -7 decade Non-specific foveal granularity RPE atrophy and loss of choriocapillaris at macula GA atrophy with prominence of large choroidal vessels CNV: rare

B. North Carolina Macular Dystrophy Very rare non-progressive condition: stabilizes in teenage years VA usually better than anticipated clinically (6/6 to 6/60) AD with complete penetrance but highly variable expression MCDR1 gene on 6q16

Grading and Prognosis Grade 1 Cluster of yellow-white, drusen-like peripheral and macular deposits Increased number and deep, confluent macular deposits Coloboma-like atrophic macular lesions Develop during 1 decade May remain asymptomatic Guarded prognosis: risk of CNV
st

Grade 2

Grade 3

Variable VA loss

C.

Progressive bifocal chorioretinal atrophy AD; gene locus also on 6q (only described in UK) but progressive Presents at birth Focus of CR atrophy: initially temporal to disc extending in all directions; similar lesion develops nasally Late: distinct areas of CR atrophy separated by normal segment

INNER RETINAL AND VITREORETINAL DYSTROPHIES

I.

JUVENILE X-LINKED RETINOSCHISIS A. Aetiology 1. Definition Bilateral progressive maculopathy peripheral retinoschisis (50%) Splitting of NFL from rest of NSR (vs. acquired retinoschisis where splitting occurs at OPL)

Differential diagnosis Congenital Degenerative peripheral retinoschisis No known inheritance pattern Secondary Vitreoretinal traction Myopic degeneration with staphyloma RVO

2. Inheritance XL i.e. mainly affects males RS1 gene on Xp22.1-22.2: retinoschisin, an adhesion protein essential for health of Muller cells (span retina forming ILM and OLM) B. Clinical 1. Symptoms Infancy: squint or nystagmus advanced peripheral retinoschisis, often with VH Childhood: reading difficulties (ages 5-10) Adulthood: VA deteriorates until first 2 decades; may remain stable until th th 5 -6 decade when further deterioration occurs 2. Signs

Foveal schisis: bicycle-wheel radial stria in almost all cases associated with cystoid changes Peripheral schisis: predominantly inferotemporal a. Oval defects: ILM and NFL b. Vitreous veils and strands: coalescence of defects leaving only retinal blood vessels c. Vitreal syneris or liquefaction: prominent d. Peripheral silver dendritic figures, vascular sheathing, pigmentary changes and retinal flecks e. Nasal dragging of retinal vessels

3. Complications VH Intra-schisis haemorrhage Neovascularisaion

 C. Management

Subretinal exudate RD (rare) Traumatic rupture of foveal schisis

1. Investigations OCT: schisis spaces in middle layers; assess progression of maculopathy ERG: normal in isolated maculopathy; negative waveform i.e. decreased bwave amplitude and normal a-wave in peripheral schisis EOG: normal in isolated maculopathy; subnormal in advanced peripheral lesions FA: mild window defect but NOT leakage 2. Treatment Avoid contact sports and boxing Treatment of associated refractive error, strabismus and amblyopia LVA and genetic counselling Topical CAI: may reduce foveal thickening and cyst-like spaces

II.

STICKLER SYNDROME A. Aetiology 1. Definition Hereditary arthro-ophthalmopathy Disorder of collagen tissue Commonest inherited cause of RD in children 2. Inheritance AD with complete penetrance but variable expression

Classification STL1 STL2 STL3 STL4

Gene COL2A1 COL11A1 COL11A2

Chromosome 12q13.11-q13.2 1p21 6p21.3

Ocular + + +

Systemic + + + -

B. Clinical
Systemic Features Facial Mid-facial hypoplasia (flat midface) Depressed nasal bridge or short nose Anteverted nares Pierre-Robin sequence Micrognathia Cleft and high-arched palate Glossoptosis (posterior tongue displacement) Upper airway obstruction Skeletal Spondylo-epiphyseal dysplasia th Joint hypermobility: OA in 3r-4 decade Slender extremities with arachnodactyly Hearing loss (progressive) Recurrent otitis media or sensorineural Cardiac Mitral valve prolapse

Ocular Features High non-progressive myopia (most common) Early childhood Vitreous liquefaction (hallmark) Optically empty vitreous (STL1) except for vitreous veils i.e. retrolenticular and circumferential equatorial membrane extends into vitreous cavity Fibrillary and beaded vitreous (STL2) Retina st RD: 50% in 1 decade (secondary to multiple or giant tears, lattice degeneration and PVR) RPE hyperplasia, vascular sheathing, sclerosis Lens Presenile cataract: frequently nonprogressive peripheral cortical wedge or fleck opacities Ectopia lentis: uncommon Glaucoma (5-10%) Congenital angle anomaly Neuro-ophthalmological (less frequent) Ptosis Strabismus

III.

WAGNER SYNDROME A. Aetiology 1. Definition Erosive vitreoretinopathy Similar changes to Stickler but not associated with systemic abnormalities 2. Inheritance AD with gene locus on 5q12-q14 B. Clinical 1. Symptoms Pseudostrabismus: congenital temporal foveal displacement, positive angle kappa Nyctalopia 2. Signs

Low myopia (< -3D) Vitreous: optically empty Preretinal membrane: avascular, greyish, extends from posterior pole to periphery CR atrophy: progressive

3. Complications th Cortical cataracts: 4 decade TRD: 50% > 45 years Glaucoma: occasional 4. Investigations FA: non-perfusion (loss of choriocapillaris) ERG: initially normal; reduced scotopic b-wave amplitude; diffuse cone-rod loss

IV.

FAMILIAL EXUDATIVE VITREORETINOPATHY A. Aetiology 1. Definition Slowly progressive condition (Criswick-Shepens syndrome) Failure of vascularisation of the temporal retinal periphery Similar to ROP but NOT associated with low birth weight and prematurity 2. Inheritance Type 1: AD (chromosome 11) with high penetrance and variable expression Type 2: XLR (NDP gene involved in Norrie disease) B. Clinical 1. Signs

Vitreous: degeneration and peripheral vitreo-retinal attachments associated with areas of white without pressure Vessels: abrupt termination in scalloped pattern at temporal equator; tortuosity, telangiectasia and neovascularisation Ridge: fibrovascular proliferation and vitreoretinal traction Temporal dragging: macula and disc

2. Differential Diagnosis ROP Coats 3. Complications st TRD: 1 decade Subretinal exudation VH Cataract NVG C. Management 1. Investigations FA: peripheral retinal non-perfusion; highlights vascular straightening 2. Treatment Laser photocoagulation or cryotherapy RD surgery Cataract surgery

V.

Goldmann-Favre Syndrome and Enhanced S-cone syndrome A. Aetiology 1. Definition Former may represent more severe variant Cones: increased 2-fold; 92% are S-cones; 15% of cones express L/M-cone opsin 2. Inheritance AR with variable expression

 B. Clinical

NR2E3 at 15q23: ligand-dependent transcription factor

1. Symptoms Nyctalopia and decreased central VA in childhood 2. Signs

Pigmentary changes: along vascular arcades or midperiphery nummular (circular) yellow pigment clumps (rather than bone spicule) Cystoid maculopathy: without leakage on FA or schisis Goldmann-Favre: vitreous degeneration and peripheral retinoschisis

3. Differential Diagnosis RP XLRS 4. Investigations ERG: S-cone hyperfunction; severe M- and L-cone impairment; nonrecordable rod function VF: peripheral to mid-peripheral loss

VI.

NORRIE DISEASE 1. Definition XLR: NDP gene mutation encoding for the protein norrin Characteristics: globular, severely dystrophic retina with pigmentary changes in the avascular periphery 2. Clinical

Congenital blindness: affected boys typically born blind Hearing and mental impairment RD: yellowish, bilateral followed by whiter mass behind clear lens Opacification: lens and cornea; leads to phthisis by age 10 Female carrier: peripheral retinal abnormalities DD: ROP, XLFEVR and Coats

OTHER VITREORETINOPATHIES Snowflake vitreoretinal degeneration AD (2q37) Stage 1: white without pressure (age < 15) Stage 2: snowflakes (age 15-25) Stage 3: vascular sheathing and pigmentation (age 25-50) Stage 4: CR atrophy (age > 60) Complications: RD, presenile cataract Other: mild myopia, vitreous degenerations, dysmorphic ONH and corneal guttata ERG: low scotopic b-wave Dominant neovascular inflammatory vitreoretinopathy AD; mapped to 11q13 nd rd 2 to 3 decade with vitreous floaters Panuveitis, obliterative vasculitis, neovascularisation, ERM PRP and PPV may be required Dominant vitreoretinochoroidopathy AD: maps to BEST1 gene on 11q13 Frequently asymptomatic Non-progressive encircling band of pigmentary disturbance with vitreous degeneration Complications: uncommon (CMO, VH, cataract) Kniest dysplasia Sporadic or AD COL2A1 defect (type 2 collagen gene also involved in STL1) Ocular: high myopia, vitreous degeneration, RD, ectopia lentis Systemic: large head, flat face, stiff limbs, enlarged joints, platyspondyly (flattened vertebra) and short stature

SYSTEMIC DISEASES WITH PIGMENTARY RETINOPATHIES

Systemic Disease Autosomal Recessive Bardet-Biedl syndrome Usher syndrome Familial juvenile nephronophthisis (renal-retinal dysplasia) Bietti corneoretinal crystalline dystrophy Friedrich ataxia (spinocerebellar ataxia) Homocystinuria Mannosidosis Mucopolysachharidosis (Heparan sulphate accumulation only is associated with RP) Hurler (IH) Sheie (IS) Sanfilippo (III) Batten disease (neuronal ceroid lipofuscinosis) Haltia-Santavuori: infantile Jansky-Bielschowsky: late infantile( onset 2-4 years) Lake-Cavanagh: early juvenile (onset 4-6 years) Spielmeyer-Vogt: juvenile (onset 6-8 years) Peroxisome disorders Neonatal adrenoleukodystrophy Refsum disease Zellweger syndrome (cerebrohepatorenal) Autosomal Dominant Alagille syndrome (Arteriohepatic dysplasia) Charcot-Marie Tooth Myotonic dystrophy (Steinert disease) Oculodentodigital dysplasia Olivopontocerebellar atrophy Stickler syndrome (arthro-ophthalmopathy) Waardenburg syndrome Wagner syndrome XL Recessive Incontinentia pigmenti (Bloch-Sulzberger syndrome) Alport syndrome Mucopolysachharidosis II (Hunter) Pelizaeus Merzbacher disease Mitochondrial Disorders(Myopathy) Kearns-Sayre syndrome CPEO , atypical RP, heart block NARP syndrome: neurogenic muscle weakness, ataxia and RP MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke

Syndrome Alagille syndrome (Arteriohepatic dysplasia)

Ocular Anterior Posterior embryotoxon Axenfeld anomaly Myopia RP Posterior

Systemic Intrahepatic cholestatic syndrome Congenital heart disease Flattened facies and bridge of nose Bony abnormalities Degeneration of lateral horn of spinal cord Muscle wasting

Charcot-Marie Tooth

RP and OA

Myotonic dystrophy (Steinert disease)

Christmas tree cataract

Retinal degeneration Pattern dystrophy ERG: subnormal/abnormal

Oculodentodigital dysplasia

Congential cataract Coloboma

Thin nose with hypoplastic alae and narrow nostrils th th Abnormality of 4 and 5 fingers Hypoplastic dental enamel Retinal degeneration (peripheral and/or macular) Myopic retinal degeneration RD common ERG: subnormal/abnormal Narrow, sheathed retinal vessels Pigment spots along vessels and periphery Choroidal atrophy and OA Vitreous liquefaction and membranous condensation Cerebellar ataxia

Olivopontocerebellar atrophy Stickler syndrome (arthroophthalmopathy)

Possible external ophthalmoplegia Progressive myopia

Joint hypermobility Arthritis

Wagner syndrome

Overlapping features with Stickler syndrome

Waardenburg syndrome

Hypertelorism Heterochromia iridis Poliosis

RPE pigmentary disturbance ERG: normal to subnormal

Cochlear deafness White forlock

Syndrome Bardet-Biedl syndrome

Ocular Anterior Posterior RP with severely diminished or extinguished ERG Progressive VF loss

Systemic Obesity Polydactyly Hypogenitalism Mild mental disability

Bietti corneoretinal crystalline dystrophy

Crystals in limbal cornea

Yellow-white crystals limited to posterior pole Round subretinal pigment Confluent loss of choriocapillaris on FA Retinal degeneration and OA Spinocerebellar degeneration Limb incoordination Nerve deafness Marfanoid appearance Cardiovascular abnormalities (thrombosis) Mental disability Macroglossia Large head and ears, flat nose Skeletal abnormality Hepatosplenomegaly Gargoyle facies Deafness Dwarfism and skeletal abn Hepatosplenomegaly Mental disability Coarse facies Aortic regurgitation Stiff joints Normal IQ and lifespan Milder somatic signs

Friedrich ataxia

Homocystinuria

Myopia Lens subluxation or dislocation Glaucoma

Fine pigmentary or cystic retinal degeneration

Mannosidosis

Storage material in retina

Mucopolysaccharidosis I H (Hurler)

Early corneal clouding

RP and OA ERG subnormal

Mucopolysaccharidosis I S (Scheie)

Early corneal clouding

RP ERG abnormal

Mucopolysaccharidosis III (Sanfilippo) Neonatal adrenoleukodystrophy

Severe RP

RP and OA ERG: extinguished

Seizures Hypotonia Adrenal cortical atrophy Psychomotor delay Blood inclusions CNS deterioration Elevated phytanic acid Partial deafness Cerebellar ataxia Ichthyosis (flaky skin) Congenital deafness Muscular hypotonia High forehead Hepatomegaly, renal cystts Deficient cerebral myelination Seizures

Batten disease (Neuronal Ceroid Lipofuscinosis) Refsum disease

Conjunctival inclusions

Bulls eye maculopathy RP and OA RP OA

Usher syndrome Zellweger syndrome (cerebrohepatorenal) Nystagmus Hypertelorism Cataract Microphthalmia

RP Retinal degeneration ERG: nonrecordable

Syndrome Incontinentia pigmenti (Bloch-Sulzberger syndrome)

Ocular Anterior Conjunctival pigmentation Cataract Nystagmus Strabismus Posterior Patchy mottling Falciform retinal fold Cicatricial RD OA

Systemic Death in male fetus Triphasic dermopathy: skin pigmentation (lines and whorls) Alopecia Dental anomalies CNS involvement Glomerular BM collagen type IV abnormality (CRF) Sensorineural deafness

Alport syndrome

Anterior lenticonous Posterior polymorphous corneal dystrophy Cataract No corneal clouding

Yellowish punctate flecks Normal ERG

Mucopolysachharidosis II (Hunter)

Retinal arteriolar narrowing ERG: subnormal

Coarse facies Short stature Mild clinical course Mental disability Inflantile progressive leukodystrophy Cerebellar ataxia and limb spasticity Mental disability Heart block

Pelizaeus Merzbacher disease

Possible RP with absent foveal reflex

Kearns Sayre syndrome

Progressive external ophthalmoplegia

Atypical RP with normal to abnormal ERG

Ptosis

Disorder Gangliosidosis GM1 Infantile (Type I)

Deficiency

Ocular Anterior Posterior

Systemic

All 3 Beta-galactosidase isoenzymes (hexosaminidase A, B and C)

Corneal clouding Tortuous conjunctival vessels High myopia

CRS in 50% Pendular nystagmus OA Papilloedema

Hurler-like facies Kyphosis Hypotonia Congestive heart failure Severe cerebral degeneration Death by age 2

Gangliosidos GM2 Tay-Sachs disease (Type I) Hexosaminidase A (most common ganglioside storage disease) CRS in 100% by 6 months nystagmus OA after 1 year Blind by 2 years Indistinguishable More common if Ashkenazi Jewish descent (100x) or French Canadian Progressive neurological deterioration: paralysis and dementia Death by age 2-4 Indistinguishable

Sandhoff disease (Type II) Mucolipodosis Type 1 (Sialidosis)

Hexosaminidase B

Corneal clouding Punctate lens opacities

CRS OA

Severe (< age 2): severe Hurler-like facies, hepatosplenomegaly, deafness, death in early childhoood Late-onset (< age 7): myoclonus and seizures; normal life span

Niemann-Pick Type A: acute neuronopathic Corneal clouding (subtle) CRS in 50% Severe CNS deterioration Massive hepatosplenomegaly Death by age 4 Hepatosplenomegaly Lungs and BM involvement CNS disease does NOT occur Longer survival

Type B: chronic neuronopathic (Seablue histiocyte syndrome)

CRS Bulls eye maculopathy

Type C: chronic neuropathic Disease Others OCA1A Farber disease Inheritance AR: 11q14-21 TYR (tyrosinase) gene TyrosinaseCeramidase negative or inactive(complete) Hair bulb incubation test negative: incubate with L-DOPA; reliable only > 5 years

Gaze palsy Abnormal eye Ocular movements

NO CRS Systemic

Gaucher disease (chronic non-neuropathic adult) OCA1B AR: 11q14-21 TYR gene Tyrosinase

Iris: thin, pale blue, characteristic pink reflex White hair and skin throughout life (diaphanous) Skin does NOT tan Nodular corneal Frequently myopic astigmatism; positiveCRS angle All forms Hoarseness, aphonia of skin neoplasia (BCC and SCC) of OCA: increased risk th opacity kappa; strabismus before 4 Dermatitis decade Pingueculum-like Lymphadenopathy VA: < 6/60; photophobia Temporal nerve fibres decussate rather than project to ipsilateral lesion Renal and cardiopulmonary disease Nystagmus: pendular, horizontal, increases in bright LGB (absent stereopsis) light; lessens with age; head nodding Asymmetric VEP: predominance in response to monocular Foveal hypoplasia; lack of perimacular arcades; stimulation; absence of misrouting excludes diagnosis of albinism CRS NO CNS involvement prominent choroidal vessels Mid-peripheral white Liver, spleen, LN, skin and BM involvement lesions Complete albinism at birth White hair and skin at birth

ALBINISM

(Yellow variant)

positive; hair bulb positive (minimially active)

Iris transillumination Photophobia Nystagmus Albinotic fundal reflex Iris: blue, yellow or brown (age and race dependent) Pigment: pupil and limbus Transillumination minimal to absent in dark-skinned Moderate-severe VF defect VA: 6/24 -6/36; photophobia Iris: blue to brown Transillumination Nystagmus; strabismus Retinal hypopigmentation Mild vision loss Same as OCA2

Increasing pigmentation with yellow-red hair and light normal skin that tans

OCA2

AR: 15q11.2-q12 OCA2 gene (formerly P gene) Most prevalent worldwide High frequency in African population

Hair and skin colour might be white at birth, darkening over time, but typically born with some pigment Hyperkeratosis and freckling in exposed areas

OCA3 (Red, Rufous or temperature sensitive)

AR: 9p; TYRP1 (tyrosinase-related protein 1) gene Occurs mainly in African descent

Skin and hair red brown Freckles and areas of hypopigmentation

OCA4

AR: MATP (membrane-associated transporter protein) gene XLR: Xp22.3 OA1 gene (uncommonly AR)

Same as OCA2

OA1 (Netteship-Falls)

Marked iris and choroidal pigment deficiency Nysagmus; myopic astigmatism Foveal hypoplasia Tessellated or mosaic fundus VA: 6/18 to 6/120 Carrier female: mosaic fundus Mild OCA (silver hair) Diminished uveal and retinal pigmentation Photophobia; nystagmus

Normal pigmentation elsewhere Melanocytes: normal in size and number in eyes and skin (skin biopsy) Giant melanocytes: abnormal melanosomes within melanocytes Occasional hypopigmented cutaneous macules More lightly pigmented than relatives Recurrent infections: early death Neutropenia, anaemia, thrombocyopaenia Lymphoproliferative syndrome (accelerated phase): hepatosplenomegaly, lymphadenopathy, leukaemia Platelet bleeding disorder (mild) Pulmonary interstitial fibrosis, granulomatous colitis, renal failure Hair and skin colour: variable Lysosomal storage disease of reticulo-endothelial system: Ceroid storage

Chediak-Higashi

AR: 1q42-43 LYST gene

Hermansky-Pudlak

AR: 10q2 HPS1 gene High frequency in Puerto Rico

Iris: blue-gray to brown (age and race dependent); normal or cartwheel effect Mild to severe nystagmus and photophobia Mild-moderate VA loss

CONGENITAL AND STATIONARY RETINAL DISEASE

I.

COLOUR VISION (CONE) ABNORMALITIES

Classification of Hereditary Colour Vision Defects Trichromatism (use abnormal proportions of 3 primary colours) Normal Deuteranomalous Protanomalous Tritanomalous Deuteranopia Abnormal green sensitive cone pigment: confuse red and green Abnormal red-sensitive cone pigment: confuse red and green Abnormal blue-sensitive cone pigment: confuse blue and yellow True colour blindness: no cone function (shades of grey) VA: 6/18 to 6/60 Nystagmus: present in childhood; improves with age Misdiagnosed as ocular albinism Genes: CNGA3, CNGB3, GNAT2 Only blue-sensitive cones; reduced in number and normally absent from fovea Clinically indistinguishable from rod monochromatism: FH, CV or ERG required 92 5 1 0.0001 1

XR XR AD XR

Dichromatism (match any colour with only 2 primary colours)

Protanopia

XR

Tritanopia

AD

0.001

Monochromatism (Achromatopsia) Presentation: congenital nystagmus, poor central VA, photoaversion and hemeralopia (day blindness0 ERG: absent cone response; relatively normal rod response DA: no cone plateau or cone-rod break

Typical (rod monochromatism)

AR

0.0001

Atypical (blue-cone monochromatism)

XR

II.

NIGHT VISION (ROD) ABNORMALITIES A. CSNB with Normal fundi 1. Definition Life-long stable abnormality of scotopic vision (abnormal rods)

Presentation: nystagmus, decreased VA or myopia In spite of poor rod vision, both amount and rate of rhodopsin regeneration following a bright light bleach are normal indicates communication failure between proximal PR end and BPC vs. RP which involves PR loss

2. Inheritance XL: most common; Xp11 AD: typified by French Nougaret pedigree; rhodopsin gene mutation AR 3. Clinical AD: non-progressive nyctalopia alone AR and XL: VA normal to occasionally 6/60, significant myopia (most cases of reduced VA, tilted disc and temporal pallor) and nystagmus Fundus: usually normal except for myopic changes 4. Investigations ERG: loss of retinal on-response with negative ERG DA: typically 2-3 log units above normal

ERG Classification Schubet-Bornshein abnormality

AR and XL

Negative ERG (most common) Maximal dark-adapted response: large a-wave but absent or much reduced b-wave Photopic cone ERG also shows some abnormalities

Complete: very poor rod function; psychophysical thresholds mediated by cones Incomplete: some rod function; elevated DA threshold

Riggs abnormality

AD

Much rarer

Reduction in amplitude but normal waveform of the photopic response which, under scotopic conditions, manifested only a slight increase in amplitude.

B. CSNB with Abnormal fundi 1. Fundus albipunctatus

Disorder of visual pigment regeneration: mutation in gene for 11-cis-retinol dehydrogenase Recovery of normal rhodopsin levels after intense light exposure may take several hours Nyctalopia with minimal rod ERG Dark adaptation for several hours results in normal ERG VA and CV typically good, though often not normal Fundus: yellow-whitish dots in posterior pole sparing fovea radiating towards periphery Differential diagnosis a. Retinitis punctate albescens: RP variant, arteriolar narrowing and severely depressed ERG that does not recover with DA b. Fleck retina of Kandori: larger, patch like flecks with less nyctalopia

2. Oguchi disease Very slow DA but rhodopsin regeneration is normal Physiologic defect: retinal circuitry rather than visual pigments Mutations: arrestin on 2q (Japanese) and rhodopsin kinase (European) Mizuo-Nakamura phenomenon: golden-yellow iridescent sheen after light exposure that disappears after DA 3. Enhanced S-cone Photopic ERG response resembles scotopic Signs: ring of RPE degeneration often seen in region of vascular arcades, CMO ERG: greatly magnified blue-cone signal; very week red-green cone function; rod function deficient May overlap with Goldmann-Favre syndrome