Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

tional integrity of the eye is not possible. Most phthisical eyes eventually become blind, painful, and cosmetically unacceptable for the patient. Potential harmful comp­ lications include corneal ulceration and perforation with the risk of ocular and periocular inflammation (i.e., pan­ ophthalmitis), sympathetic ophthalmia, and malignant transformation.3,20

Pathology

Clinical and pathologic findings of phthisical eyes are variable and depend on the underlying disease and time interval between primary lesion and enucleation. The following section describes the main clinicopathological ocular features commonly seen phthisis bulbi.

Clinical features

Phthisical eyes are usually easy to detect by inspection of the patient’s face and are summarized in Table 54.3. The diagnosis is simplified due to the unilaterality of the disease with asymmetry of the eyeballs and interpalpebral fissures. Additional indirect clinical signs include narrow lid fissures (pseudoptosis),lagophthalmos,pseudoenophthalmos,smallsized and soft, hypotonic (IOP 5 mmHg) eyes (Figure 54.1A; Box 54.3). Axial displacement in relation to the surrounding structures may occur in advanced stages, which are often associated with vision loss. The conjunctiva may be swollen (chemotic) and hyperemic. The appearance of cornea is variable displaying corneal haze, scarred, vascularization, and dystrophic calcification (Figure 54.1B). The anterior chamber is usually shallow, demonstrating a narrow to closed chamber angle. Synechia (peripheral, posterior), neovascularization of the iris surface and chamber angle (rubeosis iridis), fibrotic or fibrovascular membranes at the pupil may be present, often as a result of intraocular hypoxia or recurrent episodes of intraocular inflammation (uveitis).21,22 The lens

Table 54.3  Clinicopathological features of phthisical eyes

Microphthalmos

Enophthalmos

Reduced eyelid fissure

Strabism

Corneoscleral scarring, thickening, and shrinkage

Flattening of the anterior chamber

Intraocular inflammation (uveitis/endophthalmitis)

Synechia (peripheral/posterior)

Cyclitic/epiretinal membranes (fibrous/fibrovascular)

Cataract formation

Choroidal/ciliary body and retinal detachment

Choroidal/ciliary body, retinal, and optic nerve degeneration/atrophy

Intraocular hemorrhages

Dystrophic calcification and heterotopic ossification

Macroscopic and microscopic features

usually undergoes cataractous changes and may become floppy (lentodonesis) because of anterior displacement of the ciliary body. The choroid and retina are often detached by retrolenticular or epiretinal membranes.23–25

Macroscopic and microscopic features

Gross pathology of the external eye

External examination of enucleated phthisical eyes typically shows a soft and partially collapsed globe. The shape and size of the eyes may vary depending on the nature and dura-

Box 54.3  Clinical signs of phthisical eyes

Phthisical eyes can be characterized clinically by:

•Small and soft eyes

•Pseudoptosis and pseudoenophthalmos

•Corneal opacification and scarring

•Shallow anterior chambers and neovascularization of the iris and chamber angle

•Cataract formation

•Ciliochoroidal and retinal detachment

A

B

Figure 54.1  (A) Patient with phthisis bulbi (left eye) secondary to herpes zoster infection. (B) Phthisical eye of a 49-year-old man with history of perforating trauma to his right eye displaying corneal scarring (asterisk) and dystrophic calcification.

tion of the underlying disease as well as the age of the patient at the initial event. Phthisical eyes usually demonstrate a squared-off shape with scleral buckling behind the insertion line of the horizontal and vertical extrinsic rectus muscles. Other specimens seem to maintain their “normal” spherical shape despite marked shrinkage and decreased volume. On average, phthisical eyes are about 20% smaller in dimension compared to “normal”-sized adult eyes (24 × 24 × 24 mm).3 The cornea is usually flattened, smaller in diameter (≥20%), and hazy due to edema, scarring, or dystrophic calcification.3

Gross pathology of the internal eye

The cornea and sclera are usually markedly thickened, on average by 80% (cornea) to 50% (sclera) (Figure 54.2).3 The

anterior chamber is often shallow or collapsed; iris defects (partial, complete) from previous trauma or surgery may be present. The lens is usually thickened and cataractous. The ciliary body and retina are often detached and displayed anteriorly by a retrolenticular or epiretinal fibrotic tissue; the optic nerve head may be pulled into the vitreous cavity. Intraocular hemorrhages may be present in the anterior chamber, vitreous, or choroid.

Histopathology

All intraocular structures may be involved in phthisical eyes (Table 54.3). The cornea is usually thickened, edematous, scarred, and vascularized (57%); a fibrovascular tissue and areas of dystrophic calcification may be present in the anterior stroma next to the epithelium.3 The posterior stroma and Descemet membrane are thrown into folds by a fibrous tissue proliferation at the inner surface of Descemet membrane (stromal downgrowth) (Figure 54.3A). The endothelium, if present, may display cystic changes of its cytoplasm. Additional pathologic findings of the anterior chamber may include epithelialization and vascularization of the chamber angle and iris surface (24%), peripheral and posterior synechia with secondary angle closure, and fibrous or fibrovascular cyclitic membranes at the pupillary margin (Figure 54.3A).3 The lens usually displays epithelial proliferation,

A

B

Figure 54.2  (A) Phthisical eye of a 73-year-old male with a history of penetrating trauma. The cornea (white asterisk) is vascularized and scarred; the retina is detached (arrows) and the sclera partially thickened and thrown in folds. An encircling band (arrowheads) and a scleral buckle (black asterisk) indicate previous retinal surgery. (B) Horizontal section through a 23 × 22 × 22 mm phthisical eye demonstrates a cataractous crystalline lens (asterisk) and hemorrhage of the anterior chamber (white arrowheads) and ciliochoroidal tract The retina is completely detached (arrows) and torn anterior by a retrolenticular fibrovascular membrane.

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Figure 54.3  (A) Photomicrographs showing secondary angle closure (arrows) by a retrocorneal fibrous tissue (asterisk). The posterior corneal stroma and Descemet membrane are thrown in folds (arrowheads). Original magnification: 4× (main image) and 10× (inset). (B) The crystalline lens (inset; periodic acid–Schiff) displaying cataractogenous changes including artificial clefting of the lens cortex, differential staining between the nucleus (white asterisk) and the cortex (black asterisk), and hydropic degeneration of lens epithelial cells (arrows). Occasionally, phthisical eyes demonstrate calcification of the cortical fibers next to the lens capsule (main image). Original magnification: 20× (main image) and 10× (inset). (C) Phthisical eyes often demonstrate an almost complete separation of the ciliary body from the sclera by proliferative fibrovascular membranes pulling the ciliary body into the anterior vitreous cavity. The ciliary muscle (black asterisk) usually remains attached at the scleral spur (arrows). Secondary findings include a tubular-like proliferation of the nonpigmented ciliary body epithelium (arrowheads). Original magnification: 4× (main image) and 20× (inset).

(D) The retina of phthisical eyes often exhibits a funnel-shape appearance (inset bottom left) due to perpendicular and circumferential traction by epiretinal and retrolenticular membranes (asterisk, inset top right). In advanced stages it loses its normal structure and displays gliosis and cystoid degeneration (arrows, main image). Original magnification: 10× (main image) and 4× (insets). (E) Image demonstrating a section of thickened sclera. Chronic ocular hypotony results in loss of tension on the sclera with subsequent wrinkling and shortening of the collagen lamellae. (F) Photomicrographs showing heterotopic secondary ossification of the retinal pigment epithelium (RPE) in an eye with long-standing phthisis bulbi (asterisk, main image). Pigment-laden cells and lacunae (arrows, inset bottom right) containing fatty or hematopoietic bone marrow can often be detected within the bony structures. Additional degenerative changes of the RPE include large (pathologic) drusen formation (white asterisk, inset top right).

differential staining of nucleus and cortex, and clefting of the lens fibrils. Occasionally, calcification can be seen adjacent to the anterior lens capsule; ossification is rare and always associated with capsular breaks (Figure 54.3B). The ciliary body usually shows atrophy and fibrous shortening of the ciliary processes, thickening of the basal laminar, proliferation of nonpigmented epithelium, and is often separated from the sclera, mainly close to the scleral spur; posterior extension towards the optic disc is also possible (Figure 54.3C).21 Pathologic changes of the choroid include vasodilatation and focal vascular compression of small vascular channels as well as areas of choroidal thinning and atrophy. The retina may display full-thickness folds, fibrous epiretinal membranes, cystic degeneration of the inner nuclear layer with and without proteinaceous exudates, loss of photoreceptor cells, gliosis, and funnel-shaped retinal detachments; calcification of retinal blood vessels is occasionally seen (Figure 54.3D).26 The optic nerve is atrophic and shows proliferation of the glial cells. The sclera is thickened, mainly posterior to the insertion of the external muscles, and displays folding of the collagen lamellae due to decreased intra-ocular tension and increased water-binding to mucopolysaccharides (Figure 54.3E). Cholesterol crystals as signs of previous hemorrhage may occur in the anterior chamber, vitreous, and suprachoroidal space. Areas of heterotopic ossification, containing lacunas of fatty and hematopoietic bone marrow, are common in eyes with long-standing phthisis bulbi (Figure 54.3F).23,24 They mainly form in preand subretinal fibrovascular membranes in association with proliferating retinal pigment epithelium (RPE) cells and within the choroid; lens and sclera are rarely involved.24,27

Etiology

Phthisis bulbi cannot be understood as a specific clinical entity; rather, it is considered the endpoint of a number of ocular diseases with various stimuli. Potential risk factors contributing to phthisis bulbi include failed surgical procedures (i.e., cataract, glaucoma, retina surgery), infections and inflammation (i.e., keratitis, uveitis, endophthalmitis), intraocular malignancies (i.e., choroidal melanoma, retinoblastoma) as well as systemic cardiovascular diseases (i.e., diabetes, hypertension) (Table 54.1).3,19,28,29 Although it is not known how long an individual eye will tolerate a specific ocular damage, virtually all diseased eyes will finally become atrophic if therapeutic treatment fails.

Pathophysiology

Aqueous humor dynamics and blood–ocular barrier functions

The aqueous humor that fills the anterior and posterior chambers is important in the physiology of the mammalian eye. It provides oxygen and nutrients for the avascular tissues of the anterior segment such as cornea, trabecular meshwork, and lens and subsequently removes metabolic waste products. In addition, it maintains an IOP of about 15 mmHg that is required for the functional and morphological integ-

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rity of the eye. The aqueous humor is derived from the blood plasma and secreted in an energy-consuming process (approximately 2–3 µl/min) by a monolayer of nonpigmented epithelial cells at the inner surface of the ciliary body. Compared to the plasma, the aqueous has a low protein level (about 0.02 g/ml compared to 7 g/ml), mainly composed of albumin and transferrin.30 Other components include various growth and neurotrophic factors such as transforming growth factor-ß (TGF-ß), acidic and basic fibroblastic growth factor (aFGF, bFGF), vascular endothelial growth factor (VEGF), and pigment epithelial-derived factor (PEDF).31

To maintain an appropriate environment in the eye by restricting entry of cellular and soluble plasma components, the aqueous humor is separated from the blood by two functional barriers, the BAB and the blood–retinal barrier (BRB).32 The BAB is supported by the nonpigmented epithelium of the ciliary body, the endothelium of the iris vasculature, and the endothelium of Schlemm’s canal next to the trabecular meshwork. In contrast, the posteriorly located BRB is composed of the RPE (outer level) and the endothelial membrane of the retinal vasculature (inner level). Any perturbations of the blood–ocular barriers by trauma, disease, or drugs result in an inward movement of blood plasma constituents and may cause a plasmoid aqueous formation with disruption of the balance among the various growth factors and induce subretinal exudates and retinal edema.

Ocular hypotony and phthisis bulbi

Ocular hypotony, a key feature of phthisical eyes, is defined as IOP of ≥5 mmHg at consecutive measurements in an individual eye.28 While clinical signs and symptoms are usually reversible in acute and transient stages, chronically decreased IOP can have deleterious effects on intraocular tissue morphology and function, eventually leading to phthisis bulbi (Table 54.2).28,33,34 Although the underlying pathologies and mechanisms of ocular hypotony may be quite variable, they all work together, inducing an imbalance of aqueous production and outflow (trabecular, uveoscleral) (Figure 54.4).21,28,35,36 Subsequent alterations of aqueous flow dynamics associated with compromised oxygen supply, nutrition, and metabolic exchange within the anterior chamber are main points of concern. In particular, intraocular hypoxia has been shown to contribute to BAB breakdown associated with invasion of serum components (i.e., proteins, growth factors), inflammatory cells, and tissue edema.26

Common causes of ocular hypotony in phthisis bulbi (i.e., trauma, filtration or vitreoretinal surgery, long-stand- ing uveitis) are characterized by defects in the corneoscleral coat (i.e., external and internal fistulation), ciliary body insufficiency (i.e., cyclodialysis, cyclodestruction), choroidal and retinal detachment, or inflammation (primary and secondary) (Box 54.4).26,28,36 Intraocular inflammation in particular represents a common pathway in the patho­ physiology of ocular hypotony and phthisis bulbi. Inflammation-based IOP reduction is likely mediated by prostaglandins (i.e., prostaglandin-2α), which facilitate decreased aqueous production and increased uveoscleral outflow.37,38 While in normal, nondiseased eyes, entry of

Ocular hypotony

Hypoxia

Malnutrition Accumulation of metabolic waste products

Ocular degeneration and atrophy

Box 54.4  Potential causes of ocular hypotony in

phthisis bulbi

Persistent ocular hypotony, a key feature of phthisical eyes, results from a chronic imbalance of aqueous humor production and outflow secondary to:

•Defects in the corneoscleral coat

•Intraocular inflammation

•Insufficiency of the ciliary body epithelium

•Ciliochoroidal and retinal traction/detachment

aqueous humor into the suprachoroidal space is restricted by connective tissue strands between choroid and sclera, inflammation of the ciliary body results in stromal edema and breakdown of the functional barrier between the anterior chamber and the suprachoroidal space. Fluid transudation into the suprachoroidal space and increased uveal capillary fluid permeability lead to ciliochoroidal detachment.36,37,39 The process becomes further facilitated since only minor amounts of suprachoroidal fluid will be drained through the emissary vessels secondary to low transscleral hydrostatic pressure differences. Thus, inflammation combined with hypotony creates a self-perpetuating cycle. Similar effects with decreased aqueous production can be seen in patients with traumatic cyclodialysis secondary to perforation or glaucoma surgery,21,28 In addition, intraocular inflammation results in BAB breakdown with release of plasma proteins, cytokines, chemotactic, and angiogenic factors (i.e. TGF-ß, tumor necrosis factor-α (TNF-α), VEGF, angiopoietin-1, -2) that can contribute to migration, transformation, and proliferation of resident cells such as RPE, nonpigmented epithelial cells and Müller cells, fibrovascular tissue proliferation (i.e., cyclitic, epiretinal membranes), ocular neovascularization, and ocular hypotony.22,25,40 In

particular, cyclitic and epiretinal membranes have the potential to lower IOP by traction and forward displacement of the ciliary processes (increased uveoscleral outflow) as well as direct damage to the ciliary body epithelium (decreased aqueous production).21,39 Finally, all the processes described above may result in sclerosis and atrophy of the ciliary body and/or the adjacent intraocular tissues.37,41

Ocular wound healing in phthisis bulbi

Fibrovascular and fibrous tissue proliferation can also be observed after trauma (i.e., concussion, perforation) or complicated vitreoretinal surgery. Similar to proliferative vitreoretinopathy (PVR), it represents a specific ocular wound-healing response, which, if not treated properly, contributes to ocular hypotony and subsequent atrophy of the globe (Figure 54.4).25,42–44 Potent predisposing risk factors include long-standing retinal detachment and retinal breaks with release of RPE cells into the vitreous.

Briefly, ocular injury results in breakdown of the blood– ocular barrier with release of serum components and chemotactic factors such as fibronectin (FN), TGF-ß, and plateletderived growth factor (PDGF) into the anterior chamber and vitreous cavity. These factors accelerate migration, proliferation, and transformation of inflammatory cells and RPE.31 Later cells are able to secrete additional growth factors and cytokines like interleukins (IL-1, -6), TNF-α, and TGF-ß, contributing to proliferation and transformation of RPE and glial cells into fibroblastand myofibroblast-like cells with subsequent granulation tissue formation (i.e., fibrous, fibrovascular membranes).25,31,42–45 Membrane composition varies depending on their location within the eye (i.e., RPE, nonpigmented ciliary body epithelium, fibroblasts, myofibroblasts, inflammatory cells, collagen, and fibronectin). They can be observed adjacent to perforation wounds, anterior and posterior to the lens, as well as at the inner side (preretinal) and outer side (subretinal) of the retina. Mem-

brane contraction, mainly induced by RPE and Müller cells, will finally result in retinal and ciliary body detachment.45,46 Of particular note is anterior PVR. The progressive stages of anterior PVR include traction, incorporation of ciliary body elements, and cellular proliferation.47 It is felt that surgical intervention (vitrectomy) must be performed some time during or before the incorporation phase, as there will be no chance to re-establish the ciliary epithelium’s ability to produce aqueous humor, thus leading to phthisis bulbi.47 Anterior PVR has been previously classified as a cyclitic membrane.

Dystrophic calcification and heterotopic ossification in phthisis bulbi

Calcification and ossification are frequent end-stage changes of degenerating tissues. Both can be observed in phthisical eyes, often associated with chronic inflammation, multiple traumas, long-standing retinal detachment, or PVR.23,24,48,49 Intraocular calcium deposits are mainly composed of calcium phosphate and carbonate and typically occur in the cornea (band keratopathy), lens, RPE (drusen), and retina, “depending on low carbon dioxide tension due to metabolic inactivity.”50 In contrast, bone formation usually involves the choroid and fibrovascular or fibrocellular cyclitic membranes external to the neurosensory retina. The time between original insult and bone formation is quite variable, ranging from a few months to several years, with an average of approximately 20 years.23,48 While trauma seems to be more common in young patients with formation of compact bone tissue, inflammation is often associated with an older age group of ≥50 years, resulting in spongy bone tissue.49 Fibrous and osseous metaplasia of RPE plays a central role in the pathogenesis of heterogenic ossification, as illustrated in Figure 54.5 (Box 54.5).24,49–51 RPE cells, stimulated by inflammatory cytokines such as TNF-α, IL-1, and TGF-ß, undergo

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Box 54.5  Function of the RPE in the

pathophysiology of phthisis bulbi

The retinal pigment epithelium (RPE) is a pluripotent tissue, which plays a central role in the pathophysiology of:

•Ocular wound healing (migration, proliferation, transformation)

•Heterotopic ossification (osseous metaplasia) in phthisis bulbi

mesenchymal transformation into fibroblast-like cells and subsequent transdifferentiation into osteogenic progenitor cells, finally resulting in ectopic bone tissue.44,50 Proliferating RPE cells can often be seen adjacent to intraocular bones structures. In addition, heterotopic ossification can also be observed in tissues with abundant blood supply such as the posterior peripapillary choroid, probably because of vascular delivery of osteoblasts.23,49 These osteoblasts may be derived from circulating hematopoietic stem cells and be related to changes in choroidal blood flow that occurs during phthisis bulbi.

Conclusion

Phthisis bulbi represents an ocular end-stage disease that results from wound healing secondary to various causes such as severe trauma, inflammation, necrotizing tumors, and/or vascular diseases. It results in vision loss and continues to be an important cause of blindness. The clinical diagnosis of phthisis bulbi, which is characterized by atrophy, shrinkage, and disorganization of the globe, is a frustrating situation since therapeutic approaches are limited to symptomatic or cosmetic treatment options. Prophylactic procedures and close follow-up visits are required in patients at high risk for the development of phthisis bulbi.

3.Stefani FH. Phthisis bulbi – an intraocular florid proliferative reaction. Dev Ophthalmol 1985;10:78–160.

5.Naumann GOH, Portwich E. [Etiology and final clinical cause for 1000 enucleations: a clinicopathologic study.] Klin Mbl Augenheilkd 1976;168:622– 630.

21.Chandler PA, Maumenee AE. A major cause of hypotony. Am J Ophthalmol 1961;52:609–618.

25.Elner SG, Elner VM, Diaz-Rohena R, et al. Anterior proliferative vitreoretinopathy. Clinicopathologic, light microscopic, and ultrastructural

findings. Ophthalmology 1988;95:1349– 1357.

26.Voelcker HE, Naumann GOH. [Histopathology of persistent ocular

hypotension syndrome.] Berl Dtsch Ophthalmol Ges 1978;75:591–595.

28.Schubert HD. Postsurgical hypotony: relationship to fistulation, inflammation, choroidal lesions, and the vitreous. Surv Ophthalmol 1996;41:97–125.

31.Klenkler B, Sheardown H. Growth factors in the anterior segment: a role in tissue maintenance, wound healing, and ocular pathology. Exp Eye Res 2004;79:677– 688.

38.Kim HC, Hayashi A, Shalash A, et al. A model of chronic hypotony in the rabbit. Graefes Arch Clin Ophthalmol 1998;236: 69–74.

40.Dorrell M, Uusitalo-Jarvinen H, Aguilar E, et al. Ocular neovascularization: basic mechanisms and therapeutic approaches. Surv Ophthalmol 2007;52:S3–S19.

43.Pastor JC. Proliferative vitreoretinopathy: an overview. Surv Ophthalmol 1998;43: 3–18.

44.Hiscott P, Sheridan C, Magee RM, et al. Matrix and the retinal pigment epithelium in proliferative retinal disease. Prog Retin Eye Res 1999;18:167–190.

45.Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelia to mesenchymal phenotype. Invest Ophthalmol Vis Sci 1995;36:391– 405.

47.Lopez PF, Grossniklaus HE, Aaberg TM, et al. Pathogenetic mechanisms of anterior proliferative vitreoretinopathy. Am J Ophthalmol 1993;100:415–422.

48.Zeiter HJ. Calcification and ossification in ocular tissue. Am J Ophthalmol 1962;53:265–274.

Definition and prevalence

Myopia is the most common human eye disorder in the world. For this refractive state, the retina is located behind the focal plane so that a concave (negative-power) lens is needed to move the focal plane back to the retinal plane, restoring a focused, clear image. Definitions of myopia vary, but generally an eye is considered myopic if a negative spherical equivalent correction of at least 0.50 diopters (D) is needed to restore emmetropia, the refractive state in which images are focused on the retina. Because of varying definitions, the reported prevalence of myopia varies. In the US adult population an estimated prevalence of 25–30% is supported by multiple studies.1–6 Females are reported to have an earlier onset and a slightly higher prevalence than males.4,5,7,8 US Asians and Hispanics have a higher prevalence than whites or African-Americans.9 Chinese and Japanese populations have very high myopia prevalence rates of > 50–70%.5,8,10,11 Ashkenazi Jews, especially orthodox Jewish males, have shown a higher prevalence than other white US and European populations.11 Comparative prevalence rates from different countries show considerable variability, but confirm that myopia affects a significant proportion of the population in many countries.2,6,12–18 Worldwide, there may be as many as one billion myopic individuals (Box 55.1).19 Uncorrected myopia is an important cause of correctable low vision in developed and underdeveloped countries.20 A priority of refractive error correction is part of the World Health Organization’s global initiative, Vision 2020.21

Myopia is typically divided into two basic types. “Juvenileonset” or moderate myopia (also called “simple” or “school” myopia) most often develops and progresses between the ages of 8 and 16 years, and generally does not require a correction stronger than −5 D.1,7,22–24 In contrast, “pathologic” or high-grade myopia usually begins to develop in the perinatal period, and is associated with rapid refractive error myopic shifts before 10–12 years of age due to axial elongation of the vitreous chamber.1,7,12,23,25

Whether it occurs from continued progression of juvenileonset myopia, or from early-onset high-grade myopia, a high level of axial myopia (spherical equivalent refractive correction of −5 D or greater) is a major cause of legal blindness in many developed countries.4,11–15,26 High myopia has a prevalence of 1.7–2% in the general population of the USA1,3

Myopia

Terri L Young

and is especially common in Asia.13,14,16 In Japan, high myopia reportedly affects 6–18% of the myopic population and 1–2% of the general population.13

The public health and economic impact of myopia is considerable.1–5,7,8,10–12,23–25 Costs associated with optical corrections for adults were over US $26 billion in 2005 for glasses, contact lenses, and refractive surgery. Of this, at least 61% ($14.6 billion) was for myopic correction, and did not include costs for correcting myopia in children.

Ocular morbidities associated with myopia

Many investigators have reported on the association of high myopia with premature cataract development,27 glaucoma,28 severe retinal thinning with eventual retinal detachment (RD), and posterior staphyloma with retinal degenerative changes.1,29–45 High myopia is associated with progressive and excessive elongation of the globe, which may be accompanied by degenerative changes in the sclera, choroid, Bruch’s membrane, retinal pigment epithelium (RPE), and neural retina. Various fundoscopic changes within the posterior staphyloma develop in highly myopic eyes. These changes include geographic areas of atrophy of the RPE and choroid, lacquer cracks in Bruch’s membrane, subretinal hemorrhage, and choroidal neovascularization (CNV). Among these various fundus lesions, macular CNV is the most common vision-threatening complication of high myopia.33–37,39 Clinical and histopathologic studies have documented CNV in 4–11% of highly myopic eyes. Relative to emmetropic eyes, an approximately twofold increased risk of CNV was estimated for eyes with 1–2 D of myopia, a fourfold increase with 3–4 D, and a ninefold increase with 5–6 D.32,39,45,46 Poor visual outcome following CNV in myopic eyes is not uncommon, and often affects relatively young patients.

The risk of RD is estimated to be 3–7 times greater for persons with greater than 5 D of myopia, compared with those with a lower amount of myopia.42,45,47 Myopia of 5–10 D was associated with a 15–35-fold greater risk of RD relative to that associated with low levels of hyperopia.42,45,47 The lifetime risk for RD was estimated to be 1.6% for patients with myopia less than 3 D and 9.3% for those with more

Box 55.1  Why study myopia?

Why study myopia? Myopia has been and continues to be the most common human eye disorder worldwide, with increasing prevalence rates and health care costs. Severe degrees of myopia predispose those affected to a handful of ocular morbidities which can compromise sight and quality of life

than 5 D.42,43 A subgroup with lattice degeneration and more than 5 D of myopia had an estimated lifetime risk of 35.9%.43 The prevalence of lattice degeneration increases with increasing amounts of myopia, as measured by axial length.45,47–49 Glaucoma was observed in 3% of individuals with myopia with axial lengths of less than 26.5 mm, in 11% with axial lengths between 26.5 and 33.5 mm, and in 28% of those with longer lengths.44

Myopia is the most studied refractive error due to the high prevalence and the increased risk of associated blinding complications. Research pursuits include why and how myopia develops, and whether treatments can be developed to prevent this refractive error, or prevent progression to high amounts. A fundamental question is whether myopic development is a result of predetermined genetic50 or environmental factors51 such as excessive near work. Both appear to play a role in human myopia.

Human emmetropization process

Although myopia is highly prevalent, the majority of eyes are emmetropic in childhood. The normal postnatal development of emmetropia has been examined for clues about possible underlying mechanisms by which this is achieved. At birth (Figure 55.1A), the refractive distribution of human newborns is very broad. The mean is approximately 2 D of hyperopia, but the standard deviation is great and nearly 25% of newborns are myopic.52 The major determinants of the focal plane are the cornea and lens, while the axial length (vitreous chamber depth) determines whether the retina is located at the focal plane.53 At birth, the size, shape, and power of all are determined largely by inheritance,54 although conformational factors such as intrauterine environment and the bony orbits and eyelids can also influence eye shape and growth.55

During the first postnatal weeks and months, the ocular components and refractive state undergo rapid changes. The corneal diameter of the infant is 9–10 mm compared to the adult size of 12 mm. Due to the steep curvature, corneal power averages 51 D at birth and flattens to approximately 44 D by 6 weeks of age.56,57

Mutti et al58 found the average corneal power at 3 months of age to be 43.9 D. By 9 months it decreased to 42.8 D. Between 6 and 14 years of age, corneal power is stable.59 Lenticular power averages 34 D at birth and decreases to 28 D by 6 months of age, and to 21 D by adulthood.56 Mutti et al58,60 found the average lens power (Gullstrand–Emsley indices) showed a continual decline with age from 21.5 D at age 6 years to 19.8 D at age 14 years.

In addition to the changes in corneal and lens powers, the distribution of refractive errors narrows dramatically in

Human emmetropization process

Figure 55.1  (A) Refractive error distribution at birth. Data from Cook and Glasscock.52 (B) Refractive distribution at 3 months (dashed line) and 9 months of age. Approximately 25% of infants are myopic at birth.

By 9 months, nearly all children are emmetropic or slightly hyperopic. (Reproduced from Mutti et al.58)

the postnatal months (Figure 55.1B).7,56,58,61,62 In the infantile growth period the eyes grow from around 16 mm axial length at birth63 to an average of 19 mm at 3 months of age and over 20 mm by 9 months.58 During this time the axial length changes in a manner that moves the retina to the focal plane.63,64 As described by Mutti et al,58 “modulation in the amount of axial growth in relation to initial refractive error appeared to be the most influential factor in emmetropization of spherical equivalent refractive error.” Eyes that are initially hyperopic increase their axial length rapidly to move the retina to the focal plane. Eyes that are initially myopic have a slower axial elongation rate so that, as the cornea and lens powers decrease, the focal plane moves to the retina. The result of the controlled growth of the axial length is that nearly all eyes become emmetropic with the majority being slightly (0.5–1 D) hyperopic when measured with cycloplegia.

There is little change in refractive status in most eyes during the rest of childhood, even though there is continued change in anterior-chamber depth, lens power, and axial length. Because of the continued decreases in corneal and lens power during childhood, control of the axial elongation rate to maintain a match to the focal plane is needed until the eyes are fully mature. Refractive error distribution in the adult population has a narrow peak with most people between emmetropia and +1.0 D. This amount of hyperopia is readily compensated for by accommodation of the crystalline lens, so that most eyes are functionally emmetropic. The human eye normally maintains an axial length of within 2% of its optimal focal point.1,53,54 In an adult (~24 mm) eye, a deviation from optimal of 0.2 mm in axial length would produce a refractive error of more than 0.5 D.65

Although the individual refractive components of the corneal and lenticular dioptric powers and anterior-chamber depth follow a bell-shaped (normal) distribution, several studies have shown that the refractive status of the eye is determined primarily by variation in axial length, which does not display a normal distribution.1,22,47,54,55 Spherical refractive error usually represents a mismatch between axial length and the combined dioptric powers of the cornea and lens. Moderate myopia results from a “failure of correlation” of these components where all components fall within

normal limits, but are borderline high or low. For example, an eye with a relatively steep cornea and normal axial length could be myopic even though none of the ocular component dimensions is abnormal. Low myopia (smaller than 6 D) is usually the result of this lack of correlation. In children whose myopia is progressing the amount of progression is closely related to the increase in vitreous chamber length.66 Higher levels of myopia are due to “component ametropia,” in which the axial length exceeds normal values.53,55 “Correlational” and “component” myopia may have different genetic etiologies.

To some extent, narrowing of the distribution of refractive errors during the first postnatal months could be explained by the “passive proportional” growth of the eye.67 However, more eyes are emmetropic than would be expected from a random combination of the optical elements and the axial length.68,69 This has led to the suggestion that an active feedback mechanism coordinates the axial length with the optical elements to produce emmetropia.52,54,68–72 However, based on clinical observations, it was not possible to test this suggestion.

Animal models of emmetropization

In the 1970s, studies with animal models (primarily monkeys,73,74 chicks,75 and tree shrews76,77) demonstrated that an emmetropization mechanism exists. It has been shown in animals that this emmetropization mechanism normally controls the axial elongation rate of the eye to achieve and maintain a match of the axial length to optical power so that the photoreceptors are in focus for distant objects.78–80 Vision plays a critical role in this process (Box 55.2).

monkey86,87 and tree shrew,88,89 and is prominent in the chick.90 The “induced myopia” occurs only monocularly in form-deprived eyes, and not in the paired eye which serves as an untreated within-animal control. Thus, the myopia is clearly environmental in nature. The observation that eyelid closure myopia could not be induced in dark-reared animals further suggests that visual experience is required.91,92 Form deprivation myopia occurs consistently across species, including the grey squirrel,93 cat,94 and mouse.95

Compensation for negative lenses

Form deprivation myopia demonstrates that the visual environment plays a role in establishing and maintaining emmetropia. Recognition that the emmetropization mechanism uses visual feedback to match the axial length to the focal plane emanates from studies that used negative-power (and positive-power) lenses to shift the focal plane of the eye.96–98 As shown in Figure 55.2B, a monocular negative lens shifts the focal plane posteriorly, away from the cornea. This consistently produces a compensatory increase in the axial elongation rate of the growing eye, such that the retinal location is shifted to match the shifted focal plane (Figure 55.2C.) When measured with the lens in place, the refractive state matches the untreated fellow control eye.96,99,100 Thus, in compensating for the negative lens the eye is, in fact, restoring optical emmetropia.

With the lens removed, the eye is myopic (Figure 55.2D). Compensation can be quite accurate101–103 and negative lenses of different powers produce different axial elongation appropriate to move the retina to compensate for the lens power. Some strains of mice can develop negative lens-induced myopia, even though mice are not strongly

Form deprivation myopia

Animal models of the emmetropization process began with “form deprivation myopia” (see recent reviews78–82). Form deprivation was initially produced by tarsorrhaphy or by the placement of a translucent diffuser over the eye, held in place by a goggle or mask. This eliminates higher spatial frequencies and decreases the contrast of the retinal image, while still allowing limited transmission of light to the retina. It is now recognized that form deprivation removes the visual feedback needed to guide the eye growth to an emmetropic state and to maintain emmetropia. Form deprivation during the juvenile postnatal period causes the vitreous chamber elongation of chicks, tree shrews, macaque monkeys, and other species. The axial growth continues from a standard, slightly hyperopic state extending past a set point that would produce emmetropia to become myopic.73,75,76 Degenerative retinal fundus changes typical of human myopia were noted in monkey83,84 and tree shrew.85 A decrease in choroidal thickness also occurs in the

Box 55.2  Myopia animal models

Animal model studies of myopia provide the best source of biologically similar tissue types to test various eye growth paradigms. Their relationship to human myopia remains unclear however

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Figure 55.2  Compensation for a minus lens. In an emmetropic eye (A), the focal plane for distant objects, without accommodation, is coincident with the retina. Placing a negative-power lens in front of one eye (B) displaces the focal plane posteriorly, assuming accommodation is set by the control eye. The emmetropization mechanism produces elongation that moves the retina to the displaced focal plane (C) so that the eye’s refractive state is emmetropic with the lens in place. When the lens is removed (D), the eye is myopic.