PRESENTATION

1. MACULAR DYSTROPHIES
PRESENTOR:DR SHILLY VARGHESE
MODERATOR:DR SHILPA UMARANI

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 lutei 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 retina 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 the nuclei together
with Müller cells.

6. • 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).

7. HEREDITARY MACULAR DYSTROPHIES
• “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.

8. 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

11. X-LINKED JUVENILE RETINOSCHISIS
• 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.

12. • 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

13. PATHOPHYSIOLOGY
• 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.

14. SYMPTOMS & SIGNS
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

15. • Absolute field defects corresponding to the area of schisis.
• Propensity for causing burns in the outer layer if test laser burns are
applied

16. 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

17. • 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

19. 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.

20. STARGARDT’S DISEASE
• Autosomal recessive trait with an
estimated prevalence of 1 in 10,000.
• Associated with accumulation of
fluorescent lipofuscin pigments in
cells of the RPE.
• Specifically, A2E (bis-retinoid
pyridinium salt N-retinylidene-N-
retinylethanolamine) is the major
component of lipofuscin that is
accumulated in the RPE cells.

21. • 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

22. 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.

25. • 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.

26. • 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

27. • With angiography, the A2E blocks the exciting blue light from
reaching the dye in the choroidal circulation
• Resulting in a finding that is variously known as a dark, silent, or
masked choroid

28. • FFA-Fluorescein angiography
shows hyperfluorescence due to
window transmission defects in the
macular area at the site of RPEatrophy.
• 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.

29. • 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

30. • 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

31. 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.

32. FUNDUS FLAVIMACULATUS
• Considered as a part of the spectrum of disease including Stargardt’s
disease.
• SYMPTOMS- drop in visual acuity.

33. 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
reticular appearance.
The flecks never appear beyond the
equator

34. • 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.

35. BEST DISEASE
• Best macular dystrophy (BMD), or Best disease
• 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

36. GENETICS
• The causative gene is VMD2 (onchoromosome11q13) encoding
bestrophin.
• The protein has been localized to the RPE(REGULATION OF IONIC
MILEAU)
• Abnormal chloride conductance might be the initiator of the disease
process.

37. 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

38. SYMPTOMS
• Clinically several stages have been described
• 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

39. • Visual acuity (VA) sufficient to drive is usually preserved in at least
one eye throughout the first six decades of life
• More substantial visual loss occurring when BMD is complicated by
nodular fibrosis, choroidal neovascularizationor central geographic
atrophy

40. SIGNS
• Previtelliform stage.
This is evident as a small, round yellowish
dot at the site of foveola.

41. • Vitelliform stage
Appearance of cyst with fluid level or
sometimes clear space in center
with the material situated all round.
• Pseudohypopyon may occur when
part of the lesion regresses often at puberty
• Subretinal neovascularization
(CNVM) is complication

43. VITELLIRUPTIVE FORM
RPE atrophy in addition to
hyperpigmentation, and
atrophy of the RPE

44. • 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

46. HD OCT
• PREVITELLIFORM STAGE-
• Querques et al have described identifiable changes in between RPE
and the inner segment and outer segment interface even in the
previtelliform stage.

47. • 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.

48. 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.

49. • FFA- Fluorescein angiography shows
hypofluorescence in vitelliform stage and
hyperfluorescence late 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.

50. 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

51. DOMINANT FAMILIAL DRUSEN
• 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.

52. • 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.

53. • 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

54. MALATTIA LEVANTINESE
• ‘Malattia 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.

56. 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.
• Transmitted as an autosomal dominant disease.
• Called as central areolar pigment epithelial dystrophy and dominant
progressive foveal dystrophy.

57. • Characterized by drusen in the
posterior pole leading to disciform scar
• Sometimes staphylomatous
chorioretinal scars in the posterior pole.
Complete lack of progression is one of the
most reliable diagnostic features of the
disease, and accounts to some degree for
the amazingly good VA in some patients
with very large lesions

58. PATTERN DYSTROPHY
• 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.
• Autosomal dominant in transmission.
• Peripherin and RDS gene mutations have been identified in these families.

59. • 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.

60. • 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 .

61. • FA shows central and radiating
hypofluorescence with
surrounding hyperfluorescence

62. Multifocal pattern dystrophy
• Simulating fundus flavimaculatus: multiple,
widely scattered, irregular
yellow lesions; they may be
similar to those seen in
fundus flavimaculatus .

63. • Macroreticular (spider-shaped): initially pigment
granules are seen at the fovea;
reticular pigmentation develops that
spreads to the periphery
• FA shows hyperfluorescence
of the flecks
• Choroid is not dark

64. • Fluorescein angiography reveals
the patterns more clearly
• ERG is normal
• EOG can be variable

65. SORSBY DYSTROPHY
• 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

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

67. • Sorsby macular dystrophy.
(A) Confluent flecks nasal to
the disc;
(B) exudative
maculopathy;
(C) scarring in
end-stage disease

68. Central Areolar Choroidal
Atrophy
• 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.

69. (A) Early; (B) intermediate; (C)
end-stage

70. • 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.

71. OTHER HERIDITARY MACULAR
DYSTROPHIES
SPOTTED CYSTIC DYSTROPHY
• Autosomal dominant inheritance.
• 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

72. • 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.

73. DOMINANT CYSTOID MACULAR DYSTROPHY
• Dominant cystoid macular dystrophy (DCMD) was described in 1976
by Deutman.
• Autosomal dominant
• 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.
• OTHER INVESTIGATION:a normal ERG,
• A Subnormal EOG, and hyperopia

74. • 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.

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

76. FENESTRATED SHEEN MACULAR DYSTROPHY
(FSMD)
• 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

77. • 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

78. GLOMERULONEPHRITIS TYPE II AND DRUSEN
• Glomerulonephritis (MPGN) type II
(also known a dense-deposit disease)
develop subretinal deposits with the
clinical appearance of basal laminar
drusen

79. D’Souza and coworkers followed four MPGN patients with such drusen
for 10 years observed no progression and no vision loss during this
interval
Visual acuity tends to be preserved unless CNV, exudative drusen, or
serous detachment complicate the disease

80. • 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 workup of kidney disease.

81. REFERENCES
• 1)RYANS RETINA 6 TH EDITION
• 2)KANSKIS CLINICAL OPHTHALMOLOGY 9 TH EDITION
• 3)PARSONS DISEASE OF THE EYE 23 RD EDITION
• 4)ANATOMY&PHYSIOLOGY OF EYE 3 RD EDITION

82. THANK YOU

83. • Panel C shows the effects of reduced ABCA4 function on the accumulation of bisretinoid (yellow
symbols) on the inner leaflet of the photoreceptor outer-segment disc membranes. Mild
reduction in ABCA4 activity in Stargardt disease is associated with some bisretinoid formation;
moderate loss of function in cone–rod dystrophy is associated with intermediate amounts of
accumulation; and complete loss of function in retinitis pigmentosa results in maximal
accumulation. Panel D shows the histopathologic effects of reduced ABCA4 activity. In patients
with Stargardt disease, the rate of bisretinoid formation in the outer segments is relatively slow
and the photoreceptors are not directly injured.
• Bisretinoids are delivered to the secondary lysosomes of the retinal pigment epithelium (RPE)
during the normal phagocytosis of photoreceptor outer segments. Some of this material
accumulates beneath the RPE causing pisciform flecks that are visible on ophthalmoscopy. In
patients with cone–rod dystrophy, moderate loss of ABCA4 function results in sufficient
accumulation of bisretinoids in photoreceptor outer segments to cause some apoptosis of
photoreceptors (in cones more than rods). In patients with retinitis pigmentosa, complete loss of
ABCA4 function causes extensive accumulation of bisretinoids in photoreceptor outer segments,
apoptosis of both rod and cone photoreceptors, and associated RPE thinning.