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A. Epidemiology

  1. World Health Organization (WHO) data estimate ~40 million "blind" in 1990s
  2. Low vision in another ~110 million persons in 1990s
  3. Definitions
    1. WHO blindness definition: visual acuity <20/400
    2. USA blindness definition: best visual acuity <20/200
    3. Low vision is <20/40 in USA, <20/60 by WHO
  4. Worldwide, 80% of blindness considered preventable or curable
  5. 90% of blindness occurs in developing world

B. Four Causes of Visual Loss

  1. Refractive Error
    1. Check with pinhole; needs refraction
    2. Glasses, contacts, surgery
  2. Media Opacities
    1. Cataracts
    2. Chemical/physical trauma
    3. Hemorrhage
    4. Keratitis
  3. Macular Disease
    1. Age Related Macular Degeneration (ARMD)
    2. Diabetic edema
  4. Optic Nerve Disease
    1. Neuritis
    2. Compression - including glaucoma
    3. Nerve transection
    4. Inherited disorders
    5. Metabolic disorders

C. Main Causes of Blindness in USA

  1. Age-Related Macular Degeneration (AMD) [4]
    1. Leading cause of visual impairment over age 50 in white persons
    2. Affects retina, macula and choroid
    3. Current therapy is only mildly effective
  2. Glaucoma [2]
    1. Leading cause of blindness in blacks
    2. Important cause of blindness in whites
    3. Causes an optic neuropathy due to compression of optic nerve
    4. Elevated intraocular pressure causing the compression is detectable and treatable
  3. Cataracts [3]
    1. Main cause of low vision (but not blindness) in USA
    2. Blindness usually preventable by surgery
  4. Diabetes [4]
    1. Leading cause of blindness in working age Americans, especially blacks
    2. Overall, blindness is 25 fold more common in diabetics versus non-diabetics
  5. Trauma

D. Worldwide Causes of Blindness

  1. Cataracts
    1. Leading cause of blindness worldwide
    2. Responsible for ~50% all cases
  2. Trachoma [5]
    1. Caused by Chlamydia trachomatis serotypes A, B, Ba and C
    2. Repeat infections with these serotypes is required for clinical disease
    3. Occasionally, genital serotypes D-K can cross into the eye and cause trachoma
    4. Corneal scarring 10-20 years after infection
    5. Treatment of infection completely prevents scarring and blindness
    6. Infection is endemic in many parts of developing world (main cause of blindness)
    7. Azithromycin 1-3 doses clears >93% of infections and prevents blindness
    8. Azithromycin is more effective with better compliance than topical tetracycline
  3. Onchoceriasis
    1. "River Blindness" vector is black fly
    2. Reaction to dead worms damages ocular structures
  4. Xerophthalmia (vitamin A deficiency)
    1. Night Blindndess
    2. Dry eye with Bitots spots on conjunctiva; leads to corneal ulceration
  5. HIV Infection
    1. Affects lacrimal gland, cornea, choroid, retina, optic nerve
    2. Increasing epidemic in developing countries

E. Blindness Prevention in Developed Countries [10,11]

  1. Routine visual screening in primary care setting has not been shown to benefit
  2. Routine eye professional screening for glaucoma is strongly advocated
  3. Timely identification of eye diseases is critically important to prevent blindness
  4. Optimizing Management of Systemic Diseases
    1. Critically important for long term blindness prevention
    2. Diabetes mellitus is most important
    3. Hypertension and hyperlipidemia also important
  5. Certain types of macular degeneration may benefit from anti-oxidants

F. Vitreous Hemorrhage [6]
[Figure]: "Schematic of the Eye"

  1. Hemorrhage into the vitreous humor
  2. Incidence of spontaneous vitreous hemorrhage is ~7 per 100,000 persons per year
  3. Causes
    1. Diabetic Retinopathy (~30%)
    2. Retinal Tear (~30%)
    3. Retinal Vein Occlusion with proliferative retinopathy (~10%)
    4. Posterior vitreous detachment (<10%)
  4. Pathogenesis of Bleeding
    1. Pathologic disruption of normal vessels
    2. Bleeding from diseased retinal vessels
    3. Bleeding from new-vessels (neo-vascularization vessels are typically abnormal)
  5. Consequences of non-clearing vitreous hemorrhage
    1. Hemosiderosis bulbi
    2. Glaucoma - ghost cell, hemolytic, and hemosiderotic types
    3. Main problem is difficulty clearing blood cell debri
  6. Current treatment of non-clearing vitreous hemorrhage is pars plana vitrectomy

G. Keratitis [7]

  1. Causes
    1. Neurotrophic Keratopathy - nerve palsy, often trigeminal and/or facial nerve
    2. Dry Eyes - without or with (Sjogren Syndrome) systemic symptoms, contact lenses
    3. Rheumatoid Arthritis - includes direct inflammatory component
    4. Corneal infection - chlamydia, bacterial (contact lenses), fungal, trauma
    5. Bacterial (Pseudomonas, >90%) and fungal (Fusarium, <5%) keratitis associated with contact lens wear [12]
  2. Pathogenesis
    1. The cornea is normally bathed in tears
    2. Tears contain corneal epithelial growth and repair factors
    3. Bioactive molecules include various growth factors and cytokines
    4. Stimulation of normal tear function is partially mediated by the trigeminal nerve
    5. Normal tearing requires eyelid sensation, also the trigeminal nerve
    6. Substance P, a transmitter of the trigenimal nerve, may play a role
    7. Substance P + IGF-1 stimulate integrin receptors (alpha-5 and ß1; see below)
  3. Usually presents as reduced vision with pain, often with red eye
  4. Physical Exam
    1. Corneal epithelial erosion - direct visualization and abnormal fluorescein pattern
    2. Hypolacrimation and/or hyperemia commonly found
  5. Treatment [8]
    1. Insulin-like growth factor 1 (IGF-1) helps heal cornea
    2. Substance P is synergistic with IGF-1 for healing of neurotrophic keratopathy [8]

H. Retinitis Pigmentosa (RP)

  1. Hereditary peripheral retinopathy
  2. Affects about 1.5 million persons worldwide
  3. Genetic Disease
    1. Autosomal dominant, recessive, and X-linked forms
    2. Seven gene mutations have been found associated with RP
  4. Genes associated with RP
    1. Rhodopsin
    2. Alpha and ß subunits of rod cGMP phosphodiesterase
    3. Rod cGMP cation-gated channel protein alpha subunit
    4. Peripherin/RDS gene
    5. TULP1 and TULP 2 genes
  5. Slowly progressive retinal degeneration

I. Leber's Congenital Amaurosis (LCA) [13,14]

  1. Group of recessive, severe, infantile-onset rod-cone dystrophies
  2. Lead to progressive blindness before age 30
  3. LCA2
    1. Caused by mutations in retinal pigment epithelium specific 65K protein gene (RPE65)
    2. RPE65 is required for isomerohydrolase activity in RPE
    3. Isomerohydrolase produces 11-cis reetinal from all-trans-retinyl esters
    4. 11-cis-retinal is natural ligand and chromophore of the opsins of rod and cone photoreceptors
    5. Without 11-cis-retinal, opsins cannot capture light and transduce to electrical signals
    6. Subretinal delivery of RPE65 cDNA in LCA2 patients lead to some improvement in vision [13,14]
    7. Additional gene therapy trials are being contemplated

J. Leber's Hereditary Optic Neuropathy (LHON) ,

  1. First disease in humans linked to heritable point mutations in mitochondrial DNA
  2. Most common form of blindness in otherwise healthy young men
    1. Males affected 4 to 1 over females
    2. Average onset at 23 years of age; 90% affected by age 40
    3. Progression in weeks to months
  3. Painless, subacute, bilateral visual loss
  4. Central scotomas and abnormal color vision
  5. Visual recovery can occur, mainly in patients with T14484C mutation
  6. Dystonia may be present, usually with optic atrophy [15]
  7. Four different mutations have been identified


References

  1. Congdon NG, Friedman DS, Lietman T. 2003. JAMA. 290(15):2057 abstract
  2. Coleman AL. 1999. Lancet. 354(9192):1803 abstract
  3. Shingleton BJ and O'Donoghue MW. 2000. NEJM. 343(8):556 abstract
  4. De Jong PT. 2006. NEJM. 355(14):1474 abstract
  5. Wright HR, Turner A, Taylor HR. 2008. Lancet. 371(9628):1945 abstract
  6. Spraul CW And Grossniklaus HE. 1997. Surv Ophthalmol. 42(1):3 abstract
  7. Schwartz GS, Harrison AR, Holland EJ. 1998. Cornea. 17(3):278 abstract
  8. Chikama T, Fukuda K, Morishige N, Nishida T. 1998. Lancet. 351(9118):1783 abstract
  9. Frank RN. 2004. NEJM. 350(1):48 abstract
  10. Rowe S, MacLean CH, Shekelle PG. 2004. JAMA. 291(12):1487 abstract
  11. Goldzweig CL, Rowe S, Wenger NS, et al. 2004. JAMA. 291(12):1497 abstract
  12. Khor WB, Aun T, Saw SM, et al. 2006. JAMA. 295(24):2867 abstract
  13. Bainbridge JW, Smith AJ, Barker SS, et al. 2008. NEJM. 358(21):2231 abstract
  14. Maguire AM, Simonelli F, Pierce EA, et al. 2008. NEJM. 358(21):2240 abstract
  15. Tarsy D and Simon DK. 2006. NEJM. 355(8):818 abstract