HEREDITARY MACULAR DYSTROPHIES

MODERATOR- DR VIVEKANAND J

Anatomical landmarks

The macula is a round area at the posterior pole, lying inside the temporal vascular arcades. It measures between 5 and 6 mm in diameter, and subserves the central 15–20° of the visual field.

• Histologically, it shows more than one layer of ganglion cells, in contrast to the single ganglion cell layer of the peripheral retina.

• The inner layers of the macula contain the yellow xanthophyll carotenoid pigments lutein and zeaxanthin in far higher concentration than the peripheral retina (hence the full name ‘macula lutea’ – yellow plaque)

• The fovea is a depression in the retinal surface at the centre of the macula, with a diameter of 1.5 mm – about the same as the optic disc.

The foveola forms the central floor of the fovea and has a diameter of 0.35 mm It is the thinnest part of the retina and is devoid of ganglion cells, consisting only of a high density of cone photoreceptors and their nuclei together with Müller cells.

The umbo is a depression in the very centre of the foveola which corresponds to the foveolar light reflex, loss of which may be an early sign of damage.

• The foveal avascular zone (FAZ), a central area containing no blood vessels but surrounded by a continuous network of capillaries, is located within the fovea but extends beyond the foveola. The exact diameter varies with age and in disease, and its limits can be determined with accuracy only by fluorescein angiography (average 0.6 mm).

MACULAR FUNCTION TESTS

• Macular function tests are required for diagnosing as well as for following up of macular diseases.

• Macular function testing can be divided into • Psychophysical• Physiologic methods

PSYCHOPHYSICAL TESTS• A psychophysical test is subjective. A physical stimulus

is presented to the patient and the patient indicates verbally or by other subjective means, his detection of the stimulus.

They are as follows:• 1. Visual acuity• 2. Color vision• 3. Photostress test• 4. Amsler’s grid• 5. Two point discrimination test• 6. Entoptic imagery• 7. Maddox Rod test.

Visual acuity

• Distance visual acuity (VA) is directly related to the minimum angle of separation (subtended at the nodal point of the eye) between two objects that allow them to be perceived as distinct. In practice, it is most commonly carried out using a Snellen chart.

• Near visual acuity- Near vision testing can be a sensitive indicator of the presence of macular disease

Color vision• Colour vision tests• The Ishihara test is designed to screen for congenital

protan and deuteran defects, but is simple to use and widely available and so in practice is frequently used to screen for colour vision deficit of any type

• The Hardy–Rand–Rittler test is similar to the Ishihara, but can detect all three congenital colour defects

• The City University test consists of 10 plates, each containing a central colour and four peripheral colours from which the subject is asked to choose the closest match.

Photostress Test

• Photostress test can differentiate visual loss caused by macular disease from that caused by an optic nerve lesion.

• The visual pigments are bleached by light which causes a temporary state of retinal insensitivity, perceived by the patient as a scotoma

• The recovery of vision is dependent on the ability of the photoreceptors to re-synthesize visual pigments

• The best-corrected distance visual acuity of the patient is determined and he is asked to fixate on the light of a pen torch or an indirect ophthalmoscope held about 3 cm away for about 10 seconds.

• The photostress recovery time (PSRT) is measured by the time taken to read any three letters of the pre-test acuity line.

• The test is performed on the other, presumably normal eye and the results are compared.

• In a patient with macular lesion, the PSRT will be longer (50 seconds or more) as compared with the normal eye whereas in a patient with an optic nerve lesion there will be no difference.

Amsler Grid

• The Amsler grid is a grid of horizontal and vertical lines used to monitor a person’s central visual field.

• The chart evaluates the 20 degrees of visual field centered on fixation. There are seven charts, each chart consisting of 10 cm square.

• Chart 1: The first grid is a standard grid that tests for any general subjective patient responses to faults or distortions in the pattern. This grid has white lines on a black background and a central white dot on which the patient fixates. The grid encloses 400 small squares. Each square measures 5 mm and when the grid is held at 30 cm from the patient, each square subtends 1 degree on the retina

• Chart 2: If the patient reports on the first chart that he cannot see the central white spot, this indicates a positive scotoma. Then the second chart is used in which the diagonal lines help maintain central fixation. This helps them point out the limits of the scotoma. This chart also has white lines on a black background and a central white fixation dot

• Chart 3: The third chart has red lines on a black background and is very helpful in detecting color scotomas and desaturation, that may occur in optic nerve, chiasmal or toxic amblyopia related problems

• Chart 4: This chart comprises random dots only and is used to differentiate scotoma from metamorphopsia

• Chart 5: This chart has horizontal lines and helps detect metamorphopsia along specific meridians .

• Chart 6: This chart is similar to chart 5 but has a white background and the central lines are oriented closer for detailed evaluation .

• Chart 7: This chart has fine central grid and each square subtends an angle of half a degree when the chart is held at 30 cm from the patient .

Two Point Discrimination Test

• The ability to distinguish two illuminated points of light 2 mm diameter in size and 2 inches apart placed 2 feet away from the patient’s eye suggests good retinal functions. This is an excellent method for testing macular functions in children and uncooperative adults in the outpatient’s clinic and should ideally be performed in all patients during initial examination of the eye

Entoptic Phenomenon• Entoptic phenomenon is referred to visual perceptions that

are produced or influenced by the native structures of one’s own eye. Illumination of the fundus by parallel light rays allows visualization of small opacities located close to the retina.

• Since the columns of blood contained within retinal blood vessels are linear opacities situated in front of the retinal photoreceptors, this makes retinal blood vessels visible.

• If a focal source of light (such as small penlight) is pressed firmly against the exterior of the eye through closed lids, the arborizing pattern of retinal blood vessels can be briefly made visible. This test is used as test of retinal function.

Maddox Rod Test• Maddox rod, which is an essential

part of the trial set used for refraction, comprises a set of cylinders aligned in parallel in a frame.

• By the laws of optics, when a patient sees a point source of light through the Maddox rod, a line perpendicular to the axis of the parallel cylinders is perceived.

• Any break in this line in the center is indicative of a central/macular lesion.

• When Maddox rod is used to assess the macular functions, the light source should be placed between 33 cm to 40 cm in front of the eye and each eye should be tested uniocularly, with occlusion of the fellow eye, to get appropriate objective results.

• This is a very sensitive test that can be performed in the outpatient clinic without requirement of any specific equipment

Electrophysiological Testing

• In the retina, this electrical activity is generated at the retinal photoreceptor and retinal pigment epithelium (RPE) junction.

• Objective measures of the retinal activity

• to a great extent these are patient independent

ELECTRORETINOGRAM (ERG)

• The electroretinogram is the corneal measure of mass electrical activity generated at the retina in response to incident light.

• Gives a composite of the electrical activity from the photoreceptors, Mueller cells and the retinal pigment epithelium.

Technique of Recording the ERG• The recording requires three electrodes, the

active electrode, the reference electrode and the ground electrode. The active electrode is either placed on the cornea in the form of a contact lens

The reference electrode is placed on the patient’s forehead. It acts as a negative electrode

• Diffuse light flashes are projected using a Ganzfeld bowl and the pupils are dilated to ensure uniform light distribution across the whole retina.

• When light is flashed, the electrodes record the voltages at the respective poles and the existent potential difference is recorded.

‘a’ Wave• The ‘a’ wave is also known as the late receptor potential.

It is the initial cornea-negative deflection. It is hypothesized to arise from the photoreceptors. The amplitude is measured from the baseline preceding the response to the trough of the negative deflection.

• The time taken from the stimulus onset to the negative trough of the ‘a’ wave is called the implicit time.

• Implicit time gives an idea of the velocity of the nervous conduction.

• When light is incident on the photoreceptors, it produces local membrane hyperpolarization.

• This results in a relative negative potential at the inner photoreceptor segment and relative positive potential at the outer photoreceptor segment.

• Thus, the potential at the corneal electrode is relatively negative and results in a downward deflection of the ‘a’ wave on the ERG curve.

‘b’ Wave• The ‘b’ wave is the largest wave of the ERG and

is a cornea positive wave. It is hypothesized to arise from the Mueller cells and probably represents the activity of the bipolar cells.

• On the ascending limb of the ‘b’ wave are seen various small wavelets numbering usually from three to five which are known as the oscillatory potentials.+/

• As mentioned before, when light is incident on the photoreceptors, it produces local membrane hyperpolarization during which potassium is released in the extra-cellular space.

• The Mueller cells being cells of the glial family have no synaptic connections and respond mainly to the potassium levels in the milieu of the extra-cellular space.

• The leaked potassium in the extra cellular space by incident light is absorbed across the Mueller cell membrane and it becomes relatively positively charged.

• This results in a large positive deflection of the ‘b’ wave. As the initiating stimulus for both ‘a’ and ‘b’ waves is incident light on the retina, conditions affecting the generation of one will usually also affect the other.

• The origin of the oscillatory potentials differs from that of the ‘b’ wave.

• They are supposed to reflect activity of the feedback circuits in the inner retina.

• The genesis of the oscillatory potentials requires a bright light stimulus and hence is seen clearly only in the photopic ‘b’ wave.

• The oscillatory potentials are thought to reflect activity of the retinal vascular system and are affected in retinal vascular occlusions and vascular disorders like diabetic retinopathy.

‘c’ Wave• The ‘c’ wave is a cornea positive wave on the

ERG. It is generated from the retinal pigment epithelium mainly in response to rod photoreceptors.

• It is hypothesized that as the rods are in direct contact with the apex of the RPE cells unlike the cones, they are likely to be the primary cause of this response.

• There are five primary recorded measures of the full field ERG.

• They are• 1.scotopic rod response, • 2.maximal combined scotopic response, • 3.photopic single flash cone response, • 4.photopic 30-Hz flicker response and • 5.oscillatory potentials. The first two are recorded under scotopic

conditions. For this the eye is dark adapted for about 20 minutes.

Scotopic Rod Response• It denotes electrophysiologic response of the rod system in

isolation. • To record the scotopic rod response, a dark adapted eye is

stimulated by blue light or a dim white light which is below the threshold of the cones.

• This results in a slow positive recording with only the ‘b’ wave. • Diseases affecting the rod system like retinitis pigmentosa,

choroideremia and congenital stationary night blindness shows severe depression of this recording.

• The response is also delayed in the time to peak (implicit time).

Maximal Combined Scotopic Response• It denotes the electrophysiologic response of the retina under

scotopic conditions to a bright flash of light.• As it is a bright flash, it records both rod and cone response

and summates them.• It shows a larger amplitude and implicit time as compared

to a photopic recording as it includes both the types of photoreceptors.

• The combined scotopic response thus will be abnormal in diseases that affect either or both the photoreceptor systems, for example, retinitis pigmentosa and cone dystrophy

Photopic Single Flash Cone Response• This records the measure of the cone system of the

retina.• The eye is first adapted to bright light for about 10

minutes. • The bright background light suppresses the rods by

bleaching them completely. • The time to peak response is shorter for the cone

response as compared to the scotopic recordings and the recordings consist of both the ‘a’ wave and the ‘b’ wave.

• The amplitude of the response is also shorter as the response is only by the cone receptors (8 million cones) and does not include the rods (125 million rods).

• Conditions primarily affecting the cone system like congenital achromatopsia cause a severe depression of the photopic single flash cone response.

• In conditions like retinitis pigmentosa, this response can vary according to the level of involvement of the cones, but the amplitude is always decreased and the implicit time increased.

Photopic 30-Hz Flicker Response• Another way of isolating the cone response is to use a

30-Hz flickering light stimulus. • This is because the rods cannot respond to stimuli

at such a high frequency. • The implicit time of the flicker recording is

extremely sensitive to the changes in the cone system and shows changes much earlier than changes in amplitude and can thus detect early damage.

Oscillatory Potentials• They are high frequency wavelets seen on the ascending

limb of the ‘b’ wave. • They are prominently seen on the scotopic ERG recording. • The recording system uses specific filters which filter out

the low frequency responses and allow the high frequency wavelets to pass through thus showing the oscillatory potentials clearly.

• The oscillatory potentials are sensitive to early ischemia and hence seem to be of value in diabetic retinopathy.

MULTIFOCAL ERG• the retinal function, in certain situations the

recordings can be misleading.• In a case of Stargardt’s dystrophy, the full

field ERG can show a normal photopic response as the total summation response still has enough voltage to show a wave recording even if locally the cone function at the macula is severely affected.

• Similarly in focal retinal scars the localized deficit is missed.

• This led to the development of the multifocal ERG (mfERG) which allows simultaneous recording from multiple small areas of the retina

• mfERG was introduced by Sutter and Tran in 1992. It allows recording of multiple spatially resolved ERG responses over the central 25 degrees of the retina

• The retina is divided into multiple areas, each of which is stimulated with bright and dark stimulus frames.

• The stimulus consists of an array of 61/103/241 hexagonal elements of black or white color across a field subtending 44o horizontally and 40o vertically.

• A summed signal is generated at the cornea and with the help of a special cross correlation functio method each area can be separately studied from the summed signal.

• mfERG is especially valuable in macular diseases with small or no morphological changes clinically where vision loss cannot be explained.

• In maculopathies, the central response is diminished or lost causing loss of the peak of the response in the center which is replaced by a crater like appearance.

• Increase in the implicit time in mfERG denotes a generalized degeneration of the retina while decrease in amplitude but not implicit time indicates a localized pathology.

PATTERN ERG

• This is the ERG response to a pattern stimulus instead of a flash of light. In contrast to a full field ERG stimulus, a pattern ERG (PERG) stimulus consists of a contrast reversing pattern with overall constant luminance.

• As the function of recognition of a pattern begins at the level of the ganglion cells, PERG can be used to assess optic nerve pathology

• The important parts of the waveform that are analyzed are the initial Negative wave at 35 milliseconds (N35), followed by Positive components at 50 (P50) and 95 (P95) seconds.

• As a PERG depends on a clear image perception by the macula, corneal contact lens electrode cannot be used as it will interfere with clear vision.

• The patient is refracted and taken for the examination without cycloplegia.

• As PERG is the function of the macula, it will be abnormal in macular disorders irrespective of the peripheral retinal function.

• The PERG is one of the effective ways to distinguish between abnormalities of the ganglion cell layer and those of the visual pathway distal to the ganglion cell layer.

• The P50 component of the PERG arises distal to the ganglion cells and is thus normal in patients with optic nerve disease.

• In contrast, the N95 component is derived from the ganglion cells and is thus affected in optic nerve disease.

ELECTROOCULOGRAM• The electrooculogram (EOG) is an

investigative tool to measure the integrity of the RPE layer of the retina.

• The potential difference that is measured is actually the standing potential difference between the apical and basilar areas of the RPE cell.

• It is based on the principle of measuring the resting potential difference of the eye between the cornea (positive) and the retina (negative) in both dark adapted and light adapted conditions.

• During the test, a series of lights are blinked to the patient and the patient follows the light with saccadic movements.

• It is desirable for the pupils to be dilated. Three electrodes are placed, one at the lateral canthus, one at the medial canthus and one on the forehead.

• The lateral canthal electrode is positive while the medial canthal one is negative.

• The procedure is started by recording the baseline potential with the eye under light adaptation.

• This is followed by recording the baseline potential under dark adaptation and then the sequence is repeated.

• It is noted that the resting potential of the eye progressively decreases with the dark adaptation reaching a dark trough in about 10 minutes.

• Subsequently, the amplitude rises with the light adaptation and reaches a light peak in about 5 to 10 minutes.

• A ratio of the light peak to the dark trough is an accepted EOG measure known as Arden ratio.

• A value of the Arden ratio less than 1.65 is a subnormal response while, between 1.65 and 1.85 is a normal response while values more than 1.85 are supra-normal

• Similar to ERG, EOG is a mass response phenomenon and is not affected by localized disorders.

• All conditions affecting the ‘b’ wave amplitude affects the EOG. Hence EOG is at best a complementary test to ERG.

• Only in certain disorders like Best vitelliform dystrophy of the retina, the EOG gains special diagnostic importance as it is affected early even when the ERG is normal.

• As Best vitelliform dystrophy is an autosomal dominant disorder, the EOG is abnormal even in a carrier patient who has no fundus changes and is clinically asymptomatic.

VISUAL EVOKED POTENTIAL

• Visual evoked potential (VEP) is in fact an electroencephalogram recording of the occipital lobe.

• It thus measures the cortically evoked electrical activity that provides information about the integrity of the optic nerve and the primary visual cortex.

• It helps assess the functional state of the retina beyond the ganglion cells. As there is a large macular representation at the cerebral cortex, the VEP is primarily a macular response.

• So a large peripheral lesion can have a near normal VEP while a small macular lesion can have depressed VEP.

• VEP is measured with an electrode placed over the scalp in the occipital region (one inch above the inion).

• The VEP can either be a flash VEP or a pattern VEP. The flash VEP is a cortical response to a brief flash of bright white light while the pattern VEP is a response to patterned stimuli like a checker board or gratings.

• The overall luminance in a pattern VEP stays constant.

HEREDITARY MACULAR DYSTROPHIES

• Historically, the term “macular dystrophy” has been used to refer to a group of heritable disorders that cause ophthalmoscopically visible abnormalities in the portion of the retina bounded by the temporal vascular arcades.

An anatomical basis for classification is used commonly

• 1. Nerve fiber layer: X-linked juvenile retinoschisis.

• 2. Photoreceptors and RPE: Cone-rod dystrophy, Stargardt’s disease, Inverse retinitis pigmentosa (RP), Progressive atrophic macular dystrophy.

• 3. RPE: Best’s disease, fundus flavimaculatus, dominant drusen, pattern dystrophy, etc.

• 4. Bruch’s membrane: Sorsby’s pseudoinflammatory dystrophy, angioid streaks, myopic macular degeneration.

• 5. Choroid: Central areolar choroidal dystrophy

X-LINKED JUVENILE RETINOSCHISIS

• This X- linked recessive condition is relatively rare. The disease is caused by mutations in the retinoschisis gene (RS1) which is located on the distal arm of the X chromosome.

• The protein retinoschisin is expressed only in the retina, in the inner and outer retinal layers. Misfolding of the protein, failure to insert into the endoplasmic reticulum membrane and abnormalities involving the disulfide linked subunit assembly have been found to be abnormalities causing retinoschisis

PATHOPHISIOLOGY

• In contrast to senile retinoschisis, the split occurs in the nerve fiber layer.

• The pathology is one of structural defect in Müller cells. Typically the peripheral retinoschisis is seen in inferotemporal quadrant .

• More common is the manifestation of macular schisis that is seen in almost all cases and in roughly 50 percent of cases may be the only manifestation.

• Macular schisis can be differentiated from cystoid macular edema by absence of staining on fluorescein angiography and by the demonstration of the split in the nerve fiber layer on OCT.

SYMPTOMS• Present in the first decade itself, although reading

vision maybe maintained even up to 4th to 5th decade of life.

• Macular RPE atrophy occurs leading to gross loss of central vision.

• Field defects are absolute.

SIGNS• The diagnosis is usually straight forward on binocular

indirect ophthalmoscopy. It differs from retinal detachment in being bilateral usually, with taut dome like elevation without undulations, thin inner layer;

• absolute field defects corresponding to the area of schisis

• propensity for causing burns in the outer layer if test laser burns are applied

Left fundus picture demonstrating the large peripheral retinoschisis with almost total absence of the inner layer. traction caused by the posterior edge of the inner layer on the intact posterior retina. A few laser marks are also seen beyond the schisis area

Left eye fundus photographwith typical foveal retinoschisis

• Electroretinography is also diagnostic with the typical wave form being ‘negative’. The ‘b’ wave amplitudes are reduced while ‘a’ wave amplitudes are maintained at a near normal level and b/a ratio is <1.0 in the standard combined maximal response.

• Treatment- Surgery is recommended for vitreous hemorrhage and retinal detachments

• Retinal detachment cannot be ruled out or when it does not clear in a short period, pars plana vitrectomy can clear the hemorrhage. Retinal detachments due to breaks in the outer layer in the periphery can be corrected by scleral buckling.

STARGARDT’S DISEASE• The disease is transmitted as an autosomal recessive trait with

an estimated prevalence of 1 in 10,000. The disease is associated with accumulation of fluorescent lipofuscin pigments in cells of the RPE.1,2 specifically, A2E (bis-retinoid pyridinium salt N-retinylidene-N-retinylethanolamine) is the major component of lipofuscin that is accumulated in the RPE cells

• The use of the term Stargardt’s disease should be ideally restricted to atrophic macular dystrophy associated with flecks. Mild reduction in ABCA4 activity in

Stargard disease is associated with some bisretinoid formation on the inner leaflet of the photoreceptor outer-segment disc membranes

GENETICS• The gene involved in this disease is the ABCR gene

located on chromosome 1 and codes for a transporter protein located in the rims of rod and cone outer segments.

• It has function in the visual cycle for the regeneration of rhodopsin by accelerating the removal of ‘all-trans-retinaldehyde’ from the outer segment disks.

• A2E sensitizes the photoreceptors to light induced damage (apoptosis) leading to slow visual loss.

SYMPTOMS• The usual age of presentation is between 6

and 20 years.• Visual acuity can drop up to 6/60. Although

the disease tends to be symmetrical, asymmetry is not unknown.

SIGNS• Initial stages may show no fundus findings

leading to wrong labeling as functional blindness.

• Later stages Loss of foveal reflex followed by RPE defects in the center of macula occur later.

• Perifoveal flecks also start appearing. Fully developed fundus lesion is characterized by appearance of oval area of atrophy of RPE in the macula, typically described as “beaten bronze” appearance

• More flecks appear beyond the macula but do not extend into the periphery.

• The disk and blood vessels remain normal throughout the process

• FFA-Fluorescein angiography shows hyperfluorescence due to window transmission defects in the macular area at the site of RPE atrophy, but characteristically the rest of the fundus has relative blockade of choroidal fluorescence, termed as ‘silent choroid’ dark choroid

(relative hypofluorescence of the choroid) due to the accumulation of lipofuscin in the RPE

• ERG-The photopic and scotopic ERG is generally normal, although in advanced stages slight reduction in amplitudes of ERG are noted.

• EOG- tends to be subnormal.

• OCT-have shown expected reduction in macular function and reduction in foveal thickness. Choroidal neovascularization is a very rarely reported complication

• SD-OCT reveals selective loss of foveal photoreceptors

MANAGEMENT

• Currently, there is no treatment for the disease.• Experimental studies in knock out mice have

shown beneficial effects of isotretinoin.• The drug inhibits 11-cis-retinol dehydrogenase

and hence reduces the accumulation of A2E.• However human studies are awaited. Low

vision aids can be useful.

FUNDUS FLAVIMACULATUS• This is considered as a part of the spectrum of

disease including Stargardt’s disease.• SYMPTOMS- drop in visual acuity.• SIGNS- flecks within the foveal area. The flecks are

ill defined and can have variable shapes, crescentric, fish tail shaped, linear and circular.

Confluence of the flecks can result in a reticula appearance. The flecks never appear beyond the equator

• FFA-Fluorescein angiography expectedly shows window defects due to RPE atrophy in the involved areas, although early lesions may have no actual RPE atrophy and so may not show transmission defects

• ERG-ERG is normal in most cases, in contrast to tapetoretinal degenerations.

• EOG shows reduced Arden’s ratio.

BEST DISEASE

• Best macular dystrophy (BMD), or Best disease, is an autosomal dominant condition caused by mutations in the BEST1 gene formerly known as VMD2

• The first family with this dystrophy was described by Friedrich Best in 1905. Other designations for this disease have since been used, including vitelline dystrophy, vitelliruptive degeneration, and vitelliform dystrophy. It is one of the most common Mendelian macular dystrophies, occurring in about 1 in 10,000 individuals.

GENITICS• The causative gene is VMD2 (on

choromosome11q13) encoding bestrophin. The protein has been localized to the RPE. Abnormal chloride conductance might be the initiator of the disease process.

HISTOPATHOLOGIC - findings include increased RPE lipofuscin,loss of photoreceptors (often seen over a relatively intact RPE layer), sub-RPE drusenoid material, and accumulation of cells and material in the subretinal space.

SYMPTOMSClinically several stages have been described• Normal fovea,• Previtelliform stage • Vitelliform stage• Vitelliruptive stage(scrambled egg ) associated with

reduced vision., • Vitelliform stage with Sub-retinal neovascularization

(CNVM) is a complication that can result in significant drop in vision.

• Atrophic stage.• Color vision is affected as in any other macular disease.

SIGNS• Previtelliform stage. This is evident as a

small, round yellowish dot at the site of foveola.

• Vitelliform stage can lead to appearance of cyst with fluid level or sometimes clear space in center with the material situated all round. Sub-retinal neovascularization (CNVM) iscomplication

• Pseudohypopyon may occur when part of the lesion regresses often at puberty.

• Vitelliruptive: the lesion breaks up and visual acuity drops

• Atrophic stage can be represented by area of RPE atrophy or sometimes disciform scar if complicated by CNVM

• HD OCT

• PREVITELLIFORM STAGE- Using high-definition optical coherence tomography (HD-OCT), Querques et al have described identifiable changes in between RPE and the inner segment and outer segment interface even in the previtelliform stage.

• VITELLIFORM STAGE- characterized by the classic egg yolk appearance

• HD-OCT reveals this material as hyper-reflective lesion located between the hyporeflective outer nuclear layer and the hyper-reflective RPE layer.

• disruption of the inner segment/outer segment has also been described at this stage while other layers of the retina are intact.

SD-OCT of this eye reveals the fibrotic pillar to lie beneath the RPE, surrounded by small amounts Of subretinal fluid. Long outer segments can be seen extending from the retina into the subretinal fluid.

• FFA- Fluorescein angiography shows hypofluorescence at vitelliform stage and hyperfluorescence later due to atrophic RPE The subretinal material is strongly autofluorescent..•EOG- Typically EOG is affected early in the stage of the disease. The light-dark ratio is usually below 1.5.• ERG is completely normal.

TREATMENT

• Treatment for BEST1 disease consists primarily of recognizing choroidal neovascularization and hastening its regression with anti-VEGF therapy.

• Even in the absence of CNV, subretinal hemorrhage can occur in patients with Best disease following relatively modest head or eye trauma As a result, usually patients are cautioned against playing sports in which frequent blows to the head are to be expected. Protective eyewear is recommended for all sports

DOMINANT FAMILIAL DRUSEN

• DOMINANT FAMILIAL DRUSEN The disease is termed variously as Doynes honey-comb choroiditis, and Hutchinson-Tay choroiditis.

• GENETICS-Autosomal Dominant• EFEMP1 gene mutations have been

associated with this disorder. The gene encodes the EGF-containing fibulin like extracellular matrix protein-1.

• Described as ‘stars in the sky’ or ‘milky way’, they are seen in clusters in the posterior pole .

• The drusen are present as nodular thickening of the basement membrane of the RPE

SYMPTOMS- Vision can be affected due to CNVM, and geographic atrophy

SIGNS- The drusen in this condition are small (25–75 microns). More of them are detected on fluorescein angiography rather than on ophthalmoscopy.

MALAATIA LEVANTINESE

• ‘Malaatia levantinese’ is a term used to describe a variant of dominant drusen first seen in a family in Levantine valley in Switzerland.

• The drusen are oriented more radially in this condition

NORTH CAROLINA MACULAR DYSTROPHY • North Carolina macular

dystrophy’ as the term indicates was originally described in a family in North Carolina but has been now identified all over the world and in various ethnic groups.

• It is also transmitted as an autosomal dominant disease and is characterized by drusen in the posterior pole leading to disciform scar and sometimes staphylomatous chorioretinal scars in the posterior pole.

PATTERN DYSTROPHY

• Pigmented pattern dystrophy was originally described with black pigmentation in the macular area. Subsequent reports included yellow, gold and gray subretinal deposits as well.

• GENETICS-The most common causes of all of these different patterns have proven to be mutations in a single gene, PRPH2. The condition is autosomal dominant in transmission. Peripherin and RDS gene mutations have been identified in these families.

SYMPTOMS• Vision is usually not affected to a great

degree. However, Francis et al have reported significant vision loss in the 6th decade of life. The disease is very slowly progressive

SIGNS• Reticular (Sjögren): a network of pigmented

lines at the posterior pole. • Fundus pulverulentus is extremely rare.

Macular pigment mottling develops.

• Butterfly-shaped: foveal yellow and melanin pigmentation, commonly in a spoke-like or butterfly wing-like conformation drusen- or Stargardt-like flecks may be associated with any pattern dystrophy . FA shows central and radiating hypofluorescence with surrounding hyperfluorescence

• Multifocal pattern dystrophy simulating fundus flavimaculatus: multiple, widely scattered, irregular yellow lesions; they may be similar to those seen in fundus flavimaculatus . FA shows hyperfluorescence of the flecks; the choroid is not dark

• Macroreticular (spider-shaped): initially pigment granules are seen at the fovea; reticular pigmentation develops that spreads to the periphery

• Fluorescein angiography reveals the patterns more clearly.

• ERG is normal while EOG can be variable.

Sorsby’ Dystrophy• This condition was first described in five

British families.• GENETICS-Transmitted as an autosomal

dominant condition, mutations in the tissue inhibitor of metalloproteinase-3 (TIMP- 3) have been identified as a possible cause of the disease.

• SYMPTOMS-The disease presents as reduced central vision along with night blidness.

• SIGNS-Choroidal neovascular membrane (CNVM) formation and subretinal bleeding followed by disciform scar formation takes place, sometimes extending to the periphery as well.

• Sorsby macular dystrophy.• (A) Confluent flecks nasal to the

disc; (B) exudative maculopathy; (C) scarring in end-stage disease

Central Areolar Choroidal Atrophy

• This disease has a characteristic fundus picture with punched out area of chorioretinal atrophy in the macular area. Barring large choroidal vessels, all other layers are atrophic in the affected area in the late stages. In the early stages, non-specific granular pigmentation can be seen that can be confused with other conditions such as Stargardt’s disease. entral areolar choroidal dystrophy.

• (A) Early; (B) intermediate; (C) end-stage

• The disease affects vision in the 4th to 5th decade and progressively deteriorates to the level of 6/60 vision.

• Multifocal ERG can show reduced amplitude in the affected areas before obvious clinical atrophic changes are visible.

OTHER HARIDITARY MACULAR DYSTROPHIES

• SPOTTED CYSTIC DYSTROPHY-Mahajan et al.recently described seven members of a three generation family with autosomal dominant inheritance of a new dystrophy limited to the macula and characterized by round, flat pigmented spots with or without surrounding hypopigmentation ,

• OCT :cysts in multiple retinal layers, and neovascularization.

• O/E: Amblyopia and strabismus were frequently present in affected individuals. Visual acuity ranged from 20/20 to 20/200.

• The pathophysiology and genetic mutation responsible for this condition have not been identified.

• TREATMENT:When active macular neovascularization occurs in affected individuals, it has been responsive to either focal laser or a single injection of bevacizumab.

• DOMINANT CYSTOID MACULAR DYSTROPHY• Dominant cystoid macular dystrophy (DCMD) was

described in 1976 by Deutman278 • autosomal dominant condition characterized by

EARLY leaking perimacular capillaries, whitish punctate deposits in the vitreous,

• In the LATE stages of the disease, an atrophic central “beaten-bronze” macula was common. A second family was identified a few years later and linkage analysis mapped the chromosomal location of the disease-causing gene to the short arm of chromosome 7.

• OTHER INVESTIGATION:a normal ERG, a subnormal EOG, and hyperopia .

• The disease-causing gene for DCMD has not yet been identified.

• Hogewind and coworkers evaluated intramuscular injections of a somatostatin analog (octreotide acetate) in four patients with DCMD and seven of the eight eyes showed improvement on fluorescein angiography, with

stabilization of visual acuity.

Fluorescein angiogram of the right eye of a patient With dominant cystoid macular edema showing leakage from perifoveal capillaries.

• FENESTRATED SHEEN MACULAR DYSTROPHY (FSMD)

• Several families have been described with an autosomal dominant macular disorder , occurring as early as the first decade of life and seen as late as the fifth decade

• FUNDUS FINDING:central macular sheen with small red fenestrations

Some middle-aged family members develop a bull’s-eye pattern of stippled hypopigmentation in the central macula

• Mild functional abnormalities roughly correlate with more advanced age but patients with the red fenestrations have 20/20 visual acuity.

• Normal or mildly abnormal ERG findings have been reported

• The chromosomal location of the disease-causing gene is currently unknown.

GLOMERULONEPHRITIS TYPE II AND DRUSEN• Glomerulonephritis (MPGN) type II (also known as

dense-deposit disease) develop subretinal deposits with the clinical appearance of basal laminar drusen D’Souza and coworkers followed four MPGN patients with such drusen for 10 yearsobserved no progression and no vision loss during this intervalvisual acuity tends to be preserved unless CNV, exudative drusen, or serous detachment complicate the disease

• An abnormal EOG with a relatively normal ERG can be seen in some patients, suggesting a more global retinal dysfunction than the visible drusen would suggest.

• Histopathologic studies of the Bruch’s membrane deposits found in MPGN II demonstrate that they are morphologically and compositionally similar to the drusen found in AMD.

• Abnormal urinalysis with this phenotype in young adults should prompt a referral for work-up of kidney disease.

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