hereditary macular dystrophy

1. HEREDITARY MACULAR
DYSTROPHIES
MODERATOR- DR VIVEKANAND J

2. 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.

3. • 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)

4. • 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.

5. 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.

6. • 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).

7. 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

8. 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.

9. 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

10. 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.

11. 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

12. • 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.

13. 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.

14. • 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

15. • 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

16. • 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

17. • 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 .

18. 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

19. 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.

20. 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.

21. • 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

22. 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

23. 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.

24. 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

25. • 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.

26. ‘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.

27. • 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.

28. ‘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.+/

29. • 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.

30. • 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.

31. • 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.

32. ‘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.

33. • 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.

34. 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).

35. 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

36. 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.

37. • 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.

38. 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.

39. 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.

40. 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.

41. • 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

42. • 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.

43. • 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.

44. • 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.

45. • 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.

46. 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

47. • 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.

48. • 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.

49. 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.

50. • 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.

51. • 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.

52. • 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

53. • 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.

54. 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.

55. • 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.

56. • 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.

57. 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.

58. 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

59. 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

60. 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.

61. 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;

62. • 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 photograph
with typical foveal retinoschisis

63. • 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.

64. • 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.

65. 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

66. 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.

67. 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.

68. • 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

69. • 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

70. • 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.

71. • 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

72. 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.

73. 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

74. • 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.

75. 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.

76. 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.

77. SYMPTOMS
Clinically 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.

78. 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

79. • 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.

80. • 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.

81. • 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.

82. 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

83. 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.

84. • 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.

85. 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

86. 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.

87. 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.

88. 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.

89. • 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

90. • 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

91. • 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.

92. 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.

93. • 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

94. 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

95. • 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.

96. 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.

97. • 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.

98. • 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 .

99. • 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.

100. • 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

101. • 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.

102. 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 years
observed no progression
and no vision loss during
this intervalvisual acuity
tends to be preserved
unless CNV, exudative
drusen, or serous
detachment complicate the

103. • 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.

104. THANK YOU