Corneal dystrophy ANJU.power point presentation

Corneal dystrophies are a group of rare, genetic eye disorders. With corneal dystrophies, abnormal material builds up in the cornea (the clear, front window of the eye). Most corneal dystrophies affect both eyes. They progress slowly and run in families.

1. Corneal dystrophy DR ANJU

2. DEFINITION

3. 1890, Corneal dystrophy was first introduced by Groenouw and then Biber . Dystrophy comes from the Greek word “ wrong nourishment” The IC3D Classification was initially anatomically based Level of involvement of the corneal layers was considered. It considered clinical, pathological and genetic features Granular Dystrophy

4. International Committee for Classification of Corneal Dystrophies (2008) Historically, corneal dystrophies were classified on their phenotypic appearance. The IC3D Classification was anatomically based Level of involvement of the corneal layers was considered. Dystrophies were solely assigned to single layer most affected. It considered clinical, pathological and genetic features

5. Category Disease well defined Chromosome identified Gene identified Category 1 + + + Category 2 + + - Category 3 + - - Category 4 - ( Suspected, new, or previously documented) - - Categories for Corneal Dystrophies: International Committee for Classification of Corneal Dystrophies (2008)

6. Updated International Committee for Classification of Corneal Dystrophies (2015)

7. Revised IC3D- 2015 Need for Revision Dystrophies were classified based upon the layer most affected. To have a more accurate anatomical classification considering cellular origin Need to add histopathological and Confocal picture for better understanding Better classification of TGF β 1 dystrophies

8. Revised IC3D- 2015 Changes Made - Removed Information on genetic mutation removed – as it is rapidly changing Removed CHED Autosomal Dominant inheritance 10q23-24 dystrophy not considered as a variant of TBCD Removed Grayson- Willebrandt Dystrophy Changes Made - Added Included histopathological, electron microscopy and confocal microscopy Added Anterior segment-OCT where available

9. Corneal dystrophies Epithelial and subepithelial dystrophies Epithelial–stromal TGF β 1 dystrophies Stromal dystrophies Endothelial dystrophies

10. Revised IC3D- 2015 Classification system Epithelial and Sub-epithelial dystrophies 1. Epithelial basement membrane dystrophy (EBMD) majority degenerative, rarely C1 2. Epithelial recurrent erosion dystrophies (EREDs)—Franceschetti corneal dystrophy (FRCD) C3, Dystrophia Smolandiensis (DS) C3, and Dystrophia Helsinglandica (DH) C3 3. Subepithelial mucinous corneal dystrophy (SMCD) C4 4. Meesmann corneal dystrophy (MECD) C1 5. Lisch epithelial corneal dystrophy (LECD) C2 6. Gelatinous drop-like corneal dystrophy (GDLD) C1 Gelatinous Drop-like Corneal Dystrophy

11. Revised IC3D- 2015 Classification system Epithelial–stromal TGFBI dystrophies Reis– Bücklers corneal dystrophy (RBCD) C1 Thiel - Behnke corneal dystrophy (TBCD) C1 Lattice corneal dystrophy, type 1 (LCD1) C1—variants (III, IIIA, I/IIIA, IV) of lattice corneal dystrophy C1 Granular corneal dystrophy, type 1 (GCD1) C1 Granular corneal dystrophy, type 2 (GCD2) C1 Lattice Dystrophy

12. Revised IC3D- 2015 Classification system Stromal dystrophies Macular corneal dystrophy (MCD) C1 Schnyder corneal dystrophy (SCD) C1 Congenital stromal corneal dystrophy (CSCD) C1 Fleck corneal dystrophy (FCD) C1 Posterior amorphous corneal dystrophy (PACD) C1 Central cloudy dystrophy of François (CCDF) C4 Pre- Descemet corneal dystrophy (PDCD) C1 or C4 Macular Dystrophy

13. Revised IC3D- 2015 Classification system Endothelial dystrophies Fuchs endothelial corneal dystrophy (FECD) C1, C2, or C3 Posterior polymorphous corneal dystrophy (PPCD) C1 or C2 Congenital hereditary endothelial dystrophy 1 (CHED) C2 Congenital hereditary endothelial dystrophy 2 (CHED) C1 X-linked endothelial corneal dystrophy (XECD) C2 Fuch’s Dystrophy

14. Epithelial Basement Membrane Dystrophy (EBMD) Map-dot-fingerprint dystrophy. Cogan microcystic epithelial dystrophy. Anterior basement membrane dystrophy Poor adhesion of basal epithelial cells to abnormal basal laminar material is thought to predispose to recurrent erosions.

15. Epithelial basement membrane dystrophy (EBMD) is a disease that affects the anterior cornea, result in decreased vision and/or recurrent corneal erosions. INHERITANCE – UNCERTAIN GENETIC LOCUS – 5q31 GENE – TGFBI Risk Factors Known family history and age are probably the most important risk factors. Others include trauma such as corneal abrasion, LASIK, or other intraocular surgery.

16. Symptoms – Asymptomatic, pain, lacrimation, blurred vision Signs – Irregular geographic grayish white superficial corneal lesions with distinct scalloped borders ( maps) alone or in combination with irregular,round or oval whitish gray opacities single or clustered (dots) or parallel curvilinear lines in the paracentral cornea ( finger prints) or ground glass appearance ( bleb pattern)

17. MAPS DOTS FINGERPRINTS BLEBS

18. HISTOPATHOLOGY Histology shows thickening of the basement membrane with deposition of fibrillary protein between the basement membrane and the Bowman layer. Basal epithelial cell hemidesmosomes are deficient

19. treatment First line treatment options usually involve the use of night time lubricating ointments or hypertonic saline ointments. Symptomatic erosions may be treated with bandage contact lenses, antibiotic ointments, or patching. Various procedures in case of recurrent corneal erosions include such as anterior stromal puncture (outside the visual axis), YAG laser micropuncture , cautery, epithelial debridement and/or diamond burr polishing, phototherapeutic keratectomy (PTK), and extended bandage contact lens wear

20. Meesmann corneal dystrophy Inheritance autosomal dominant Genetic locus 12 q13 (KRT3) , 17q12 (KRT12) Stocker–Holt variant Gene keratin K3 and keratin K12 Onset early childhood stationary or slowly progressive Symptoms : asymptomatic mild blurring of vision glare , photophobia foreign body sensation Signs include multiple tiny intraepithelial vesicles extend to the limbus and are more numerous in the interpalpebral area with clear surrounding epithelium. whorled wedged shaped opacities , cyst like lesions or refractile linear opacities.

21. Irregular thickening of EBM and intraepithelial cyst

22. The thickened and disorganized epithelium demonstrates intraepithelial cysts

23. TREATMENT No treatment for asymptomatic patients Preservative free lubricating eye drops For acute corneal erosions – broad spectrum topical antibiotics , lubricating eyedrops, hypertonic saline solution eyedrops (5%) during day and ointment (6%) at night, BCL For recurrent corneal erosions– epithelial debridement of the involved area with topical broad spectrum antibiotics and lubricating eyedrops, excimer laser PTK

24. Lisch Epithelial Corneal Dystrophy (LECD) X linked dominant Genetic Locus Xp22.3 Specific gene unknown

25. Clinical features Painless, gradually worsening visual acuity that is not correctable with lenses. Gray, feathery, band-shaped corneal lesions, sometimes in whorled patterns on slit lamp examination. Dense collections of clear intraepithelial micro-cysts on retro-illumination. Unilateral or bilateral lesions. Lesions do not stain with fluorescein or rose bengal . No epithelial erosions are observed

26. In the suprabasal and parabasal layers, vacuolated cells progress to the epithelial surface,where they adopt elongated fl at squamous shapes

27. Gelatinous Drop-like Corneal Dystrophy (GDLD) Subepithelial amyloidosis. Primary familial amyloidosis (Grayson). Autosomal recessive inheritance Genetic Locus 1p32. Gene-- Tumor-associated calcium signal transducer 2 (TACSTD2, previously M1S1). Onset 1 st - 2 nd decade progressive

28. Symptoms include significant photophobia, foreign body sensation , redness, watering and decrease in vision. Signs include initially subepithelial lesions progresses to small, multiple grayish nodules (mulberry lesions), In advanced cases stromal opacities with large nodules and the cornea resembles the kumquat fruit ( kumquat lesions) PATHOLOGY: deposition of sub epithelial and stromal amyloid

29. In later life, patients may also develop stromal opacification or develop larger nodular, kumquat-like lesions massive amyloid in a subepithelial lesion

30. Management Preservative free lubricating eyedrops If nodules are large, superficial keratectomy with or without AMG or EXCIMER laser PTK In advanced cases keratoplasty– DALK or PK

31. CLASSIFICATION OF STROMAL DYSTROPHY Reis– Bücklers corneal dystrophy Thiel- Behnke corneal dystrophy Lattice corneal dystrophy Granular corneal dystrophy (Type 1 and 2) Macular corneal dystrophy Schnyder corneal dystrophy Congenital stromal corneal dystrophy Fleck corneal dystrophy Posterior amorphous corneal dystrophy Central cloudy dystrophy of François TGF β 1 DYSTROPHIES NON TGF β 1 DYSTROPHIES Epithelial- Stromal dystrophy Stromal dystrophy

32. Autosomal Dominant Affected gene 5q31, TGFB1 Childhood Recurrent epithelial erosions, DOV Also known as corneal basement dystrophy type1 Geographic like opacities throughout bowman membrane and superficial stroma, extending to limbus and deep stroma, more irregular diffuse opacities with clear interruptions Reis- Bucklers Corneal Dystrophy (Category 1)

33. HPE- Bowman layer is replaced by a sheet-like layer of granular Masson trichrome–red deposits Optical Coherence Tomography - Prominent hyperreflective material at the level of the Bowman layer , thickest at centre Electron Microsopy - Subepithelial electron-dense, rod- or trapezoidal-shaped bodies identical same as GCD1 Treatment is directed at the recurrent erosions. Excimer keratectomy achieves satisfactory control in some patients.

34. Autosomal Dominant 5q31, TGFB1 gene Early childhood Recurrent epithelial erosions, DOV Scattered subepithelial opacities throughout bowman membrane Symmetrical subepithelial honeycomb opacities Peripheral cornea uninvolved Theil Behnke Corneal Dystrophy (Category 1)

35. HPE- thickened abnormal subepithelial fibrous layer (that replaces the Bowman layer - sawtooth-like surface Optical Coherence Tomography- Prominent hyperreflective material at the level of the Bowman layer extending into the epithelium Electron Microsopy - curly collagen fibers 9 to 15 nm No optimal treatment

36. GRANULAR CORNEAL DYSTROPHY Former Alternative Names and Eponyms Type 1-Corneal dystrophy Groenouw type I (classic) Type 2-Avellino dystrophy or Combined granular-lattice dystrophy

37. GCD - TYPE 1 *IC3D Classification of Co Genetics C1 Inheritance Autosomal dominant Genetic Locus 5q31 Gene Transforming growth factor beta–induced—TGFß1 Product Hyaline

38. ONSET AND COURSE Onset Childhood, as early as 2 years of age. Course Slowly progressive, with most patients maintaining good vision and visual acuity only rarely dropping to 20/200 after 50yrs of age.

39. SIGNS Onset is early in life with discrete white central anterior stromal deposits resembling resembling sugar granules or breadcrumbs or glass splinters separated by clear stroma On direct illumination- opacities appear white On indirect illumination-small translucent dots with vacuoles and glassy splinters or crushed bread crumb appearance

40. MORPHOLOGY Glassy splinter Clinical picture of GCD TYPE 1 Crushed bread crumb

41. SYMPTOMS Glare and photophobia are early symptoms Visual acuity decreases as opacification progresses with age. Recurrent erosions are seen frequently .

42. LIGHT MICROSCOPY AND STAINING Multiple stromal deposits may extend from deep epithelium to descemet membrane. Granular material is hyaline and stains bright red with Masson trichome .

43. Treatment Medical treatment include artificial lubricants, Bandage soft contact lenses with antibiotic drops and ointments Surgical management include excimer laser phototherapeutic keratectomy (remove superficial opacities) a nd others include penetrating or deep lamellar keratoplasty

44. GRANULAR CORNEAL DYSTROPHY TYPE 2 Former Alternative Names and Eponyms Avellino dystrophy Combined granular-lattice dystrophy

45. GRANULAR CORNEAL DYSTROPHY TYPE 2 Genetics C1 Inheritance Autosomal dominant Genetic Locus 5q31 Gene Transforming growth factor beta–induced—TGFBI Product Hyaline and amyloid

46. ONSET AND COURSE Onset Homozygous patients earlier onset (diagnosed, as early as 3 years of age) heterozygotes(diagnosed as early as the age of 8yrs) Course Slowly progressive. Homozygotes demonstrate more rapid progression

47. SIGNS Stellate shaped or snow flake like opacities appear between anterior and mid stroma Dash lines also present deeper than snow flake opacities. Hyaloid deposits typical of granular and amyloid deposits typical of lattice seen.

48. RETROILLUMINATION Dash lines and translucent dot like opacities

49. SYMPTOMS Vision decreases with age as the central visual axis becomes affected Pain accompanies epithelial erosions.

50. LIGHT MICROSCOPY AND STAINING Corneal opacities extend from the basal epithelium to the deep stroma . Opacities stain with Masson trichrome and/or Congo red

51. LATTICE CORNEAL DYSTROPHY TYPE 1 Former Alternative Names and Eponyms Classic LCD Biber - Haab -Dimmer

52. GENETICS LCD 1 Genetics C1 Inheritance Autosomal dominant Genetic Locus 5q31 Gene Transforming growth factor beta–induced—TGFBI Product Amyloid

53. ONSET AND COURSE Onset First to second decade Course Progressive, often with marked visual decrease by the fourth decade .

54. SIGNS Glass like branching lines in stroma . Refractile lines , central subepithelial ovoid white dots and diffuse stromal haze -early in the life. Stroma -ground glass appearance but peripheral cornea remains clear. Recurrent epithelial erosions common

55. RETROILLUMINATION Refractile lines or lattice lines best visualised in retroillumination mode. These lines start centrally and superficially and spread centrifugally and deeper.

56. LIGHT MICROSCOPY AND STAINING Amyloid deposits characteristically stain positive with Congo red . Red green Birefringence under polarized light Light microscopy Deposition of amyloid heavily in anterior stroma Also in subepithelial area Stromal deposition of amyloid distorts the collagen lamellar architecture

57. LATTICE CORNEAL DYSTROPHY TYPE 2 Alternative names Gelsolin type Or Finnish Familial amyloidosis Or Meretoja syndrome Or Amyloidosis (type V) Or Familial amyloidotic polyneuropathy type IV Inheritence - Autosomal dominant Gene locus- 9q3 Gene – Gelsolin/GSN Due to systemic involvement, not a true dystrophy

58. SYSTEMIC FEATURES Characteristic facial mask Dermatochalasis Lagophthalmos Pendulous ears Cranial and peripheral nerve palsies Dry and lax skin with amyloid deposition . Mutated gelosin -deposited in the conjunctiva, sclera and ciliary body, along the choriocapillaries , ciliary nerves and vessels and optic nerves.

59. Treatment for LCD Antibiotics and BCL can treat the epithelial erosions in LCD 1 and 2 Dry eye syndromes in LCD 2 can treat with topical lubricants,hydrophilic contact lens and lacrimal duct plugs Surgical options like keratoplasty in later life Penetraing keratoplasty and DALK are the options PTK useful in epithelial erosions,opacifications and in recurrence of changes after KP

60. MACULAR CORNEAL DYSTROPHY Former Alternative Names and Eponyms Groenouw corneal dystrophy type II Fehr speckled dystrophy

61. GENETICS Genetics C1 Inheritance Autosomal recessive Genetic Locus 16q22 Gene Carbohydrate sulfotransferase 6 gene—CHST6 Product Glycosaminoglycans

62. ONSET AND COURSE Onset Cornea is clear at birth Cloudiness appears at 3-9yrs of age Course Slowly progressive

63. SYMPTOMS Severe visual impairment occurs between 10 and 30 years of age. Corneal sensitivity is reduced. Photophobia and painful recurrent erosions rare

64. SIGNS Initially, central, superficial, irregular whitish fleck-like opacities. Extends up to limbus and the deep stroma down to descemet membrane. Cornea is much thinner than normal Stroma between opacities diffusely cloudy

65. LIGHT MICROSCOPY AND STAINING Breaks in the Bowman layer Glycosaminoglycans (GAGs) diffusely accumulate intracellularly and extracellularly throughout the corneal stroma Descemet membrane and endothelium are involved Alcian blue stain Colloidal iron stain

66. Treatment Initial medical management include artificial tears, lubricants, NSAISDs for pain Corneal transplantation is the gold standard once MCD visually significant Penetrating KP is the most common surgical treatment

67. STROMAL DYSTROPHY: A COMPARISON Features Granular dystrophy Macular dystrophy Lattice dystrophy Age of onset Deposits 1st decade 1st decade 1st decade Symptoms 3rd decade or asymptomatic 1st decade 2 nd decade Heredity AD AR AD Reduced vision By 4th or 5th decade 1st or 2nd decade By 2nd or 3rd decade Erosions Uncommon Common Variable Opacities Discrete, sharp borders Intervening stroma clear early but becomes hazy Subepithelial spots Not to limbus Indistinct margins Hazy intervening stroma Extends to limbus Endothelium affected Early Refractile tiny lines and dots Diffuse central haze Limbal zone clear except in extreme cases

68. STROMAL DYSTROPHY: A COMPARISON Features Granular dystrophy Macular dystrophy Lattice dystrophy Corneal thickness Normal Thinned Normal Histochemical stains Masson's trichrome Luxol fast blue Antibodies to microfibrillar protein Thioflavine -T (fluorescence) PAS Colloidal iron Alcian blue Metachromatic dyes PAS Congo red Crystal violet ( metachromasia ) Material accumulated Hyaline Glycosaminoglycans Amyloid Distinguishing clinical characteristics Clear limbal zone Opacities reach limbus Cornea thinned unless decompensated Lattice lines

69. Diagnosed in second- third decade Associated with Hyperlipoproteinemia Autosomal Dominant 1p36 locus, UBIAD1 gene Initially- central comma shaped subepithelial crystals Later- arcus lipoides HPE- Intracellular and extracellular esterified, unesterified phospholipids, cholesterol (Stained by Oil Red O) Schnyder Corneal Dystrophy (Category 1) Polarised microscopy- Birefringent crystals of cholesterol in superficial stroma under polarized light Electron Microsopy - Numerous Electron lucent spaces in cornea (dissolved cholesterol crystals )

70. Symptoms: visual impairment and glare Signs include central haze , progressing to widespread full thickness over time subepithelial crystalline opacities prominent corneal arcus is typical progress gradually centrally Treatment by excimer keratectomy or corneal transplantation

71. Autosomal Dominant 12q21.33 locus, Decorin gene Congenital Diffuse, bilateral corneal clouding Flake-like opacities throughout stroma (more anteriorly ) Increased stromal thickness Electron Microscopy- Normal collagen lamellae are separated by areas of amorphous substance with small filaments ( Decorin ) Congenital Stromal Corneal Dystrophy (Category 1)

72. Autosomal Dominant 2q34 locus, PIKFYVE gene Congenital Asymptomatic Dandruff-like opacities sparsely scattered in stroma Electron Microscopy- Swollen, vacuolated keratocytes - GAGs and complex lipids Fleck Corneal Dystrophy (Category 1)

73. Autosomal Dominant 12q21.33 locus, (KERA), (LUM), (DCN), (EPYC) gene Onset in third decade Asymptomatic Diffuse gray-white sheet-like opacities in any layer of stroma (most prominent posteriorly ) Decreased corneal thickness Corneal flattening HPE- Colloidal iron stains positive extracellular material in the posterior stroma Posterior Amorphous Corneal Dystrophy (Category 1) Electron Microscopy- Dilated mitochondria

74. Central Cloudy Dystrophy of Francois (Category 4) Unknown inheritance, AD has reported No genetic locus identified Onset in first decade Asymptomatic Axially distributed, polygonal gray -white cloudy stromal opacities separated by linear areas of clear cornea (resembles posterior crocodile shagreen ) HPE- Undulating deep stroma , positive staining for GAGs

75. Unknown inheritance Associated with X-linked ichthyosis—Xp22.31 locus Onset in third decade Asymptomatic Punctate opacities anterior to Descemet membrane ASOCT- Hyper reflective dots located anterior to Descemet membrane Pre-Descemet Corneal Dystrophy

76. Fuchs Endothelial Corneal Dystrophy (FECD) Inheritance -- Most are sporadic, with occasional AD inheritance. Mutation in COL8A2 has been identified in an early onset variant and in the TCF4 gene in most other cases. Onset is usually in middle age or later. more common in women Symptoms: Gradually worsening blurring, particularly in the morning, due to corneal oedema. Signs : Cornea guttata-- the presence of irregular warts or ‘excrescences’ on Descemet membrane secreted by abnormal endothelial cells

77. Specular reflection shows tiny dark spots caused by disruption of the regular endothelial mosaic and Progression occurs to a ‘beaten metal’ appearance Endothelial decompensation gradually leads to central stromal oedema and blurred vision, worse in the morning. Epithelial oedema develops in more advanced cases, with the formation of microcysts and bullae Rupture of bullae is associated with marked acute pain secondary to the exposure of nerve fibres . Subepithelial scarring and peripheral vascularization may be seen in longstanding cases.

78. In FECD, Descemet’s membrane is abnormally thickened, with attenuation or absence of the posterior nonbanded zone and replacement with abnormal collagen, known as wide-spaced collagen

79. Clinical staging

80. scattered, punctate, refractile endothelial guttae Decompensating cornea with the irregular surface and epithelial bullae indicated by scattered surface reflection

81. Confocal microscopy image of ECs in FECD- the numerous excrescences (guttae) of Descemet’s membrane as well as the irregular size and shape of the cells

82. the normal anterior banded zone (arrow), the markedly thickened and diffusely banded posterior collagenous zone guttae High-power electron micrograph of PCL showing a spindle-shaped bundle with 110-nm collagen banding (wide-spaced collagen, white arrow )

83. treatment Conservative options include topical sodium chloride 5% drops or ointment, reduction of IOP and use of a hair dryer for corneal dehydration. In Ruptured bullae, the use of bandage contact lenses, cycloplegia, antibiotic ointment and lubricants. Anterior stromal puncture may be helpful. Posterior lamellar ( DSAEK or DMEK) and penetrating keratoplasty Options in eyes with poor visual potential include conjunctival flaps and amniotic membrane transplantation. topical Rho-kinase inhibitor to stimulate endothelial cell proliferation and improve function

84. Posterior Polymorphous Corneal Dystrophy (PPCD) Autosomal dominant. Genetic Locus PPCD 1: 20p11.2-q11.2. PPCD 2: 1p34.3-p32.3. PPCD 3: 10p11.22. Gene PPCD1: unknown. PPCD2: mutation in COL8A2. PPCD 3: mutation of zinc finger E box–binding homeobox 1 (ZEB1).

85. VESICLES, CONFLUENT VESICLES, BAND LIKE LESIONS

86. PAS staining and Masson’s trichrome staining: The endothelium is replaced with flat epithelial-like cells that grow focally as more than 1 layer of cells In vivo confocal microscopy showing vesicular lesions and band-like structures with irregular edges within the endothelium associated with polymegathism of endothelial cells

87. Congenital Hereditary Endothelial Dystrophy (CHED) Bilateral corneal condition characterised by cloudy cornea present from birth or infantile in onset Classified as AD ( CHED 1) or AR (CHED2) IC3D eliminated CHED1 and CHED 2 now called as CHED Mutation of SLC4A11 ( Solute carrier family 4, sodium borate transporter,member 11) Genetic Locus 20p13. dysfunction of corneal endothelium is a hallmark of CHED

88. Light microscopy: edema of basal epithelial cells with subepithelial lacunae (open arrowhead) and breaks (arrowhead) in the Bowman layer. Thickened Descemet membrane with no visible endothelial cells

89. Signs Diffuse corneal edema, thickening of DM Corneal edema varies from grey ground glass to total corneal opacification On retroillumination , Descemet’s membrane may show a beaten copper appearance. Treatment lamellar ( DSAEK,DSEK,DMEK) or Penetrating Keratoplasty ( gold standard)

90. THANK YOU

91. LATTICE CORNEAL DYSTROPHY LCD type 1 Variants (III, IIIA, I/IIIA, IV)

92. Epithelial Recurrent Erosion Dystrophies (EREDs) VARIANTS Franceschetti corneal dystrophy (FRCD). Dystrophia Smolandiensis (DS). Dystrophia Helsinglandica (DH).