CHAPTER 1
General Topics in Ophthalmology
Approach to the Patient: Exam and History
History: demographics, referring doctor, chief complaint, history of present illness, past ocular history, ocular medications, past medical and surgical history, medications and allergies, family history
External and orbit: inspection, palpation, lymph nodes, skin, interpupillary distance, exophthalmometry, globe displacement, eyelid position, lid eversion, Schirmer’s testing
Visual acuity (VA): distance with and without correction, pinhole, near acuity, stereopsis, color, contrast, retinoscopy, cycloplegia, refraction, lensometry, prescription
Visual fields: confrontation, Amsler’s grid, Goldmann or Humphrey automated perimetry
Motility: ductions, versions, Hirschberg’s test, cover tests
Pupils: shape, size and reactivity, swinging flashlight testing for APD
Slit lamp examination: lids/lacrimal/lashes, conjunctiva/sclera, cornea, anterior chamber (AC), iris, lens, gonioscopy, fundus biomicroscopy
Tonometry: applanation, time of day
Dilated fundus examination: disk/macula/vessels/periphery, direct and indirect ophthalmoscopy, scleral depression, color drawings, photos, fluorescein angiography, ultrasound
Assessment, plan, counseling: in general, all ophthalmology problems are problems with either optics or anatomy. Attempt to stratify disease into typical versus atypical: if typical, then treat typically or observe; if atypical, then do full work-up.
Embryology and Development
NEURAL ECTODERM Derived from the folds of the neural plate and forms the optic vesicle and cup. Gives rise to the retinal pigment epithelium (RPE), iris sphincter and dilator muscles, iris pigment epithelium (IPE), the pigmented and nonpigmented ciliary epithelium, and the optic nerve (ON).
SURFACE ECTODERM Forms lens, corneal epithelium, lacrimal gland, epidermis of the lids, and epithelium of the adnexal glands and conjunctiva.
1
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2 GENERAL TOPICS IN OPHTHALMOLOGY
Figure 1–1 Average eye measurements in millimeters.
NEURAL CREST Forms most connective tissues of the eye and its adnexal structures. Gives rise to the corneal keratocytes and endothelium of the cornea and trabecular meshwork (TM), the iris and choroidal stroma (pigmented and nonpigmented cells), the ciliary smooth muscle, the fibroblasts of the sclera, and the ON meninges. Also forms orbital fibroadipose tissues, the satellite cells of the extraocular striated muscles, the pericytes of the vascular channels of the orbit, the orbital nerves (including the trigeminal ganglion) and associated Schwann’s cells, and the orbital cartilage and bone.
MESODERM Contributes very little to the head and neck mesenchyme through the somites. Forms the striated extraocular muscles, vascular endothelia, and circulating blood elements.
EYE MEASUREMENTS See Figure 1–1.
Emergencies
IMMEDIATE INTERVENTION Chemical burns, central retinal artery occlusion, orbital hemorrhage.
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GENETICS 3
URGENT ATTENTION Endophthalmitis, orbital cellulitis, globe laceration or intraocular foreign body (IOFB), macula-on RD, acute glaucoma.
Epidemiology/Statistics
LEADING CAUSES OF BLINDNESS Cataract, glaucoma, and trachoma account for more than 70% of cases of blindness throughout the world. The leading cause of pediatric blindness is xerophthalmia from vitamin A deficiency. Other leading causes include onchocerciasis, ocular trauma, bacterial and fungal keratitis, leprosy, diabetes mellitus, and age-related maculopathy.
POPULATION STATISTICS For a normal bell curve, one standard deviation above and below the mean includes 66% of the observed population; two standard deviations above and below the mean encompass 95%; three standard deviations above and below the mean include 99% of the population.
STATISTICAL TESTING The p value is the probability that the null hypothesis, if true, will be rejected.
Posttest probability: Bayes’ theorem
Sensitivity ¼ true positives total with disease. Describes how good the test is to find disease; thus, a good screening test has high sensitivity.
Specificity ¼ true negatives total without disease. Describes how good the test is to rule out disease; thus, a good confirmatory test has high specificity.
Type 1 error: rejecting a null hypothesis that is in fact true; the probability of commiting a type 1 error is designated as a, which is conventionally 0.05 for most studies.
Type 2 error: failing to reject a false null hypothesis or chance effect cannot be ruled out (often from inadequate sample size). The chance of a type 2 error, or missing a specified difference should it exist, is designated as b and is often 0.10. The power of a study is the complement of b or 1 – type 2 error.
Genetics
See Table 1–1 for a list of selected heritable ocular disorders with known genetic mutations.
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4 GENERAL TOPICS IN OPHTHALMOLOGY
TABLE 1–1
Selected Heritable Ocular Disorders with Known Genetic Mutations
Condition |
Gene |
Locus |
|
|
|
Anterior Segment Conditions |
|
|
Aniridia |
PAX6 |
11p13 |
Avellino dystrophy |
big-h3 |
5q31 |
Axenfeld-Rieger anomaly |
FKHL7 |
6p25 |
Corneal dystrophy, granular (CDGG1) |
big-h3 |
5q31 |
Corneal dystrophy, Meesmann |
K3 |
12q12–q13 |
|
K12 |
17q12–q21 |
Cornea plana congenita (CNA1 and CNA2) |
|
12q21 |
Iridogoniodysgenesis anomaly (IRID1) |
|
6p25 |
Iridogoniodysgenesis syndrome (iris hypoplasia) |
RIEG1 |
4q25 |
Lattice corneal dystrophy (LCD1) |
big-h3 |
5q31 |
Macular corneal dystrophy |
|
16q22 |
Megalocornea (X-linked) |
|
Xq12–q26 |
Microcoria |
|
13q31–q32 |
Peters’ anomaly |
PAX6 |
11p13 |
|
PITX2 |
4q25 |
Posterior polymorphous dystrophy |
|
20q11 |
Reis-Buckler (CDRB) |
big-h3 |
5q31 |
Rieger syndrome, type 1 |
RIEG1 |
4q25 |
Rieger syndrome, type 2 |
|
13q14 |
Schnyder’s crystalline corneal dystrophy |
|
1p36–p34.1 |
Lens Disorders |
|
|
Cataract, anterior polar 1 (CTAA1) |
|
14q24–qter |
Cataract, anterior polar 2 (CTAA2) |
|
17p13 |
Cataract, cerulean type I (CCA1) |
|
17q24 |
Cataract, cerulean type II (CCA2) |
CRYBB2 |
22q11.2–q12.2 |
Cataract, congenital total |
|
Xp |
Cataract, dominant, congenital |
CRYGA |
21q22.3 |
Cataract, Coppock-like (CCL) |
CRYGA |
2q33–q35 |
Cataract, Marner type (CAM) |
|
16q22.1 |
Cataract, posterior polar (CPP) |
|
Lpter–p36.1 |
Cataract, Volkmann type |
|
1p36 |
Cataract, dominant, zonular pulverulant (CZP) |
GJA3 |
13q11–q12 |
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GENETICS 5
TABLE 1–1 (Continued)
Selected Heritable Ocular Disorders with Known Genetic Mutations
Condition |
Gene |
Locus |
|
|
|
|
|
Cataract, lamellar, zonular pulverulant, Coppock |
GJA8 |
1q21.1 |
|
Cataract, zonular with sutural opacity (CCZS) |
|
17q11–q12 |
|
Ectopia lentis, simple |
Fibrillin |
15q21.1 |
|
Primary Glaucomas |
|
|
|
Glaucoma, adult onset POAG (GLC1B) |
|
2cen–q13 |
|
Glaucoma, adult onset POAG (GLC1C) |
|
3q21–q24 |
|
Glaucoma, adult onset POAG (GLC1D) |
|
8q23 |
|
Glaucoma, adult onset POAG (GLC1E) |
|
10p15–p14 |
|
Glaucoma, open angle, juvenile onset (GLC1A) |
Myocillin |
1q23–q25 |
|
Glaucoma, primary infantile (GLC3A) |
CYP1B1 |
2p21 |
|
Glaucoma, primary infantile (GLC3B) |
|
1p36 |
|
Glaucoma, pigment dispersion type |
|
7q35–q36 |
|
Vitreoretinopathies |
|
|
|
Familial exudative vitreoretinopathy (EVR1) |
Norrin |
11q13–q23 |
|
FEVR X-linked (EVR2) |
|
Xp11.4–p11.23 |
|
Myopia, Bornholm eye disease, X-linked |
|
Xq28 |
|
Neovascular inflammatory vitreoretinopathy |
|
11q13 |
|
Norrie disease |
Norrin |
Xp11.4–p11.23 |
|
Primary retinal dysplasia, X-linked (PRD) |
Norrin |
Xp11.4–p11.23 |
|
Retinoschisis (RS) |
XLRS1 |
Xp22.2–p22.1 |
|
Stickler’s syndrome, type I (STL1) |
COL2A1 |
12q13.1–p13.3 |
|
Stickler’s syndrome, type II (STL2) |
COL11A2 |
6p22–p21.3 |
|
Wagner syndrome type 1 (WGN1) |
|
5p14.3 |
|
Wagner syndrome type 2 (WGN2) |
COL2A1 |
12q13.11 |
|
Retinal Disorders |
|
|
|
Achromatopsia 1 |
CNGA3 |
14 |
|
Achromatopsia 2 |
|
2q11 |
|
Achromatopsia 3 |
|
8q21–q22 |
|
Albinism |
|
|
|
Oculocutaneous, OCA1-A (tyrosinase ) |
Tyrosinase |
11q14–q21 |
|
Tyrosinase |
11q14–q21 |
||
Oculocutaneous, OCA1-B (yellow) |
|||
Oculocutaneous, OCA2 (tyrosinase þ) |
P |
15q11.2–q12 |
|
|
|
(Continued)
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6 GENERAL TOPICS IN OPHTHALMOLOGY
TABLE 1–1 (Continued)
Selected Heritable Ocular Disorders with Known Genetic Mutations
Condition |
Gene |
Locus |
|
|
|
Oculocutaneous, OCA3 (brown) |
TYRP-1 |
9p23–p22 |
Che´diak-Higashi syndrome (CHS1) |
LYST |
1q42.1–q42.2 |
Hermansky-Pudlak syndrome (HPS) |
Transmembrane |
10q23.1–q23.3 |
|
protein |
|
Ocular albinism, OA1 (Nettleship-Falls) |
OA1 |
Xp22.3 |
˚ |
|
Xp11.4–p11.23 |
Ocular albinism, OA2 (Aland eye dis.) |
|
|
Ocular albinism with sensorineural deafness |
|
Xp22.3 |
Atrophia areata (helicoid chorioretinal degen.) |
|
11p15 |
Bardet-Biedl syndrome, BBS 1 |
|
11q13 |
Bardet-Biedl syndrome, BBS 2 |
|
16q21 |
Bardet-Biedl syndrome, BBS 3 |
|
3p13–p12 |
Bardet-Biedl syndrome, BBS 4 |
|
15q22.2–q23 |
Bardet-Biedl syndrome, BBS 5 |
|
2q31 |
Central areolar choroidal dystrophy |
|
17p |
Choroideremia |
REP1 |
Xq21.1–q21.3 |
Color vision defects |
|
|
Blue cone monochromacy (CBBM) |
Red, green genes |
Xq28 |
Deuteranopia |
Green genes |
Xq28 |
Dominant tritanopia |
Blue genes |
7q31.3–q32 |
Protanopia |
Red genes |
Xq28 |
Cone dystrophies |
|
|
Cone dystrophy, dominant (COD3) |
GUCA1A |
6p21.1 |
Retinal cone dystrophy 1 (RCD1) |
|
6q25-q26 |
Retinal cone dystrophy 2 (RCD2) |
Recoverin |
17p13.1 |
XL progressive cone dystrophy (COD1) |
|
Xp11.4 |
XL progressive cone dystrophy (COD2) |
|
Xq27 |
Cone rod dystrophy, CORD 1 |
|
18q21.1–q21.3 |
Cone rod dystrophy, CORD 2 |
CRX |
19q13.1–q13.4 |
Cone rod dystrophy, CORD 3 |
ABCR |
1p21–p13 |
Cone rod dystrophy, CORD 5 |
|
17p13–p12 |
Cone rod dystrophy, CORD 6 |
GUC2D |
17p13 |
Cone rod dystrophy, CORD 7 |
|
6cen–q14 |
Congenital stationary night blindness |
|
|
Oguchi’s disease, RHOK-related |
RHOK |
13q34 |
Oguchi’s disease, SAG-related |
Arrestin (SAG) |
2q37.1 |
CSNB 1 |
|
Xp11 |
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GENETICS 7
TABLE 1–1 (Continued)
Selected Heritable Ocular Disorders with Known Genetic Mutations
Condition |
Gene |
Locus |
|
|
|
CSNB 2 |
CACNA1F |
Xp11.23 |
CSNB 3, PDE6B-related |
PDE6B |
4p16.3 |
CSNB 4, RHO-related |
RHO |
3q21–q24 |
CSNB, Nougaret |
GNATI |
3p21 |
Doyne’s honeycombed retinal dystrophy |
EFEMP1 |
2p16 |
Gyrate atrophy |
OAT |
10q26 |
Leber’s congenital amaurosis, LCA 1 |
GUC2D |
17p13 |
Leber’s congenital amaurosis, LCA 2 |
RPE65 |
1p31 |
Leber’s congenital amaurosis, LCA 3 |
CRX |
19q13.3 |
Macular dystrophies |
|
|
Macular dystrophy, age-related (ARMD1) |
ABCR |
1q25–q31 |
Macular dystrophy, age-related (ARMD2) |
RDS/peripherin |
1p21–p13 |
Macular dystrophy, peripherin-related |
|
6p21.2–p11.2 |
Macular dystrophy, dominant cystoid |
|
7p21–p15 |
North Carolina macular dystrophy (MCDR1) |
|
6q14–q16.2 |
Progressive bifocal chorioretinal atrophy |
TIMP3 |
6q14–q16.2 |
Sorsby’s fundus dystrophy |
ABCR |
22q13–qter |
Stargardt’s disease, STGD 1 |
|
1p21–p13 |
Stargardt’s disease, STGD 2 |
|
13q34 |
Stargardt’s disease, STGD 3 |
|
6cen–q14 |
Stargardt’s disease, STGD 4 |
|
4p–1q13 |
Vitelliform macular dystrophy (Best’s) |
VMD21 |
11q13 |
Retinoblastoma |
p100 |
13q14 |
Retinitis pigmentosa |
|
|
Digenic RP (ROM/RDS) |
RDS/peripherin |
6p21.2–p11.2 |
Over 10 autosomal recessive genes |
Arrestin, ROM1, |
2q37, 11q13, |
|
etc. |
etc. |
Over 10 autosomal dominant genes |
|
1p21–p13, etc. |
At least 5 X-linked genes identified |
ABCR, etc. |
Xp21, etc. |
Mitochondrial RP |
RPGR, etc. |
mtDNA |
Usher’s syndrome, USH 1A |
MTTS2 |
14q32 |
Usher’s syndrome, USH 1B |
|
11q13.5 |
Usher’s syndrome, USH 1C |
Myosin 7A |
11p15.1 |
Usher’s syndrome, USH 1D |
|
10q |
Usher’s syndrome, USH 1E |
|
21q21 |
(Continued)
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8 GENERAL TOPICS IN OPHTHALMOLOGY
TABLE 1–1 (Continued)
Selected Heritable Ocular Disorders with Known Genetic Mutations
Condition |
Gene |
Locus |
|
|
|
Usher’s syndrome, USH 1F |
|
10 |
Usher’s syndrome, USH 2A |
|
1q41 |
Usher’s syndrome, USH 2B |
|
not 1q |
Usher’s syndrome, USH 3 |
|
3q21–q25 |
Retinitis punctata albescens |
RDS / peripherin |
6p21.2–p11.2 |
|
RHO |
3q21–q24 |
|
RDH5 |
12q13–q14 |
|
RLBP1 |
15q26 |
Optic Nerve Disorders |
|
|
Coloboma of ON with renal disease (ONCR) |
PAX2 |
10q24.3–q25.1 |
Dominant optic atrophy, Kjer type (OPA1) |
|
3q27–q28 |
Leber’s hereditary optic neuropathy |
|
MtDNA |
X-linked optic atrophy (OPA2) |
|
Xp11.4–Xp11.2 |
Lid Disorders |
|
|
Blepharophimosis syndrome, BPES1 |
|
3q22–q23 |
Blepharophimosis syndrome, BPES2 |
|
7p21–p13 |
Congenital ptosis, dominant |
|
1p34.1–p32 |
Eye Movement Disorders |
|
|
Congenital fibrosis of extraocular muscles 1 |
|
12p11.2–q12 |
Congenital fibrosis of extraocular muscles 2 |
|
11q13.2 |
Congenital fibrosis of extraocular muscles 3 |
|
16q24.2–q24.3 |
Kearns-Sayre syndrome |
|
MtDNA |
Progressive external ophthalmoplegia 1 (PEO1) |
|
10q23.3–q24.3 |
Progressive external ophthalmoplegia 2 (PEO2) |
|
3p21.2–p14.1 |
Progressive external ophthalmoplegia 3 |
|
4q |
Nystagmus, dominant congenital |
|
6p12 |
Nystagmus, X-linked congenital |
|
Xq26–q27 |
Ocular Development Disorders |
|
|
Anophthalmos, X-linked |
|
Xq27–q28 |
Holoprosencephaly |
SIX3 |
2q21 |
Microphthalmia |
|
14q32 |
Microphthalmia with linear skin defects (NILS) |
|
Xp22 |
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|
|
GENETICS |
9 |
|
|
TABLE 1–1 (Continued) |
|
|
|
|
|
|
|
|
|
|
|
Selected Heritable Ocular Disorders with Known Genetic Mutations |
|
|
|
||
Condition |
Gene |
Locus |
|
|
|
|
|
|
|
|
|
Myopia 2 (MYP2) |
|
18p11.31 |
|
|
|
Myopia 3 (MYP3) |
|
12q21–q23 |
|
|
|
Nanophthalmos |
|
11p |
|
|
|
Selected Systemic Disorders with Ocular Findings |
|
|
|
|
|
Abetalipoproteinemia |
MTP |
4q22–q24 |
|
|
|
Alagille syndrome |
JAG1 |
20p12 |
|
|
|
Alport’s syndrome (autosomal recessive) |
COL4A4 |
2q35–q37 |
|
|
|
Alport’s syndrome (X-linked) |
COL4A5 |
Xq22–q24 |
|
|
|
Ataxia-telangiectasia |
ATM |
11q22–q23 |
|
|
|
Gardner’s syndrome |
APC |
5q21–q22 |
|
|
|
Incontinentia pigmenti (type I) |
|
Xp11.21 |
|
|
|
Incontinentia pigmenti (type II) |
|
Xq28 |
|
|
|
Lowe’s oculocerebrorenal syndrome |
InsP-ase |
Xq24–q26 |
|
|
|
Marfan syndrome |
Fibrillin |
15q21.1 |
|
|
|
Multiple endocrine neoplasia (type II A and B) |
RET |
10q11.2 |
|
|
|
Myotonic dystrophy |
Myotonin |
19q13.2–q13.2 |
|
|
|
|
DM2 |
3q |
|
|
|
Neurofibromatosis (NF1) |
Neurofibromin |
17q11.2 |
|
|
|
Neurofibromatosis (NF2) |
Schwannomin |
22q12.2 |
|
|
|
Neuronal ceroid lipofuscinosis |
|
|
|
|
|
Infantile (CLN1) |
Palmitoyl- |
5p32 |
|
|
|
|
thioesterase |
|
|
|
|
Classic late infantile (CLN2) |
|
11p15.5 |
|
|
|
Juvenile, Batten disease (CLN3) |
CLN2 |
16p12.1 |
|
|
|
Variant late infantile (CLN5) |
CLN3 |
13q21.1–q32 |
|
|
|
Variant late infantile (CLN6) |
CLN5 |
15q21–q23 |
|
|
|
Oculodentodigital dysplasia (ODDD) |
|
6q22–q23 |
|
|
|
Oculopharyngeal muscular dystrophy |
PAPB2 |
14q11.2–q13 |
|
|
|
Osteoporosis-pseudoglioma syndrome (OPS) |
|
11q12–q13 |
|
|
|
Refsum’s disease with increased pipecolic acid |
|
10p |
|
|
|
Renal-coloboma syndrome |
PAX2 |
10q24.3–q25.1 |
|
|
|
Spinocerebellar ataxia with muscular dystrophy |
SCA7 |
3p21.1–p12 |
|
|
|
Tuberous sclerosis 1 |
TSC1 |
9q34 |
|
|
|
Tuberous sclerosis 2 |
TSC2 (tuberin) |
16p13.3 |
|
|
|
|
|
(Continued) |
|
|
|
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