Ophthalmology Explorer 1st Edition

Ophthalmology

Dhaval Patel

MD (AIIMS)

1st Edition

Explorer

MD (AIIMS)

Dhaval Patel

[email protected]

by ophthalmologyexplorer.blogspot.com

1st edition, April 2014

This is a compilation effort from my preparation notes and other sources, thus

any contributions or comments are welcomed in the effort to improve this book.

Therefore, feel free to e mail me at

1 PREFACE

The CLASS is knowing what to say, when to say and when to stop.

Dear Friends,

If you are reading this, then either you are approaching your final ophthalmology exams or you are preparing for further study courses in ophthalmology.

So first thing I want you to know is the course for this exam include all aspects of ophthalmology in different amounts and nobody knows it perfectly. This preparation manual I have prepared during my residency and added up while preparing for senior residency/ fellowship examinations preparation which may serve as a small guide to your preparation. It will also serve as a good collection of facts which we might forget/neglect during overall MD/MS exam preparation.

So whatever it may serve you, I am proud of what I have prepared and I feel it worth sharring with all emerging ophthalmologist friends.

All the Best..!!

2

INDEX

Exploring EYE ... 6

Basic Sciences ... 90

Optics & Refraction ... 122

Cornea ... 160 Lens ... 192 Glaucoma ... 205 Retina ... 226 Uvea ... 264 Strabismus ... 275 Neurophthalmology ... 284 Oculoplasty ... 310 Community Ophthalmology ... 337 Miscellaneous ... 342 Lateral Thinking ... 356

The Class Questions ... 364

Important History ... 369

3

Exploring EYE ... 6

AAO Color Codes of Topical Medication: 6 Age Related Changes ... 6

Aquaporins ... 7

Acquisition time ... 7

Axis and Angles ... 8

Bimodal Age Distribution ... 8

Blocks ... 9

Cell Cycle Phase Facts ... 9

Collagen Collection ... 10

Contents of Important Fluids ... 11

Chromosomes for Eye ... 13

Connexins ... 19

Craniosynostosis ... 20

Diameters ... 20

Drug Resistance ... 21

Dye for Eye ... 21

Electromagnetic Spectrum ... 21

Evolutions of anesthetic techniques for cataract surgery ... 22

FDA Approved Drugs ... 23

FDA Device Classification ... 26

Field of View ... 27

First in Genetics ... 27

Fellow Eye Risk ... 28

Frequency of Probes ... 29 Genes ... 29 Giant Cells ... 35 Growth Factors ... 35 Half Life ... 36 HLA ... 37

HLA wise Diseases ... 37

Disease wise HLAs ... 37

Host Cell Receptors ... 38

Host for Parasites ... 39

Hypersensitivity in Eye ... 39

IHC Markers ... 40

Inheritence ... 41

Inside Retinal Layers ... 42

Interferons Therapy & Eye ... 43

Intraocular Gases ... 44

Intracameral Dosages ... 44

Intrastromal Dosages ... 45

Intravitreal Dosages ... 45

Intravitreal Implants ... 46

Iris Nodules & Pathology ... 48

Laser Facts ... 48

Brief History ... 48

Instrument Wavelengths ... 49

Therapeutic Wavelengths ... 49

Laser settings for glaucoma ... 50

4

Laser Parameters for PTK ... 51

Modes of Laser ... 51

Laser Mediums ... 52

Laser Safety Classification ... 52

Latest Drugs ... 53 Mechanism of Action ... 57 MIP ... 58 MMPs ... 58 Molecular Weights ... 59 MUCins ... 59 NV % ... 60 OCT Review ... 61

Optic Nerve Segments ... 62

Orders of Abberations ... 63

Percentages % Primer ... 63

Phacomatosis ... 65

Principles ... 66

Radiation and Eye... 67

Rates ... 67

Recurrence % ... 68

Refractive Indices ... 69

Resolutions ... 70

RB Stats ... 71

Racial predilection of Diseases ... 72

Studies and Trials ... 72

DR ... 72

DME ... 74

ROP... 76

ARMD ... 77

Vitreomacular interface (VMI) diseases ... 81 Glaucoma ... 82 ON ... 83 NAION ... 83 MISC ... 83 Surface Tension ... 84 Specific Gravity ... 84 Surface Area ... 85 Survival Rates ... 85 Test Distances ... 86 Thickness ... 87 VEGF Facts ... 88

Vitreous cavity volume displacement ... 89

Water Content ... 89

Basic Sciences ... 90

Optics & Refraction ... 122

Cornea ... 160 Lens ... 192 Glaucoma ... 205 Retina ... 226 Uvea ... 264 Strabismus ... 275

5 Neurophthalmology ... 284 Oculoplasty ... 310 Community Ophthalmology ... 337 Miscellaneous ... 342 Lateral Thinking ... 356

The Class Questions... 364

Important History ... 369

6

Exploring EYE

AAO Color Codes of Topical Medication:

Based on the American Academy of Ophthalmology recommendations to the FDA to aid patients in distinguishing among drops and thus minimize the chance of using an incorrect medication

 Purple Cap: Alpha-Adrenergic Receptor Agonists  Yellow or Blue Cap: Beta-Blockers

 Green Cap: Cholinergic Agonists, Miotics  Orange Cap: Carbonic Anhydrase Inhibitors  Turquoise/Teal Cap: Prostaglandin Analogues  Red Cap: Mydriatic/ cycloplegic agents

 Tan Cap: Anti-infectives

 Pink Cap: Steroids/ Anti-inflammatory  Gray Cap: Nonsteroidal anti-inflammatories  Dark Blue: beta-blocker combination

Age Related Changes

 Ganglion cell loss: 5000/year  Endothelial cell loss: 0.6%/year

 Decrease in ACD due to increase LT: 20 microns/year  Age related loss of VF sensitivity: 1 db/year

 15.6-μm decrease in choroidal thickness for each decade of life  LENS thickness increases 0.2 mm per 10 year.

20 year: 3.8 mm 40 year: 4.4 mm

7 60 year: 4.8 mm

80 year: 5.2 mm

 central anterior chamber depth decreases 0.01 mm/year

Aquaporins

 Water channels are known as aquaporins and lens epithelial cells contain an abundance of these.

 MIP26 is believed to be a very old (and not very efficient) member of the aquaporin family and is termed aquaporin O.

 Types

o AQP0 (MIP) in lens fiber

o AQP1 in cornea endothelium, ciliary and lens epithelia and trabecular meshwork o AQP2 is not present in eye and is restricted to the kidney collecting duct

o AQP3 in conjunctiva

o AQP4 in ciliary epithelium and retinal Müller cells o AQP5 in corneal and lacrimal gland epithelia

 AQP1 protects against vascular leakage by stabilizing the formed vessels.

 NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel.

Acquisition time

 Pentacam: 2 sec  OCT: 1 to 5 sec

 Visante ASOCT: 3.3 sec

o Anterior segment scan ( 16×6mm): 256 A-scan/ 0.125 sec o High resolution scan: 512 A-scan/ 0.25 sec

8 o Pachymetry scan: 128 A-scans/0.5 sec

 Dynamic light scattering DLS for lens pathology: 5 sec  CSLO: 1.6 sec

Axis and Angles

Axis of the Eye

FOVea

o Fixation Axis: This is a straight line that joins center of rotation of eyeball with fixation point o Optical Axis: A line passing through center of cornea, center of lens and posterior pole of

retina is the optical axis of eyeball

o Visual Axis: A line joining point of fixation with fovea and passing through nodal point of eyeball is called visual axis. Nodal point of eyeball is just anterior to posterior capsule of lens. Fixation point is the point which is being seen with fovea at any particular moment.

o Pupillary Line: This is a straight line that passes through center of pupil

Angles of the Eye

o Angle Alpha is the angle formed between optical axis and visual axis. AOV o Angle Kappa is the angle formed between visual axis and pupillary axis. KaVPa o Angle Gamma is the angle formed between optical axis and fixation axis. GOF POsitive angle Kappa results in pseudoeXotropia. K-POX

Bimodal Age Distribution

 Craniopharyngioma (peaking in the first 2 decades and again in the years 50 to 70  Thyroid orbitopathy (for women occur from ages 40 to 44 years and 60 to 64 years; for

men from ages 45 to 49 years and 65 to 69 years)

9  Glaucoma in SWS: (early-onset/congenital-type and later-onset)

 Ocular Trauma

Blocks

Facial Blocks: LOAN

 van Lint‘s block: Blocking the peripheral branches of facial nerve  O‘Brien‘s block: Facial nerve trunk block at the neck of mandible

 Atkinson‘s block: In it superior branches of the facial nerve are blocked by injecting anaesthetic solution at the inferior margin of the zygomatic bone.

 Nadbath block: facial nerve is blocked as it leaves the skull through the stylomastoid foramen.

Other Blocks

 Retrobulbar block was introduced by Herman Knapp in 1884  Peribulbar block was described in 1986 by Davis and Mandel

Cell Cycle Phase Facts

 Thymocyte- T cells: G0 arrest  Stem Cells: G0 arrest

 Endothelial Cells: G1 arrest

 central zone epithelial cells of lens capsule: G0 arrest

 In the G1 phase of the cell cycle, the RB-protein is hypophosphorylated. In S, G2, and M, it is hyperphosphorylated.

10  p53 mediates arrest of the cell cycle in the G1 phase after sublethal DNA damage

 Rb gene arrests cells in the G1 or G1/S-phase of the cell cycle, and stops further proliferation.

 Mitomycin C acts on all phases of cell cycle.

Collagen Collection

 Type 1: corneal stroma, tarsal plate  Type 2: vitreous

 Type 3: ciliary process

 Type 4: Descemet membrane, lens capsule, PNBZ, basal lamina of corneal epithelium  Type 5: Bowman membrane

 Type 7: ABZ

 Cornea total Collagen 15%

o fibrous collagens types I, II, III and V  Type I 50-55%

 Type III ~ 1%  Type VI 25-30% o non-fibrous collagen type IV

 Type IV 8-10%

o filamentous collagens types VI, VIII, IX and X

o basal lamina of the epithelium contains type IV collagen o Bowman‘s layer: type V

o predominant collagen (about 90%) of the stroma is type I

o Descemet's membrane contains predominantly type IV collagen, with about 10% type V

11

 BM of ciliary process and ciliary muscles ECM: laminin and collagen types I, III, and IV

 human trabecular meshwork: collagen types I and III and elastin

 Juxtacanalicular Tissue: collagen type III but no collagen type I or elastin

 steroid-induced glaucoma shows increase in fine fibrillar material stains for collagen type IV in the subendothelial region of the Schlemm canal

 anterior uveitis: reducing the density of collagen type I in the extracellular matrix of the ciliary body leading to increase in uveoscleral flow

 lamina cribrosa of the human optic nerve head: collagen types I through VI, laminin, and fibronectin

 Topical prostaglandin F2alpha treatment reduces collagen types I, III, and IV in the monkey uveoscleral outflow pathway

Contents of Important Fluids

 BSS: Na, K, Ca, Mg, Cl, Citrate, Acetate

BSS plus: ―+ HCO3, PO4, Glucose, Glutathione Aqueous: ―+ Lactate, Ascorbate, Protein

 M.K. Media (4days): Tc199, Dextran, PH 7.0-7.5, Osmolality 295-355, gentamycin sulphate 75-150 micro gm/ml, HEPES as buffer, Phenol red as indicator

 K-Sol: Tc 199, MEM & Earles media, HEPES, Gentamicin, Chondroin sulphate 2.5%  Dexol: MEM, 1.35% Chondrotin Sulphate, 1mM Sodium pyruvate, 1mM non- essential

amino acids, Antioxidants, 1% dextran40.

 Optisol GS: MEM, 1.35% Chondrotin Sulphate, 1mM Sodium pyruvate, 1 mM non-essential aminoacids, Antioxidants, 1% dextran40, ATP, Iron, cholestrol, L-hydroxyproline, Vitamins, 2 antibiotics- Gentamycin, Streptomycin

 Procell: MEM,1.35%chondrotin sulphate,1mM sodium pyruvate1mM,Non-essential aminoacids,Antioxidants,Dextran40, Humen insulin 10 ug/ml & Human epidermal growth factor hEGF 10ng/ml to improve long term endothelial survival after PKP

 Eusol-C: Store at 4 deg.C, Dextran, Sodium Piruvate, Glucose, Essential & non-essential aminoacids, mineral salts, Vitamins, Gentamin, hepes buffer, Bicarbonate, Phenol Red

12  Organ culture medium: Fetal Bovine Serum, L-Glutamine, Earle's salts and 0.44%

Mercaptoethanol in addition to the other constituents present in most intermediate storage media

 Aqueous contents

Relative to plasma, aqueous humor has

o Slight hypertonicity and acidity (pH 7.2 in AC)

o Marked excess of ascorbate (15 times greater than arterial plasma) o Marked deficit of protein (0.02% in aqueous vs. 7% in plasma)

o Only calcium and phosphorus are in concentrations of about one-half that in plasma. o Chloride and bicarbonate vary from 20% to 30% above or below plasma levels. o Sight excess of lactic acid

o Slight deficit of sodium, bicarbonate, carbon dioxide, and glucose

o Protein and antibodies in aqueous equilibrate with those in serum when a plasmoid aqueous occurs with an anterior uveitis

o Albumin/globulin ratio is similar to plasma, although there is less gamma globulin

 Tear contents o Lipid layer

 Wax, cholesterol, fatty acid esters o Aqueous layer

 Water

 electrolytes (Na+, K+ Cl–, HCO3–, Mg2+)

 proteins (albumin, lysozyme, lactoferrin,transferrin, ceruloplasmin),  immunoglobulins (IgA, IgG, IgE, IgM)

 cytokines

 growth factors (EGF, TGF-α, TGF-β1, TGF-β2, bFGF, HGF, VEGF, substance P)

13  others (glucose, vitamins)

o Mucinous layer

 Sulfomucin, cyalomucin, MUC1, MUC4, MUC5AC o IgD has not been detected in any study of human tears.

Chromosomes for Eye

Chromosome 1:

 Fuch‘s dystrophy, COL8A2, AD

 Posterior polymorphous dystrophy, PPCD2, AD  Stickler syndrome, COL2A, AD

 Gelatinous drop like dystrophy, TYACSTD, AR  Schnyder corneal dystrophy, MJNFR, AD  EDS, EDS6, AR  Congenital glaucoma, GLC3B, AR  JOAG, Myocillin, AD  Stargardt‘s, ABCA4, AR  ARMD, CFH1  Usher syndrome, AR

 Chediak higashi syndrome, LYST, AR  Leber‘s congenital amaurosis, RPE65, AR

Chromosome 2:

 Congenital Glaucoma, CYP1B1, AR  Oguchi‘s disease, Arrestin, AR

14  PXE, laminin/fibrillin, AR

 Autosomal dominant drusen, EFEMP1, AD  Fleck dystrophy, PIP5K3, AD

Chromosome 3:

 BPES 1 (with premature ovarian failure) and BPES 2 (without premature ovarian failure) are caused by type 1 mutations in FOXL2 gene

 Von Hippel–Lindau syndrome Inheritance is AD condition caused by a mutation of the VHL gene clusterin

 Retinitis pigmentosa, Rhodopsin, AD  Xeroderma pigmentosa, NER enzyme, AR

 Alkaptonuria, homogentisate 1-2 dihydroxygenase, AR  Kjer autosomal dominant optic atrophy, OPA1, AD

Chromosome 4:

 Axenfield Rieger syndrome, PITX2, AD  CSNB, PDE6, AR

 Wolfram syndrome, WFS1, AR

 Hurler syndrome, alpha L iduronidase, AR  Bietti dystrophy, CYP4V2, AR

 Fraser syndrome, FRAS1, AR

Chromosome 5:

 Treacher Collins syndrome (mandibulofacial dysostosis) Inheritance is AD with high penetrance and variable expressivity, although 60% of cases occur with no family history and are thought to arise by de novo mutation. The gene involved is the ‗treacle‘ gene TCOF1 on chromosome 5q.

15  Cri du chat syndrome (partial deletion of 5p)

 Mutations in TGFB1 on chromosome 5 cause CDB1, CDB2, lattice type 1, lattice type 3A, Avellino, and granular dystrophy. These are therefore allelic variants.

Chromosome 6:

 Adult-onset macular vitelliform dystrophy is caused by mutation in the RDS gene on chrn Dysromosome 6p, as well as the BEST1 gene in common with juvenile-onset Best dystrophy.

 VEGF

 Pattern dystrophy, RDS/ peripherin, AD  Axennfeld reiger syndrome, FOXC1, AD

Chromosome 7:

 Galactosemia classic, galactose 1 phosphate uridyl transaferase, AR  Pigment dispersion syndrome, AD

Chromosome 8:

Chromosome 9:

 Lattice 2, gelsolin, AR

 Nevoid BCC syndrome, PTCH, AD  Rilet Day syndrome, IKBKAP, AR

Chromosome 10:

 Crouzon syndrome Inheritance is usually AD, but 25% of cases represent a fresh mutation. The gene (FGFR2) has been isolated to chromosome 10.

16  MEN2B, RET proto-oncogene, AD

 Gyrate atrophy, OAT, AR  NTG-COAG, optineurin, AD

Chromosome 11:

 Aniridia, peter‘s, AD keratitis, Axenfed reiger: PAX6, AD  Nanophthalmos, NNO1, AD

 Best disease, 11q13 bestrophin, AD  FEVR, frizzled 4 gene, AD

 OCA, TYR/OCA2, AR  CFEOM2: 11q13

Chromosome 12:  CFEOM-1:

 Cornea plana, KERA, AR  CHSD, DCN, AD  Meesman dystrophy, KRT3, AD  Fundus albipunctatous, RDH5, AR Chromosome 13:  Retinoblastoma, 13q14, AD  Sclerocornea, HCCS, AD  Microphthalmos, Trisomy 13  Congenital microcornea, AD

17  Late onset fuchs dystrophy, FECD2, AD

 CFEOM-3

Chromosome 14:

 Oculopharyngeal dystrophy Inheritance is AD caused by mutation on chromosome 14q.

Chromosome 15:

 Marfan syndrome: FBN1, AD

Chromosome 16:

 Posterior Polar Cataract: mutation of PITX3 gene  Macular dystrophy, CHST6, AR

 Pseudo xantoma elasticum, ABCC6, AR  Fish eye disease, LCAT, AR

 Tyrosenemia, tyrosine amino transferase, AR

Chromosome 17:

 Meesman dystrophy, AD  NF1, NF1, AD

 Cystinosis, CTNS, AR

Chromosome 18:

 Edwards syndrome (trisomy 18)  Transthyretin

18 Chromosome 19:

Chromosome 20:

 CHED AD, CHED1 20911, AD  CHED AR< CHED2 20p13, AR  PPMD2, VSX1, AD

Chromosome 21:

 Down syndrome (trisomy 21)

 Homocystinuria: Inheritance is AR with the gene locus on chromosome 21q.22.3.

Chromosome 22:  NF2, NF2, AD

 Sorsby dystrophy, TIMP3, 22q13, AD

Chromosome X: XR

 Fabry disease, alpha galactokinase  CSNB, calcium channels  Megalocornea, LTBP2  Coat‘s disease, NDP  FEVR, NDP  Retinitis pigmentosa, RPGR  Choroderemia, REP1

19 XD

 Lowe syndrome, OCRL1  Alport‘s syndrome, COL4A3  Aicardi syndrome

 Incontinentia pigmenti: NEMO gene on chromosome Xq28.  Ichthyosis, STS

Chromosome Y:

Connexins

 At electrical synapses a cytoplasmic bridge is formed by specialized proteins called connexins. Six connexins form a hexagonal tube that projects out of the plane of the plasma membrane of one participating cell; this unit is called a connexon.

 Connexin 43:

o gap junctions of lateral membranes of lens epithelial cells o oculodentodigital syndrome

 Connexin 46 and 50:

o Transmembrane proteins forming lens fiber gap junction is typically 16 nm thick o connexin 50 or MP70 is most prevalent in outer cortical fibers, where it undergoes

age-related degradation to MP38, which continues in functional gap junctions.  connexin mutations can give rise to congenital cataracts

 Connexin 50, connexin 37, and connexin 40 are all encoded by genes consisting of a single exon on chromosome 1q21

 A zonular pulverulent cataract has been localized to chromosome 13 near the connexin 46 gene.

20

Craniosynostosis

SPOT:

Scaphocephaly: sagittal suture closure (aka 'dolichocephaly')

Plagiocephaly: unilateral Coronal suture (anterior) or Lamboid (posterior) Oxycephaly: coronal suture plus any other suture, like the lambdoid Trigonocephaly: metopic suture closure

Syndromes Apert syndrome Crouzon syndrome Pfeiffer syndrome Saethre-Chotzen syndrome

Diameters

 Collagen fibres in corneal stroma: 25 nm diameter, 60 nm spacing between each pair  Collagen fibres in vitreous: 10 nm diameter

 Lens fibre diameter: 10.5 um

 Zonular fibres: 70-80 nm diameter, grouped into bundles of 5-50 um diameter  Cone diameter: 2 um with 0.3 um spacing

21

Drug Resistance

 CMV UL97 mutations (a CMV DNA polymerase mutation that confers ganciclovir

resistance) were detected in 3% of patients treated with ganciclovir over 3 months and in none treated less than 3 months.

Dye for Eye

 Anterior Segment (Capsule staining) o 0.5% indocyanine green

o 0.15% trypan blue (less costly when compared to the cost of ICG)  Posterior Segment

o ICG: ILM staining  0.05% o IFCG: 0.05% o TB: ERM stain  0.06% o BBG: ILM staining  0.05%, 0.025% o TA o PB o BrB o NaF

Electromagnetic Spectrum

22  Ultraviolet C rays: This band is blocked by the ozone layer of atmosphere.

 Ultraviolet B rays: This band is responsible for snow blindness and photo keratitis caused by welding arc. Prolonged exposure to these rays can cause formation of pingicula and pterigium.

 Ultraviolet A rays: This band of UV rays is absorbed by crystalline lens and thus retina is protected against their bad effects. Prolonged exposure to these rays causes cataract formation. IOLs implanted during cataract surgery have chromophores [inhibitors of UV rays] to protect retina against UV rays.

 Visible Rays: VIBGYOR

 Infrared A rays are responsible for macular burn in solar eclipse [photo retinitis].  Infrared rays B and C can cause corneal opacity and cataract formation on prolonged

exposure.

Evolutions of anesthetic techniques for cataract surgery

 General anesthesia 1846  Topical cocaine 1881 Koller

 Injectable retrobulbar cocaine 1884 Knapp

 OrbicuIaris akinesia 1914 Van lint, O'Briens Atkinson  Hyaluronidase 1948 Atkinson

 Peribulbar 1970 kelman (but not published)  Posterior peribulbar 1985 Davis and Mandel  limbal 1990 Furata et al.

 Anterior peribulbar 1991 Bloomberg

 Pinpoint anesthesia 1992 Fukasawa and Furata  Topical tetracaine 1992 Fichman

 Topical plus intracameral 1995 Gills  No anesthesia 1998 Agarwal

23  Cryoanalgesia 1999 Gutierrez-Carmona

 Xylocaine jelly 1999 Koch and Assia

 Hypothesis, no anesthesia 2001 Pandey and Agarwal  Viscoanesthesia 2001 Werner, Pandey, Apple et al

FDA Approved Drugs

Drugs Approved in 2012

 Cystaran (cysteamine hydrochloride); Sigma Tau Pharmaceuticals; For the treatment of corneal cystine crystal accumulation due to cystinosis, Approved October 2012

 Jetrea (ocriplasmin); Thrombogenics; For the treatment of symptomatic vitreomacular adhesion, Approved October 2012

 Lucentis (ranibizumab injection); Genentech; For the treatment of diabetic macular edema, Approved August 2012

 Zioptan (tafluprost ophthalmic solution); Merck; For the treatment of elevated intraocular pressure, Approved February 2012

Drugs Approved in 2011

 Eylea (aflibercept); Regeneron Pharmaceuticals; For the treatment of neovascular (wet) age-related macular degeneration, Approved November 2011

Drugs Approved in 2010

 Zymaxid (gatifloxacin ophthalmic solution); Allergan; For the treatment of bacterial conjunctivitis, Approved May 2010

Drugs Approved in 2009

 Acuvail (ketorolac tromethamine); Allergan; For the treatment of pain and inflammation following cataract surgery., Approved July 2009

 Bepreve (bepotastine besilate ophthalmic solution); Ista Pharmaceuticals; For the treatment of itching associated with allergic conjunctivitis, Approved September 2009

 Besivance (besifloxacin 0.6% ophthalmic suspension); Bausch & Lomb; For the treatment of bacterial conjunctivitis, Approved June 2009

24  Ozurdex (dexamethasone); Allergan; For the treatment of macular edema following branch

retinal vein occlusion or central retinal vein occlusion, Approved June 2009

 Zirgan (ganciclovir ophthalmic gel); Sirion Therapeutics; For the treatment of acute herpetic keratitis, Approved September 2009

Drugs Approved in 2008

 Akten (lidocaine hydrochloride); Akorn; For anesthesia during ophthalmologic procedures, Approved October 2008

 Astepro (azelastine hydrochloride nasal spray); Meda Pharmaceuticals Inc.; For the treatment of seasonal and perennial allergic rhinitis, Approved October 2008

 Durezol (difluprednate); Sirion Therapeutics; For the treatment of inflammation and pain associated with ocular surgery, Approved June 2008

Drugs Approved in 2007

 AzaSite (azithromycin); InSite Vision; For the treatment of bacterial conjunctivitis, Approved April 2007

Drugs Approved in 2006

 Lucentis (ranibizumab); Genentech; For the treatment of neovascular (wet) age related macular degeneration, Approved June 2006

Drugs Approved in 2004

 Macugen (pegaptanib); Pfizer / Eyetech Pharmaceuticals; For the treatment of wet age-related macular degeneration., Approved December 2004

Drugs Approved in 2002

 Restasis (cyclosporine ophthalmic emulsion); Allergan; For the treatment of low tear production., December 2002

Drugs Approved in 2001

 Lumigan (bimatoprost ophthalmic solution); Allergan; For the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension, Approved March 2001

 Travatan (travoprost ophthalmic solution); Alcon; For the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension, Approved March 2001

25  Valcyte (valganciclovir HCl); Roche; For the treatment of cytomegalovirus retinitis in patients

with AIDS, Approved March 2001 Drugs Approved in 2000

 Betaxon; Alcon; For lowering IOP in patients with chronic open-angle glaucoma or ocular hypertension, Approved February 2000

 Quixin (levofloxacin); Santen; For treatment of bacterial conjunctivitis, Approved August 2000

 Rescula (unoprostone isopropyl ophthalmic solution) 0.15%; Ciba Vision; For the treatment of open-angle glaucoma or ocular hypertension, Approved August 2000  Visudyne (verteporfin for injection); QLT; For the treatment of wet age-related macular

degeneration (wet AMD), Approved April 2000 Drugs Approved in 1999

 Alamast; Santen; pemirolast potassium ophthalmic solution, Approved September 1999  ZADITOR; Ciba Vision; Treatment for the prevention of itching of the eye, Approved July

1999

Drugs Approved in 1998

 Alrex; Bausch & Lomb, Pharmos; Treatment for seasonal allergic conjunctivitis, Approved March 1998

 Cosopt; Merck; Treatment for glaucoma or ocular hypertension, Approved April 1998  Lotemax; Bausch & Lomb, Pharmos; Treatment for post-operative eye inflammation,

Approved March 1998

 Salagen Tablets; MGI Pharma; Treatment for Sjogren's Syndrome, Approved February 1998  Viroptic; King Pharmaceuticals; Treatment for inflammation of the cornea in children due to

herpes simplex virus, Approved February 1998

 Vitravene Injection; Isis Pharmaceuticals; Treatment for CMV in AIDS patients, Approved August 1998

Drugs Approved in 1997

 Acular (ketorolac tromethamine ophthalmic solution) 0.5%; Allergan; Treatment for

postoperative inflammation in patients who have undergone cataract extraction, Approved January 1997

26  Acular (ketorolac tromethamine ophthalmic solution) 0.5%; Allergan; Treatment for

post-surgical inflammation following cataract extraction, Approved November 1997  BSS Sterile Irrigating Solution; Alcon; Treatment during ocular surgical procedures,

Approved December 1997 Drugs Approved in 1996

 AK-Con-A (naphazoline ophthalmic); Akorn; Over-the-counter combination vasoconstrictor/antihistamine product for opthalmic use, Approved January 1996  Alphagan (brimonidine); Allergan; Treatment for open-angle glaucoma and ocular

hypertension, Approved September 1996

 Ocuflox (ofloxacin opthalmic solution) 0.3%; Allergan; Treatment for corneal ulcers, Approved May 1996

 OcuHist; Pfizer; Over-the-counter antihistamine eye drop, Approved January 1996  Vistide (cidofovir); Gilead; Treatment for cytomegalovirus (CMV) retinitis, Approved June

1996

 Vitrasert Implant; Chiron; Drug delivery system for the treatment of cytomegalovirus, Approved March 1996

FDA Device Classification

3 classes of ophthalmology devices

1. Class I devices (eg, refractometers, perimeters, sunglasses, visual acuity charts) are usually considered minimal-risk devices. Although these devices are subject to general controls, most of them are exempt from premarket review by the FDA. With few exceptions, manufacturers can go directly to market with a class I device.

2. Class II devices (eg, phacoemulsification units, tonometers, vitrectomy machines, daily-wear contact lenses) are usually considered moderate-risk devices. Class II devices are those for which general controls alone are insufficient to ensure safety and effectiveness and for which methods exist to provide such assurances. These devices, in addition to general controls, are subject to special controls, which may include special labeling requirements) mandatory performance standards, and postmarket su rveillance. With few exceptions, class II devices requi re premarket review by the FDA.

27 3. Class III devices (eg, excimer lasers, intraocular lenses, extended -wear contact lenses,

intraocular fl uids) are considered significant-risk devices that present a potential unreasonable risk of illness or injury. Class III devices are those for which insufficient information exists to ensure safety and effectiveness solely through general or special controls. Class III devices cannot be marketed in the United States until the FDA determines that there is a reasonable assurance of safety and effectiveness when used accordi ng to the approved indications for use. Most class III devices come to market

through the premarket approval (PMA) process and require an extensive review by the FDA before approval is granted for marketing.

Field of View

 Standard Fundus Camera: 20, 30 and 50 degrees  RetCam: 130 degrees

 Optos: 200 degrees of retina (equator is at 180 degrees) 

First in Genetics

Wow…!! It’s amazing that all of following diseases first described in each category has an eye manifestation…!!! (Ref: Alex Levin MD, WEI, PA, USA)

1st AD: Piebaldism 1st AR: alkaptonuria

1st XR: red green colour deficiency 1st XD: Incontigenta pigmenti 1st Mitochondrial: LHON 1st digenic: RP

28 1st two-hit hypothesis: Retinoblastoma

1st contiguous gene deletion syndrome: anridia syndrome of wagner

Fellow Eye Risk

 Keratoconus: 50% of normal fellow eyes will progress to keratoconus within 16 years  PXG: A patient with unilateral PXG and only PXF in the fellow eye is at high risk (50% in 5

years) of developing glaucoma in the fellow eye. A patient with unilateral PXG who does not have PXF in the fellow eye has only a low risk of developing glaucoma in the normal eye.  Patients with advanced AMD (late ARM) in one eye, or even moderate vision loss due to

non-advanced AMD in one eye, have about a 50% chance of developing advanced AMD in the fellow eye within 5 years.

 In Age related Macular Hole, risk of involvement of the fellow eye at 5 years is around 10%.  In NAION, Involvement of the fellow eye occurs in about 10% of patients after 2 years and

15% after 5 years.

 AAION affects 30–50% of untreated patients of which one-third develop involvement of the fellow eye, usually within 1 week of the first.

 7% of patients with CRVO develop a nonsimultaneous venous occlusion of the fellow eye within 2 years

 The risk of any vascular occlusion in the fellow eye is estimated to be 0.9% per year.  The Macular Photocoagulation Study (MPS) reported that the 5-year risk of

neovascularization in fellow eyes of individuals with unilateral neovascular AMD was 10% in those without large drusen and 30–46% in those with large drusen

 POHS with CNVM, 20% risk over a 2-3-year period of developing choroidal neovascularization in the macula of the fellow eye

 50-75% of patients with angle closure in one eye will have an attack in the fellow eye often within 1 year (up to 10years) despite miotic treatment. Prophylactic laser iridotomy in fellow eyes of patients presenting with unilateral acute PAC also appears to be safe and effective in preventing acute PAC in 100%, and in preventing long-term rise in IOP in 89%

29  Acute retinal necrosis may occur in the fellow eye in approximately 30% of patients at an

average interval of 4 weeks.

 Chances of RD in fellow eye varies from 9-40%.

Frequency of Probes

 USG: 10 MHz  Ultrasonic Pachymetry: 10-20 MHz  UBM: 50 MHz  HI-SCAN: 35 MHz

Genes

 Genotypic heterogeneity: multiple genes causing single disease  Phenotypic heterogeneity: single gene causing multiple disease

 PXF: LOX L1  BPES: FOX L2  Pterygium: KL-6

 Lowe‘s syndrome: OCRL1 gene  TGFB1: aka BIGH3

o 5q31.2

o Protein produced by corneal epithelium o Phenotypic heterogeneity

GREAT

 Granular  Reis Buckler

30  EBMD

 lAttice  Thiel Behnke

 PAX6, 11p13: phenotypic heterogeneity o Aniridia

o Gillespe o WAGR

 Axenfield Reiger Spectrum (AD) – genotypic heterogeneity, multiple genes causing same disease o GJA1 (connexin 43)  6p21 o FKHL7/ FOXC1  6p25 o PITX2/ RIEG1 4q25 o RIEG2  13q14 o COL4A1  13q34

(MCQ: all except type question, so remember its Chromosomes 4, 6 and 13)

 Fuchs: genetic heterogeneity

o Following all genes do cause Fuchs and other diseases mentioned below.  COL8A2: PPMD

 SLC4A11: CHED  ZEB1: PPMD

 PITX2: homeobox gene  Peters, ARS, AN, Iris hypoplasia  KCNJ13: upregulates ZEB1

31  Keratin genes: cytokeratin 12 + 3

o KRT3: 12q13  Meesman o KRT12: 17q12  Stocker Holt

 Keratoconus: VSX1, SOD1

 Glaucoma Genes nosology:

o GLC is name given to primary gene loci by HUGO: Human Genome Organisation, Geneva

o GLC1: open angle (only 10% pt): AD  Only 3 genes are known till now

 GLC1A: JOAG 36%, POAG 4%  1q23-25  MYOC/TIGR  GLC1B: POAG  2q  nI IOP

 GLC1C: POAG 3q  high IOP  GLC1D: POAG  8q23  high IOP

 GLC1E: POAG/NTG 16%  10p14  Optineurin (OPTIc NEURopathy INducing), nI IOP

 GLC1F: POAG  7q

 GLC1G: POAG 5%  5q  WDR36 (WD Region 36) o GLC2: close angle

o GLC3: congenital (>25%): AR

 GLC3A: 2p21  CYP1B1, cyrochrome P450 gene  GLC3B: 1p36

 GLC3C: 14q24

 MYOC is responsible for 5.5% PCG

32 o Pseudoexfoliation syndrome: LOXL1, 15q24-25

o Genes associated with MMP

 MMP9 downregulated during acute PACG

 SNP rs17576 of MMP9 at chromosome 20q11 is strongly associated with acure PACG.

o Genes Causing Early-Onset or Familial Glaucoma  CYP1B1, Cytochrome p450  Congenital glaucoma

 LTBP2, Latent transforming growth factor beta binding protein 2  Congenital glaucoma

 PITX2, Paired-like homeodomain 2  Axenfeld-Riegers  FOXC1, Forkhead box C1  Anterior segment dysgenesis  PAX6, Paired box 6  Aniridia

 MYOC, Myocilin  Primary open-angle glaucoma (juvenile and familial)  OPTN, Optineurin Familial normal-tension glaucoma

 TBK1, TANK-binding kinase 1  Familial normal-tension glaucoma  LMX1B (9q34, glaucoma associated with nail-patella syndrome) o Glaucoma Gene Testing

 Congenital glaucoma  CYP1B1, LTBP2

 Anterior segment dysgenesis  FOXC1, PITX2, PAX6  Primary open-angle glaucoma  MYOC

 Normal-tension glaucoma  OPTN, TBK1, OPA1

 Eyelid Tumors genes o BCC:

 Sonic hedgehog pathway

 PTCH1 (patched 1): in BCNS or Gorlin syndrome o SeCA:

33  Muir Torre Syndrome

 MMR- Mismatch Repair genes (MSH-2, MSH-6, MLH-1)  MSI- high frequency of Micro Satelite Imbalance

o Merkel Cell Carcinoma

 MCPyV: Merkel Cell Polyoma Virus  70% cases

 LTA: Large T Antigen binds to host proteins, forces cell into S-phase

o Cutaneous Malignant Melanoma

 C-KIT activating mutations  chronic sun damage MM (Acral MM, Mucosal MM)

 BRAF activating mutations V600E (90%)  Non chronic sun damage MM  Nevi

 P16INK4a-Rb pathway: loss of function mutation of CDKN2A  Familial melanoma (dysplastic nevus syndrome)

 Melanocortin receptor (MC1R) varients  increased risk of MM and BCC independent of cutaneous pigmentation

 ARMD

o Complement factor H gene (CFH): 1q32 o Apolipoprotein E: 19q13.2

o Many others..BIG BIG list!!

 Retinal/Macular Dystrophies

o Best macular dystrophy BEST1, Chr11 AD/AR o Stargardt disease ABCA4, Chr 1 AR

o Stargardt-like dominant macular dystrophy ELOVL4 Chr 6 AD o Pattern dystrophy PRPH2 Chr 6 AD

34 o Autosomal dominant radial drusen EFEMP1 Chr 2 AD

o North Carolina macular dystrophy Unknown Chr 5 and 6 AD o Spotted cystic dystrophy Unknown Unknown AD

o Dominant cystoid macular edema Unknown Chr 7 AD

o Fenestrated sheen macular dystrophy Unknown Unknown AD o Glomerulonephritis type II CFH Chr 1 AR

 Mutations of LHON

o 11778: 98% patients, VA < 20/200, worst prognosis

o 14484: 10-15% patients, high incidence of spontaneous VA recovery, best prognosis o 3460: 8-15% of patients, high incidence of visual recovery, family history positive

 Gene therapy: for LCA, RPE 65 gene, NEJM 2008 study, Lancet 2009  Ocular development genes:

o Sonic hedgehog o Paired box

 PAX2: (during optic vescicle, causes ocular-renal coloboma syndrome)  PAX6 (eye development)

o Other downstream genes  CHX10, FKHL7 (6p15, forkhead transcription factor, ? neural crest), PITX2

 Genes causing Diabetes: ALR2, RHGE, TGF beta1  Uveal melanoma gene: DDEF1 gene, chromosome 8q  The ATP-binding cassette

o Subfamily A:ABCA

35  Zellweger syndrome

 Stargardt disease (ABCA4)

 Autosomal recessive retinitis pigmentosa  Cone-rod dystrophy

o Subfamily G: ABCG

 ABCG2: limbal stem cells 

Giant Cells

 Langhans giant cells: peripheral ring of nuclei, associated with tuberculosis, sarcoidosis  Touton giant cells: midperipheral ring of nuclei surrounded by a peripheral ring of lipid,

associated with xanthogranulomatous disease

 Foreign body giant cells: randomly dispersed nuclei, associated with foreign material and fungi

Growth Factors

 INF-Y: decreases angiogenesis  PEGF: decreases neovascularisation  Angiopoeitin: decreases leakage

o Angiopoietins-1–4 (Ang1–4) form a family of growth factors involved in angiogenesis o only Ang1 and Ang2 currently are known to have roles in ocular neovascular disease o Endothelial cells are a primary source of Ang2 production where it is stored in

Weibel–Palade bodies (WPB) from which it can be released by a variety of stimuli  Myofibroblasts are derived from keratocytes under influence of TGF beta1.

 HGF and KGF are predictor of corneal epithelial healing.  Keratocytes apoptosis is mediated by IL-1.

36  PKC beta is most important in DR pathogenesis. It increases basement membrane

permeability.

 Angiogenesis is regulated by a balance between VEGF and PEDF (pigment endothelium derived factor), as evidence is emerging that PEDF may inhibit new blood vessel growth.  PDGF-B is a growth factor structurally related to VEGF. The contributions of PDGF-B to

angiogenesis are mediated largely through its effects on mural cells such as pericytes and vascular smooth muscle cells.



Half Life

 IVTA

o Normal eye: 41 days o Vitrectomised eye: 16 days o Aphakic eye: 6.5 days  PST o Aqueous: 11 days o Vitreous: 17 days o Plasma: 25 days  Intravitreal Bevacizumab 1.25mg o 4.32 days rabbit o 5 days in humans  Intravitreal Ranibizumab 0.5 mg o 3 days in monkeys  Strontium-90: 28 years

37

HLA

HLA wise Diseases

 A2: JIA

 A11: Sympathetic ophthalmia

 A29: birdshot chorioretinopathy (90-100% association)  B5, B12: behcet's dz

 B7: toxoplasmosis, POHS, serpiginous choroidopathy, ankylosing spondylitis, APMPPE  B8: Sjögren‘s syndrome, sarcoidosis

 B12: Ocular cicatricial pemphigoid  B13: sarcoidosis

 B27: PAIR  Ankylosing spondylitis (88%), Reiter‘s syndrome (85–95%), inflammatory bowel disease (60%), psoriatic arthritis (also B17).

 B51: behcet‘s disease, eales

 Bw54: Posner-Schlossman syndrome, VKH?  DR2: POHS, intermediate uveitis, APMPPE  DR4: VKH, SO, OCP.

 DR2/15: pars planitis and Multiple Sclerosis

Disease wise HLAs

 Keratoconus: A9/10/12, B5/21  PXF: A1/33, B8

 OHT progression to Glaucoma: B7/12  AMD: A3, CW02/07

 Diabetic Retinopathy (DR) development: DR1/7  Diabetic Retinopathy (DR) proliferation: DR4, DQ8

38  Retinal vasculitis: B44

 Eales: B51, DR1/4  IU: B8/51, DR2

 Pars Planitis: DR15/17/51

 VKH: HLA-DR4 and HLA-Dw53 are more common in Chinese patients, HLA-DR1 and HLA DR4 more common in Hispanic patients, and HLA DRB1 in Indian patients

 SJS: significantly increased incidence of HLA-B12, HLA-Aw33, and DRw53  HSV EM: HLA-DQw3

 TEN: HLA-B12

 ocular lesions of SJS: HLA-B44

 Birdshot choroidopathy: White, HLA-A29, 96%

 Ankylosing spondylitis: White and asians, HLA-B27, 89%  Behçet's disease: Japanese, HLA-B5, 68%

 Reiter's syndrome: White, HLA-B27, 80%  POHS: White, HLA-B7-77%, HLA-DR2-81%

Host Cell Receptors

 Adenovirus type 37: CD46  Epstein–Barr virus: CD21

 Herpes simplex virus: Heparan sulfate  Human cytomegalovirus: Heparan sulfate  Human papillomavirus: Integrin a6

 Influenza virus: Sialic acid  Rhinovirus: ICAM-1

39

Host for Parasites

 Definitive:

o Toxoplasma gondii: domestic and wild cats o Echinococcus granulosus: dog

o Taenia solium: human  Intermediate host

o Taenia solium: pig

o Toxoplasma gondii: animals including humans o Echinococcus granulosus: sheep, cattles, pigs

o Francisella tularensis: rabbit, squirrels, cats, foxes, raccoons o Brucellosis: veterinarians and abattoir workers

o Oncocerca volvulus: many species of black fly simulium  Both definitive and intermediate:

o Taenia solium: human

Hypersensitivity in Eye

Gell, Coombs, and Lackmann‘s classification of Hypersensitivity Reactions o Type 1: VKC, AKC, SAC, GPC

o Type 2: OCP, PV, DH

o Type 3: SJS, RA, SLE, PAN, RP

o Type 4: TB, WG, Contact dermatitis, herpes disciform keratitis, sarcoidosis, transplant rejection

40

IHC Markers

 Melanoma markers: HMB45, melan A, tyrosinase, S-100 , MITF

 Epithelial markers: Cytokeratins (CAM 5.2, AE1, AE3, CK7, CK20, involucrin, etc.)  Endothelial markers: Factor VIII, CD34

 Muscle markers: Muscle specific actin (MSA), smooth muscle action (SMA), desmin, myogenin

 Neuroendocrine tumors: Chromogranin  Melanoma: HMB45, S100

 Neural tumor: S100, Leu7  Fibrous histiocytoma: CD68

 Spindle cell carcinoma: Cytokeratin

 Rhabdomyosarcoma: Desmin, Vimentin, Muscle specific actin, Myoglobin, Myogenin, MyoD1, Caveolin-3

 lymphoid tumors o CD3: T cells

o CD5: T cells, mantle cells, SLL/CLL o CD10: follicular lymphoma

o CD20: B cells

o CD23: follicular dendritic cells o Bcl-2: follicular, anti-apoptosis o Bcl-1: cyclin D1, mantle cell

 Retinoblastoma is positive for neuron-specific enolase (also found in aqueous of RB), class III tubulin isotype (h4), microtubuleassociated protein 2 (MAP2), and synaptophysin; they are negative for glial fibrillary acidic protein and S-100 protein

 Retinal stem cell marker: nestin, CD 34  Mitosis specific marker in cornea: Ki67

41  Limbus Stem Cells: CK 5/14+ve, CK 19+ve, P63+ve, Vimentin+ve, ABCG2, alpha-enolase

(5+14 =19)

 Central Corneal Cells: CK 3/12+ve, Connexin 43+ve (3 x 4 = 12, 4.3) 



Inheritence

 All vitreoretinopathy are AD except o Norrie  XL

o XLRS  XL

o Glodman favre  AR o Stickler  AD but rarely AR o FEVR  AD AR XR

 All MPSs are transmitted by the AR mode, except MPS II (Hunter syndrome) which is XR.

 albinism inheritance

o All OCA are AR except ADOCA o OA are XR.

 All corneal dystrophies are AD except o Macular  AR

o Gelatinous droplike  AR o LCD type 3  AR

42 o CHED type 2  AR

 Microcornea: AD Megalocornea: XR

 Familial ectopia lentis is AD Ectopia lentis et pupillae is AR.

 Simple myopia and simple hypermetropia: AD

Inside Retinal Layers

 The nuclei of the Müller cells lie in the inner nuclear layer, whereas the nuclei of the photoreceptors lie in the outer nuclear layer.

 The nerve fiber layer contains the axons of the ganglion cells.

 The inner plexiform layer has axons of the bipolar and amacrine cells and the synapses of the ganglion cells.

 The outer plexiform layer has connections between the photoreceptors, horizontal cells, and bipolar cells.

 The footplates of the Müller cells form the internal limiting membrane.

 cell bodies whose processes project into the lateral geniculate and pretectal nuclei ganglion cell layer

 Müller's cell nuclei  inner nuclear layer  Photoreceptors nuclei  Outer nuclear layer

 horizontal and bipolar synapses  outer plexiform layer  amacrine and bipolar cell synapses  inner plexiform layer  storage of dietary vitamin A  retinal pigment epithelium (RPE)

43  high baseline cyclic guanosine monophosphate (cGMP) levels and membrane

depolarization  photoreceptor layer

 flame-shaped retinal hemorrhages  nerve fiber layer  dot hemorrhages  inner nuclear layer

 Hard exudates  OPL  Soft exudates/ CWS  NFL

Interferons Therapy & Eye

 Alpha 2a: capillary hemangioma  Alpha 2b: papilloma

 Beta 1a:

o Avonex: for MS, intramuscular, once weekly

o Rebif: for MS, subcutaneous, thrice weekly, EVIDENCE Trial  Beta 1b:

o Betaseron and Extavia: for MS, subcutaneous  Gamma

44

Intraocular Gases

Physical characteristics

Intracameral Dosages

 Vancomycin: 1 mg/ml  Cefazolin: 1 mg/0.1 ml

 Cefuroxime: 1 mg/0.1 ml (ESCRS Study)  Gatifloxacin: 100 mcg/0.1 ml  Moxifloxacin: 100 mcg/ 0.1 ml  Amphotericin B: 5-10 mcg/0.1 ml  Irrigating fluid o Vancomycin: 25-50 mcg/ml o Gentamycin: 0.008 mg/ml

 Adrenaline tartarate: 1:10,000 (0.1 ml of 1:1000 is diluted with 0.9ml)  Pilocarpine: 0.1 ml of the drug (25 mg/ml) is diluted in 0.1 ml ringer lactate

Gases Mol wt. Purity (mole%) Expansion Longevity (days) Nonexpansile conc. (%) Air 29 99.99 0 5-7 ---- SF6 146 99.9 1.9-2.0 times 10-14 18 C3F8 188 99.7 4 times 55-65 14

45

Intrastromal Dosages

 Voriconazole: 50 microgram/ 0.1 ml  Amphotericin B: 5-7.5 microgram/0.1 ml  Ciprofloxacin: 0.3 mg/0.1 ml

 MMC: 0.02-0.04% for 15-30 sec to reduce post-operative interphase haze

Intravitreal Dosages

 Antibiotics o Vancomycin: 1mg/0.1ml o Ceftazidime: 2.25mg/0.1ml o Amikacin: 400 migrogram/0.1 ml o Gentamycin: 200 migrogram/0.1 ml  Antifungals o Voriconazole: 50-100micrgram/0.1ml o Amphotericin B: 5 migrogram/0.1 ml  Antivirals o Ganciclovir (Cytovene): 200–400 mg/0.1 mL o Foscarnet (Foscavir): 1200 mg/0.05 mL o Cidofovir (Vistide): 20 mg/0.1 mL  Steroids o Dexamethasone: 400 mcg/0.1 ml o Triamcinolone acetonide: 1-4 mg/ 0.1 ml  Anti VEGFs

46 o Bevacizumab AVASTIN: 1.25 mg in 0.05 ml

 1 ampoule: 0.2 ml

 1 vial: 4 ml or 16 ml of 25 mg/ml o Ranibizumab LUCENTIS: 0.5 mg in 0.05 ml o VEGF Trap EYELEA: 0.05, 2, 4 mg in 0.05 ml o SiRNA: 70-300 mcg

Intravitreal Implants

 Dexamethasone intravitreal implant (DEX implant; Ozurdex, Allergan, Irvine, CA) o delivers the steroid intravitreally for 6 months

o consists of poly (lactic-co-glycolic acid), a DEgradable polyester and dexamethasone

o single-use applicator through a 22-gauge

o uveitis and macular edema caused by retinal vein occlusion o 350 µg and 700 µg version

o Uses NOVADUR Delivery system

o GENEVA (dexamethasone implant) study: Global Evaluation of implantable dexamethasone in retinal Vein occlusion with macular edema (GENEVA) study  Vitrasert ganciclovir implant

o poly(vinyl alcohol) and poly(ethylene vinyl acetate)

o delivers the medication for approximately 32 weeks (8 months) and has been shown to halt the progression of CMV

o nondegradable o 5/4.5 mg implant o Releases 1 mcg/ hour

o Approaches concentration of 4 ug/ml intravitreal  Retisert fluocinolone implant

47 o blend of the drug with poly(vinyl alcohol) and methylcellulose

o 0.59 mg pellet embedded in a nonbiodegradable scaffold designed to be implanted in the vitreous cavity via a sclerotomy and anchored by a suture to the eye wall o releases drug at steady state between 0.3 and 0.4µg/day for approximately 30

months

o used most commonly for treatment of chronic non-infectious posterior uveitis. o Studied for DME also

 Iluvien fluocinolone implant

o narrow cylinder 3.5 × 0.37 mm o 25-gauge

o lowest dose format (0.2 µg/day) o higher-dose (0.5 µg/day) system o FAVOR (iluvien) study

 I-vation triamcinolone implant

o helical screw coated with triamcinolone acetonide that delivers the drug intravitreally for 36 months

o 25-gauge

o drug is entirely within the coating on the helical structure and not within the bulk of the device

 ECT CNTF Implant

o which allows the intravitreal implantation of a chamber containing live cells programmed to release CNTF

o 1.5 ng/day

o possible efficacy for age-related macular degeneration (AMD) involving geographic atrophy and for RP

o 2 years or more

 ECT technology anti-VEGF implant o NT-503

48 o For ARMD

 Brimonidine Intravitreal Implant

o Patients With Geographic Atrophy Due to Age-related Macular Degeneration (AMD)

o This is a randomized, double-masked, dose-response, sham-controlled evaluation of the safety and efficacy of brimonidine tartarate intravitreal implant in patients with geographic atrophy from age-related macular degeneration. It is hypothesized that the implant may promote the release of neuroprotective factors that may slow the progression of retinal degenerative disease.

Iris Nodules & Pathology

 Lisch nodule, neural crest hamartoma: NF 1

 JXG nodules are composed of histiocytes and Touton giant cells: JXG

 Koeppe nodules are collections of inflammatory cells, near pupillary margin: granulomatous and non-granulomatous uvetis

 Bassaca Nodules are seen at base: only in granulomatous uveitis (sarcoid, Tb, syphilis, VKH); often look gelatinous

 Brushfield spots are stromal hyperplasia: Downs syndrome  Berlin nodules are seen in angle: granulomatous uveitis

Laser Facts

Brief History

 1917 - A. Einstein: Laser possible.

 1958 - C.H. Townes, A.L. Schawlow: Theoretical basis for lasers.  1960 - T. Maiman: Built first laser.

49  1963 - C. Zweng: First medical laser trial (retinal coagulation).

 1965 - W.Z. Yarn: First clinical laser surgery.

Instrument Wavelengths

(Chronological order in nm)

 SWAP: 440, blue light

 Retinal Thickness Analyser RTA: green, 540-nm HeNe laser  Hertmann Shack‘s Aberrometer: 575 nm

 HRT- CSLO: 670 diode  GDX-SLO: 780 diode  IOL Master: 780 diode  Lenstar: 820, SLD

 Macular OCT (Posterior Segment OCT): 830  RNFL OCT: 810/850, SLD

 AS-OCT: 1310, SLD  Swept Source OCT: 1050

Therapeutic Wavelengths

(nm)

 Excimer laser: 193, Argon Fluoride (ultraviolet)  Excimer laser: 308, Xenon Cloride (ultraviolet)

 Excimer laser trabeculostomy ELT: 308, Xenon Cloride  Argon blue-green: 488

 Df Nd YAG: 512 (green)

50  Argon green: 514

 Yellow dye laser: 577 for DME  Krypton red or Dye red: 620-630

 He Ne Gas laser: 632, for Laser interferometry  Rostaporphin PDT: 664 nm

 Diode: 689, PDT (its verteporphin‘s peak absorption)  Ruby laser: 694, red

 Infrared diode laser: 780, IOL Master  Transpupilary thermotherapy, DLCP: 810

 subthreshold micropulse STMP diode 810nm: for DME  Intralase: Nd: YLF, wavelength is 1053 nm

 Nd YAG: 1064

 Ho YAG: 2100, used for laser thermokeratoplasty  Erbium YAG: 2940, for laser phacoemulsification  CO2 laser: 10600

Laser settings for glaucoma

 ND YAG PI: 500u, 5-15mJ, 12ns pulse, 1-3 pulse/sec  Argon PI: 50u, 1000mW, 0.1-0.2s,

 Laser pupilloplasty: 200u, 0.2s, 400mW  Laser sphincterotomy: 50u, 0.01-0.05s, 1.5W  ALT: 50u, 100ms, 1000mW

 SLT: 400u, 0.5-1.2mJ

51

Laser settings in Retina

 PRP: df NdYAG

o 200-500 micron spot size o 200-500 ms

o 200-500 mW

 Macular Grid Laser: df NdYAG o 50-100 micron spot size o 50-100 ms

o 50-100 mW

Laser Parameters for PTK

 Fluence: 160 ± 10 mJ/cm2  Repetition rate: 5 Hz

 Ablation rate: 0.20-0.35 mm per pulse

 Ablation diameter: 5.5–6 mm including a 0.5 mm transition zone  Ablation depths:

o Epithelium 40 mm (default value) or as determined by pachymetry

o Stroma: Depth of scar or opacity (postoperative corneal thickness should be at least 250 mm)

Modes of Laser

There are three modes of laser: continuous, Q-switched and mode-locked.

o Laser from continuous mode has a constant power and is measured in watts. o Q-switched and mode-locked increases the energy by compressing the energy in

52 o Mode-locked laser compresses the laser more than Q-switched laser and therefore

produces more energy.

Laser Mediums

 Solid state lasers have lasing material distributed in a solid matrix, e.g., the ruby or neodymium-YAG (yttrium aluminum garnet) lasers. The neodymium-YAG laser emits infrared light at 1.064 micrometers.

 Gas lasers (helium and helium-neon, HeNe, are the most common gas lasers) have a primary output of a visible red light. CO2 lasers emit energy in the far-infrared, 10.6 micrometers, and are used for cutting hard materials.

 Excimer lasers (the name is derived from the terms excited and dimers) use reactive gases such as chlorine and fluorine mixed with inert gases such as argon, krypton, or xenon. When electrically stimulated, a pseudomolecule or dimer is produced and when lased, produces light in the ultraviolet range.

 Dye lasers use complex organic dyes like rhodamine 6G in liquid solution or suspension as lasing media. They are tunable over a broad range of wavelengths.

 Semiconductor lasers, sometimes called diode lasers, are not solid-state lasers. These electronic devices are generally very small and use low power. They may be built into larger arrays, e.g., the writing source in some laser printers or compact disk players.

Laser Safety Classification

The International Safety Classification of Lasers divides the lasers into 4 groups. Group 3 is subdivided into 3a and 3b. Class 3b and above is damaging to the eye and their powers are 5MW and above. All lasers used in ophthalmology are classed as 3b and above. Safety goggles should always be worn by people in the vicinity.

Class I: Do not emit hazardous levels.

Class II: Visible light lasers that are safe for momentary viewing but should not be stared into continuously; an example is the aiming beam of ophthalmic lasers, or laser pointers. Class III: Unsafe for even momentary viewing, requiring procedural controls and safety equipment.

53 Class IV: Also pose a significant fire and skin hazard; most therapeutic laser beams used in ocular surgery are in this class

Latest Drugs

 Lampalizumab: new monoclonal antibody that inhibits complement factor D, which is a rate-limiting enzyme of the alternative complement pathway, first positive treatment result for patients with dry age-related macular degeneration and geographic atrophy.

 Pazopanib is a small molecule lipophilic potent and selective multitargeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that inhibits angiogenesis.

o Pazopanib eye drops o 5-10 mg/ml TID

o failed to reduce as-needed ranibizumab injections by ≥ 50%  AGN-150998:

o Designed Ankyrin Repeat Proteins (DARPins) o Concept Study

o Selectively binds to vascular endothelial growth factor-A with high binding affinity.  ROCK inhibitors:

o Rho-kinase inhibitors (ROCK)  novel drug in glaucoma

o human trabecular meshwork and Schlemm‘s canal cells to produce reversible changes in cell shape, focal adhesions and decreases in stress of the actin fibers. This resulted in an increase in permeability of the Schlemm cells‘ monolayer by 80% o decrease intraocular pressure by 25% to 32% and have a duration of action of 10 to

12 hours

o ATS907, ATS8535, AR-12286, AR-13324, AMA0076

 nitric oxide-donating prostaglandin F2-alpha analog  BOL-303259-X o comparable to latanoprost

54  Aganocides: novel class of compounds that mimic the body‘s natural defense against

infection

o NVC-422  Phase IIb clinical trial to treat adenoviral conjunctivitis.

 Voclosporin (Luveniq): novel immunomodulatory drug that inhibits the calcineurin enzyme, was originally developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, but with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration.

 Mapracorat:

o selective glucocorticoid receptor agonist (SEGRA)

o similar anti-inflammatory and immunosuppressive effects as the glucocorticoids but with a decreased potential of the steroid side effects

o Phase II study is evaluating its effectiveness in preventing the signs and symptoms of allergic conjunctivitis. In addition, a Phase III study is underway for the

treatment of ocular inflammation after cataract surgery.

 CF101: adenosine A3 receptor agonist

o Adenosine has been shown to inhibit leukotriene B4 (LTB4), which is part of the arachidonic acid cascade for the synthesis of prostaglandins and leukotrienes o For patients with moderate to severe dry eye

 Lifitegrast: lifitegrast is a potent and selective small molecule drug being investigated for the treatment of dry eye and ocular allergy. It inhibits T-cell inflammation by blocking the binding of two key cellular surface proteins that mediate the chronic inflammatory cascade.

 SMO Inhibitors (Smoothin): for advanced BCC o Cyclopamine (SMO Inhibitors):

55  naturally occurring sterol alkaloid, topical drug is in clinical trials

 it is obtained from Veratum calnifornicum (rocky mountain corn lily) ingestion of which causes serious malformation known as cyclopia and hence the name given cyclopamine

o Vismodegib (GDC-0449):  Synthetic small molecule  Orally active

o Statins o Vitamin D3

 Downstream SHH pathway inhibitors o Rapamycin (sirolimus)

 Macrolide antibiotic

 Inhibits MTOR in GLI1-transforme cells  No human stdies for BCC

o MYCN anti-sence oligonucleotides  No human studies for BCC

 BRAF inhibitors: for Malignant Melanoma o Sorafinib (pan BRAF)

o PLX4032 (V600E-BRAF)  C-KIT inhibiors

o Imatinib  Sutent: Sunitimab

o orally available multi-kinase inhibitor o Inhibits c-Kit, VEGFR, PDGFR etc

56 o Synergistic effects with radiation and chemotherapy

o Combination of Sutent, tamoxifan, cisplatin

 Tegretin (Bexarotene): for CTCL (Mycosis Fungoides)

 FOVISTA: Binds PDGF-B, phase 3 trials going on for wet AMD and CNVM.  Natalizumab: alpha 4 integrin



NT- 501

o

intra-vitreal implant is a Ciliary Neurotrophic Factor (CNTF) secreting encapsulated cell device

o

CNTF is a cytokine, which is a survival factor for various neuronal cells and seems to prevent neurodegeneration.

o CNTF may act through the IL-6 receptor.

o

A semi-permeable membrane encapsulates genetically engineered human RPE cells that secrete CNTF. It prevents host antibodies and immune cells from entering the device but allows nutrients to diffuse in, to nourish the cells within and CNTF to diffuse out. This holds promise for retinitis pigmentosa and dry age related macular degeneration



Bevasiranib (CAND5) is a siRNA which switches off VEGF production, but clinical effect is not seen till the preexisting VEGF is cleared. It has a potentially longer duration of effect than currently available anti-VEGF agents. It is well tolerated at multiple doses.

 Vatalanib is a VEGF receptor tyrosine kinase inhibitor given orally.

 Fenofibrate is drug of the fibrate class used to treat dyslipidemia. Raises HDL and lowers LDL and triglycerides and typically is used in combination with a statin. It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα). PPARα activates lipoprotein lipase and reduces apoprotein CIII, which increases lipolysis and elimination of triglyceride-rich particles from plasma.

 Fenretinide in Dry AMD: This drug is an oral vitamin A binding protein antagonist and is being studied in patients with geographic atrophy (GA).It halts the accumulation of retinol (vitamin A) toxins through affinity for retinol-binding protein. One of the hallmarks of dry macular degeneration is the accumulation of lipofuscin that is responsible for drusen

formation and geographic atrophy. One year interim data showed that fenretinide slowed the growth of geographic atrophy lesions by 45% in the 300 mg dose.

57  Copaxone (glatiramer acetate): weekly vaccination, Macular degeneration, Alzheimer‘s

disease and Multiple sclerosis

 Citicholine (Cytidin-5-diphposphocholine): It is similar in action to levodopa. When administered in adult patients with strabismic amblyopia (1gm\day i.m for 15 days), it has showed improvement lasting over 6 months including improvement in contrast sensitivity and VEP.

Mechanism of Action

 Local anesthetics block the generation and conduction of nerve impulses  General Anesthetics: multiple

 Fluoroquinolones: bactericidal agents that act by inhibiting DNA replication. They have dual targets, topoisomerase II (DNA gyrase) and topoisomerase IV

 Tetracyclines: broad-spectrum antibiotics that inhibit bacterial protein synthesis by binding to the 30-S ribosomal subunit of the bacteria

 Aminoglycosides: inhibit bacterial protein synthesis by binding irreversibly to the bacterial 30S ribosomal subunit.

 Glycopeptides (Vancomycin and teicoplanin): inhibit peptidoglycan synthesis in the bacterial cell wall by complexing with cell wall precursors

 Macrolides: bacteriostatic agents that inhibit bacterial RNA-dependent protein synthesis by binding reversibly to the 23S tRNA of the 50S ribosomal subunits

 Chloramphenicol: bacteriostatic agent that inhibits protein synthesis by binding reversibly to the peptidyltransferase component of the 50S ribosomal subunit and prevents the

transpeptidation process of peptide chain elongation

 SMX-TMP: competitively inhibit the bacterial modification of p-aminobenzoic acid into dihydrofolate, and trimethoprim inhibits bacterial dihydrofolate reductase

 Bacitracin and gramidicin: Bacitracin disrupts bacterial cell-wall synthesis by inhibiting the dephosphorylation of a lipid pyrophosphate, while gramicidin interferes more with cell membrane permeability

 Polymyxins: interact with the phospholipids of the bacterial cell membrane, which increases the cell permeability and disrupts osmotic integrity. This process results in leakage of intracellular constituents, leading to cell death