Clinical review

Myopia
Douglas R Fredrick Shortsightedness is becoming more common. Douglas Fredrick describes recent research into this condition and discusses future management of patients
Myopia is a leading cause of loss of vision throughout the world, and its prevalence is increasing. Although most researchers agree that peoples refractive status is in large part genetically determined, a growing body of evidence shows that visual experiences early in life may affect ocular growth and eventual refractive status. This review describes recent human and animal research into the pathogenesis of myopia and discusses implications for the management of patients.

Summary points
The prevalence of pathological myopia leading to vision impairment is increasing in many parts of the world Animal models in multiple species show that early visual experience affects growth of the eye and eventual refraction Ocular growth is modulated by biochemical processes occurring in the retina, choroid, and sclera Topical medications and bifocal spectacle lenses or rigid lenses may slow the progression of myopia but cannot prevent pathological myopia

Department of Ophthalmology, University of California, 10 Koret Way, San Francisco, CA 94143-0730, USA Douglas R Fredrick associate clinical professor of ophthalmology dfred@itsa.ucsf.edu
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Methods
This review article was prepared by searching Medline for citations of articles in English using the keyword myopia. In addition, abstracts from the annual meetings of the Association for Research in Vision and Ophthalmology were reviewed.

Fig 1 High (pathological) myopia often leads to atrophy of the choroid and subsequent retinal macular degeneration, with loss of central visual acuity and high incidence of retinal detachment, glaucoma, and strabismus

Myopia, commonly referred to as shortsightedness, is a common cause of visual disability throughout the world. The World Health Organization has grouped myopia and uncorrected refractive error with cataract, macular degeneration, infectious disease, and vitamin A deficiency among the leading causes of blindness and vision impairment in the world.1 People with myopia can be classified in two groups, those with low to modest degrees of myopia (referred to as simple or school myopia, 0 to 6 dioptres) and those with high or pathological myopia (greater than 6 dioptres). Simple myopia can be corrected with spectacles or contact lenses, whereas high (pathological) myopia is often associated with potentially blinding conditions such as retinal detachment, macular degeneration, and glaucoma (fig 1). The prevalence of myopia varies by country and by ethnic group, reaching as high as 70-90% in some Asian populations.2 3 In Japan it is estimated that more than one million people suffer from vision impairment associated with high myopia.4 According to epidemiological evidence the prevalence of myopia is increasing, especially in Asian populations.5 The prevalence of pathological myopia is estimated at 1-3% in population based studies.6 In addition to the human cost of visual disability, there is a profound economic cost to society. In the United States, for example, the treatment of
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myopia costs an estimated $250m (173m, 281m) per year.7 As the prevalence of simple myopia increases, the incidence of pathological myopia may also increase. Since no current treatments can reverse the structural changes of pathological myopia, preventing myopia has long been a goal of ophthalmologists and scientists researching vision. Understanding the mechanisms and factors that affect ocular growth is prerequisite to development of these therapeutic strategies. refractive variables of patient and parents; lack of adequate randomisation, control group, and follow up; and poor therapeutic compliance. In the past decade, well designed epidemiological protocols have been used to investigate the epidemiology of myopia.8

Genetic factors and refractive status

The two lines of research that support the idea that myopia and refractive errors are in large part genetically determined come from twin studies and studies of refractive errors in parents and their children. Two well conducted and well controlled studies show that refractive errors are much more strongly correlated in monozygotic twins than in dizygotic twins.9 10 A study of the correlation between refractive error in parents and siblings showed stronger correlations than would be expected by chance.11 Zadnik et al conducted perhaps the best longitudinal prospective study into refractive errors in parents and children.12 All components of refraction were measured in children, and refractive error was measured in parents. The study showed that children with myopic parents, although not yet myopic themselves, tended to have longer eyes than children with non-myopic parents, resulting in a predisposition to becoming myopic later in life. Genetic studies of families with a strong history of pathological myopia have uncovered two polymorphisms and two separate loci for high myopia, indicating an autosomal dominant predisposition for the development of pathological myopia.13 14 Additional evidence supporting the role of genetics in the development of myopia includes the wide variability of the prevalence of myopia in different ethnic groups.15 The prevalence of myopia in Asia is as high as 70-90%, in Europe and America 30-40%, and in Africa 10-20%.

Definition and epidemiology

To obtain clear vision, the eye must accurately focus an image in space on the retina. The main ocular determinants of refraction are the focusing power of the cornea and crystalline lens and the length of the eye. In myopia, the image is focused in front of the retina because the cornea or lens curvature is too strong or the eye is too long (axial myopia). When the optical components focus the image perfectly on the retina, this is described as emmetropia, and when the eye focuses the image behind the retina, this is described as hyperopia. Refractive error is measured in dioptres (D), and myopia is designated with a minus sign. Mild myopia is 0 D to 1.5 D, moderate 1.5 D to 6.0 D, and high myopia 6.0 D or more. Pathological myopia occurs with more than 8.0 D, although retinal disease, cataract, and glaucomathe associated threats to visioncan also occur in patients with moderate and high myopia. At birth, most infants are hyperopic, but when the eyes grow they usually become less hyperopic and by age 5-8 years emmetropic. This process, wherein the refractive state of childrens eyes shifts in magnitude and reduces in variance to reach near emmetropia, is called emmetropisation. The question for researchers is how much of this emmetropisation process is genetically determined and how much it is modulated by early visual experience, and epidemiological research into this question must be carefully conducted. Historically, most research into myopia has been limited by its retrospective nature; lack of measurement of ocular

Visual experience and ocular growth

People who wear spectacles for myopia may remember being told that they would ruin their eyes if they read in the dark or in a moving car or held the book too close to their faces (fig 2). The idea that the way in which we use our eyes early in life can affect ocular growth and refractive error is gaining scientific credence. It has been hypothesised that prolonged reading or the retinal blur of prolonged near work leads to the development of myopia. This is supported by evidence showing an increase in the prevalence of myopia from near 0% to rates found in the Western population in aboriginal peoples exposed to a Western curriculum of education.16 The correlation between level of academic achievement and the prevalence and progress of myopic refractive errors is strong; people whose professions entail much reading during either training or performance of the occupation (lawyers, physicians, microscopists, and editors) have higher degrees of myopia, and the myopia may progress not just in peoples teenage years but throughout their 20s and 30s.3 1720 Although it has been presumed that people with higher intelligence have higher degrees of myopia, these studies have been confounded by the higher degrees of educational attainment and cumulative amount of near work in patients with a higher IQ,
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Fig 2 Epidemiological research confirms a strong correlation between near work, such as reading, and progression of myopia. This process may continue through the third decade of life and is not limited to simple school myopia

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progressive myopia through the direct physical effect of prolonged accumulation, but according to current theory prolonged near work leads to myopia via the blurred retinal image that occurs during near focus. This retinal blur initiates a biochemical process in the retina to stimulate biochemical and structural changes in the sclera and choroid that lead to axial elongation.28 Accommodation problems People with shortsightedness have poorer ability to focus accurately by accommodation, which leads to even more retinal blur and defocus. In this model, the infant eye at birth is hyperopic or shorter than it should be in order to focus incoming light properly. Early visual experiences affect the growth of the eye. Deprivation of formed vision leads to an eye that grows in uncontrolled fashion, ever searching for a focal point, bypassing emmetropia, and developing axial myopia. People who do not have a strong predisposition for myopiawho have no family history of high myopia or who come from an ethnic group with no strong preponderance of myopiaalso begin life hyperopic, and emmetropisation occurs until the images are properly focused on the retina, when the process stops. Further myopiogenic stimuli such as prolonged reading or occupations that require extensive near work may lead to mild myopia later in life. Familial factors In children with a familial or ethnic predisposition to myopia the emmetropisation process continues, but they become mildly myopic early in life (fig 4). When they are exposed to myopiogenic factors, such as extensive near work, which produces blur and defocused images on the retina, myopisation consequently proceeds unchecked, searching for a focal point, which causes axial elongation and moderate myopia in late adolescence. Additional myopiogenic

Visually deprived retina Temporal Nasal

Hemiocular elongation

2 weeks hemiretinal occlusion

Fig 3 Chick model of form deprivation myopia. In the avian model of experimental myopia, hemiocular occlusion leads to hemiretinal visual deprivation. This visual deprivation leads to focal elongation of the eye, indicating local control of scleral growth controlled by the visual experience at the level of the retina and sclera

and intelligence per se thus cannot be correlated strongly with myopia.

Animal models of myopia

Observations by researchers that altering the visual experience of young animals can affect the growth of the eye have led to the experimental use of animals to investigate myopia. Whether using primates (monkeys, marmosets, or tree shrews) or chickens, investigators have shown that when a clear, formed image is not allowed to be focused on the retina (by suturing up eyelids or placement of translucent goggles) high myopia will develop in the eyes of young animals.2124 The ocular growth seems to be focally controlled in birds eyes, as hemiretinal occlusion leads to only hemiocular elongation (fig 3). The chicken model has been used to try to characterise the possible signal that triggers retinal, choroidal, and scleral growth. Possible modulators of growth include acetylcholine, dopamine, vasoactive intestinal polypeptide, and glucagon.25 Altering the visual environment leads to changes in the synthesis of mRNA and the concentration of matrix metalloproteinase. Further elucidation of the biochemical processes in these animal models of myopia may have implications for treating myopia in humans. Before we conclude that myopia in humans is analogous to experimentally induced myopia in animal models, we should bear in mind that naturally occurring disease processes causing deprivation of formed vision do affect human infants. In periocular haemangiomas and congenital cataracts, the two conditions that have been most studied, occlusion of the visual axis occurs in the first few months of life.26 27 In eyes that are not treated promptly, axial elongation and myopia develop. Other conditions that are associated with myopia include congenital ptosis; perinatal, vitreal, and retinal haemorrhages; and inflammatory keratitis. These naturally occurring experiments of deprivation of formed vision are consistent with the animal models previously described.

Proposed mechanisms of myopia development Infant eye hyperopic (+0.50 D to +2.50 D)

Visual deprivation Congenital cataract Ptosis Periocular haemangioma

Genetic predisposition Parents:refractive error Ethnicity

No genetic predisposition

Axial elongation Myopia

Ages 5 to 8 Mild myopia (-0.50 D to -2.0 D)

Ages 5 to 8 Emmetropia

Intervention Bifocals Antimuscarinics Rigid contact lenses

Myopiogenic factors Reading Near work Ages 8 to 14 Moderate to high myopia (-2.0 D to -5.0 D)

Myopiogenic factors Reading Near work Ages 8 to 14 Mild myopia (-0.50 D to -2.0 D)

College/postgraduate occupation

College/postgraduate occupation

Models for the development of myopia

Retinal blur On the basis of epidemiological studies of myopia, experimental animal models of myopia, and analysis of people with visual deprivation early in life, a model of myopia development can be postulated (fig 4). Prolonged near work was thought to lead to
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Ages 20 to 28 High myopia (> -6.0 D)

Ages 20 to 28 Mild to moderate myopia (-1.0 D to -4.0 D)

Fig 4 Myopiogenic factors such as genetic predisposition and ethnicity, coupled with visual experience, may lead to abnormal ocular growth resulting in myopia

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factors such as extensive near work in secondary or postgraduate school or in an occupation can lead to higher degrees of myopia. This model raises the question whether any interventions should be recommended to stop or slow this abnormal process of myopisation.

Additional educational resources

Review articles Norton TT. Animal models of myopia: learning how vision controls the size of the eye. Inst Lab Anim Res J 1999;40:59-77. Smith EL, Hung LF. The role of optical defocus in regulating refractive development in infant monkeys. Vis Res 1999;39:1415-35. Goss DA, Zhai H. Clinical and laboratory investigations of the relationship of accommodation and convergence function with refractive error. A literature review. Doc Ophthalmol 1994;86:349-80. Ongoing studies Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) study (www.nei.nih.gov/neitrials/static/study72.htm) Contact Lens and Myopia Progression (CLAMP) study (www.nei.nih.gov/neitrials/static/study81.htm). Study of rigid contact lenses versus spectacles on progression of myopia Correction of Myopia Evaluation Trial (COMET) (www.nei.nih.gov/neitrials/static/study9.htm). Study of bifocals versus single vision lenses

Therapeutic interventions to prevent myopia

Most myopic children will develop only low to moderate levels of myopia, but some will progress rapidly to high myopia. Risk factors for the development of high myopia include ethnicity, parental refraction, and rate of progession of myopia. In those children at risk, interventions should be considered. Efforts to prevent the progression of myopia date back centuries, and eye exercises, medications, and hygiene have been proposed to prevent weak eyes. Most modern efforts have been focused on decreasing the accommodative requirements of the eyes. Anticholinergics such as atropine have been used in combination with bifocals in an attempt to slow the progression of myopia. Although progression is slowed during treatment, the long term effects seem to be a difference of no more than 1-2 dioptres, and no cases of pathological myopia have been prevented with this treatment. Anticholinergics may act by a direct affect on the retina. Pirenzepine is a selective antimuscarinic that has no anti-accommodative effects. It has been shown to retard experimental myopia in chickens through a direct effect on the retina and sclera, and its efficacy is currently being investigated in a multicentre trial. Other biochemical modulators of scleral growth are currently being investigated in animal models, and limited human trials are under way. Accommodative effort and retinal blur can be minimised by bifocal glasses, which change the focal point for near work. Use of bifocals may slow the rate of progression of myopia; prospective randomised trials are addressing this question.29 Rigid or gas permeable contact lenses may offer a mode of treatment that may be effective in slowing the progression of myopia.30 The rate of progression of myopia is slower in patients using these contact lenses than in patients using lenses that are placed in spectacles.31 The exact mechanism by which rigid contact lenses prevent axial myopia from developing is unclear. Laser refractive surgery can eliminate the refractive condition of myopia, but it does not decrease the rate of the blinding conditions of retinal detachment, macular degeneration, and glaucoma associated with high myopia.32 Other interventions have included the use of vitamins, scleral surgery to provide shortening of the eye, biofeedback, ocular hypotensives, ocular relaxation techniques, and acupuncture, and proponents of these treatments often make unsubstantiated and exaggerated claims of success. Their efficacy has not been confirmed in randomised controlled trials.

tion may induce more myopia. Parents should consider the use of bifocal lenses to prevent retinal blur in patients with known accommodative lag and provide adequate lighting for reading and advocate a healthy balance of physical activity coupled with encouragement to enjoy the activity of reading. Doctors should encourage young shortsighted people to participate in clinical trials investigating strategies to prevent myopia.
Competing interests: DRF has done consultancy work for Novartis.
1 2 3 Pararajasegaram R. Vision 2020the right to sight: from strategies to action. Am J Ophthalmol 1999;182:359-60. Chow YC, Dhillon B, Chew PT, Chew SJ. Refractive errors in Singapore medical students. Singapore Med J 1990;31:472-3. Wong TY, Foster PJ, Hee J, Ng TP, Tielsch JM, Chew SJ, et al. Prevalence and risk factors for refractive errors in an adult Chinese population in Singapore. Invest Ophthalmol Vis Sci 2000;41:S324. Takashima T, Yokoyama T, Futagami S, Ohno-Matsui K, Tanaka H, Tokoro T, et al. The quality of life in patients with pathologic myopia. Jpn J Ophthalmol 2001;45:84-92. Rajan U, Tan FT, Chan TK. Increasing prevalence of myopia in Singapore school children. In: Chew SJ, Weintraub J, eds. Proceedings of the fifth international conference on myopia, Toronto, Ontario, Canada, June 22-24, 1994 . New York: Myopia International Research Foundation, 1995:41-6. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002;109:704-11. Javitt JC, Chiang YP. The socioeconomic aspects of laser refractive surgery. Arch Ophthalmol 1994;112:526-30. Negrel AD, Maul E, Pkharel GP, Zhao J, Ellwein LB. Refractive error study in children: sampling and measurement methods for a multi-country survey. Am J Ophthalmol 2000;129:421-6. Hammond CJ, Snieder H, Gilbert CE, Spector TD. Genes and environment in refractive error: the twin eye study. Invest Ophthalmol Vis Sci 2001;42:1232-6. Teikari JM, ODonnell J, Kaprio J, Koskenvuo M. Impact of heredity in myopia. Hum Hered 1991;41:151-1. Teikari J, ODonnell J, Kaprio J, Koskenvuo M. Genetic and environmental effects on oculometric traits. Optom Vis Sci 1980;66:594-9. Zadnik K, Satariano WA, Mutti DO, Sholtz RI, Adams AJ. The effect of parental history of myopia on childrens eye size. JAMA 1994;271:1323-2. Young TL, Ronan SM, Drahozal LA, Wildenberg SC, Alvear AB, Oetting WS, et al. Evidence that a locus for familial high myopia maps to chromosome 18p. Am J Hum Genet 1998;63:109-19. Young TL, Ronan SM, Alvear AB, Wildenberg SC, Oetting WS, Attwood LD, et al. A second locus for familial high myopia maps to chromosome 12q. Am J Hum Genet 1998;63:1419-24. Saw SM, Katz J, Schein OD, Chew SJ, Chan TK. Epidemiology of myopia. Epidemiol Rev 1996;18:175-87. Young FA, Leary GA, Baldwin GR. The transmission of refractive errors within Eskimo families. Am J Optom Physiol Optics 1969;46:676-85. Tay MT, Au Eong KG, Ng CY, Lim MK. Myopia and educational attainment in 421,116 young Singaporean males. Ann Acad Ed Singapore 1992;21:785-91.

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Conclusion
Until these treatments have been developed further parents of myopic children should ensure that refractive errors are corrected accurately as overcorrec1198

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18 Saw S, Neito, FJ, Katz J, Schein OD, Levy B, Chew S. factors related to the progression of myopia in Singaporean children. Optom Vis Sci 2000;77:549-54. 19 Teasdale TW, Schmidt E. Myopia and its relationship to education, intelligence and height: preliminary results from an on-going study of Danish draftees. Acta Ophthalmol Suppl 1988;185:41-3. 20 Dunphy EB, Stoll MR, King SH. Myopia among American male graduate students. Am J Ophthalmol 1968;65:518-21. 21 Raviola E, Wiesel TN. An animal model of myopia. N Engl J Med 1985;312:1609-15. 22 Wallman J, Turkel J, Trachtman J. Extreme myopia produced by modest change in early visual experience. Science 1978;201:1249-51. 23 Siegwart JT Jr, Norton TT. The susceptible period for deprivationinduced myopia in tree shrew. Vision Res 1998;38:3505-15. 24 Whatham AR, Judge S. Compensatory changes in eye growth and refraction induced by daily wear of soft contact lenses in young marmosets. Vision Res 2001;41:267. 25 Crewther DP. The role of photoreceptors in the control of refractive state. Prog Retina Eye Res 2000;19:421-57. 26 Hoyt CS, Stone RD, Fromer C, Billson FA. Monocular axial myopia associated with neonatal eyelid closure in human infants. Am J Ophthalmol 1981;91:197-200. 27 Robb RM. Refractive errors associated with hemangiomas of the eyelids and orbit in infancy. Am J Ophthalmol 1977;83:52-8. 28 Diether S, Gekeler F, Schaeffel F. Changes in contrast sensitivity induced by defocus and their possible relations to emmetropization in the chicken. Invest Ophthalmol Vis Sci 2001;42:3072-9. 29 Hyman L, Gwiazda J, Marsh-Tootle WL, Norton TT, Hussein M, the COMET Group. The correction of myopia evaluation trial (COMET), design and general baseline characteristics. Control Clin Trials 2001;22:573-92. 30 Walline JJ, Mutti DO, Jones LA ,Rah MJ, Nicholls KK, Watson R, et al. The contact lens and myopia progression (CLAMP) study: design and baseline data. Optom Vis Sci 2001;78:223-33. 31 Khoo CY, Chong J, Rajan U. A 3-year study on the effect of RGP contact lenses on myopic children. Singapore Med J 1999;40:230-7. 32 Zadnik K. Its the retina, stupid. Optom Vis Sci 2001:78:179-80.

Lesson of the week Cat scratch disease

Alexander Williams, Christopher D Sheldon, Terry Riordan
Unilateral lymphadenopathy of the groin is commonly seen in general practice. We report on a patient with initial features suggestive of sarcoidosis, but who, after careful history taking and further investigation, had cat scratch disease. positive result, indicating past infection with the Epstein-Barr virus. There was no evidence of infection with Mycoplasma pneumoniae, Coxiella burnetii (Q fever), or Chlamydia psittaci (all titres were < 10 with the complement fixation test). Serology for Bartonella was performed with an immunofluorescence kit (MRL Diagnostics, Central Public Health Laboratory, London). Although the IgM titre for Bartonella henselae was < 20, that for IgG was > 256. The IgM titre for Bartonella quintana < 20 and for IgG was 1 in 64. These findings were consistent with a recent infection with B henselae. Computed tomography of the patients abdomen confirmed enlarged lymph nodes in her right groin. No lymphadenopathy was detected intra-abdominally. Her liver appeared normal both before and after the addition of contrast, but some low density areas were detected in the spleen. Other organs in her upper abdomen appeared normal. After four months there were still persistently increased titres of IgG to B henselae, and IgM had increased to > 20. Interestingly, titres to B quintana also increased, IgG to > 128 and IgM to > 20. This may represent cross reactivity. The patient improved over time. She was not given antibiotics, and results of liver function tests returned to normal. At final follow up she recalled that a neighbours cat had scratched her in the groin about a month before she became unwell. Cat scratch disease should be considered in patients with lymphadenopathy
St Thomas Health Centre, Exeter EX4 1HJ Alexander Williams general practitioner Royal Devon and Exeter Hospital, Wonford, Exeter EX2 5DW Christopher D Sheldon consultant chest physician Public Health Laboratory, Royal Devon and Exeter Hospital Terry Riordan consultant microbiologist Correspondence to: A Williams su1838@eclipse. co.uk
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Case report
A 29 year old woman visited her general practitioner with a painless swelling in the right groin. She was referred to a surgeon, who aspirated the node. The aspirate contained blood and a range of lymphoid cells, suggesting a reactive lymph node. Ultrasonography confirmed numerous large lymph nodes in the right groin. Lymphadenopathy was not present elsewhere. The pelvis appeared normal on ultrasonography. Two hypoechoic lesions were found in the right lobe of the liver posteriorly, and multiple similar lesions were found in the spleen, but no para-aortic lymphadenopathy was seen. The surgeon took a biopsy specimen of the lymph node. This showed a reactive lymph node with prominent geminal centres and focal areas in keeping with necrotising granulomata. Cultures were Gram negative. Stains for acid fast bacilli and fungi gave negative results, and there was no evidence of caseating necrosis. Sarcoidosis was suspected, and the patient was referred to a chest physician. She had no symptoms of systemic disease and had a good appetite, steady weight, and no night sweats. She had never smoked but did have several allergies, including eczema and perennial rhinitis. At initial presentation a full blood count gave normal results. The erythrocyte sedimentation rate was increased at 25 mm in the first hour. A liver function test showed increased concentrations of alkaline phosphatase 188 iu/l (normal range 25-75 iu/l), aspartate aminotransferase 177 iu/l (8-39 iu/l), and -glutamyltransferase 164 iu/l (12-43 iu/l). Serum amylase concentrations were 30 iu/l, within normal range (23-71 iu/l). A monospot test for infectious mononucleosis gave a negative result. A test for Epstein-Barr nuclear antigen antibody gave a
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Discussion
Cat scratch disease mainly affects children and young adults (80% of those affected are under 21). Most patients develop regional lymphadenopathy, preceded by an erythematous papule at the site of inoculation. In a survey of 268 patients with cat scratch disease all had lymphadenopathy and other systemic symptoms but less than half had lymphadenopathy alone.1 Systemic disease is more common in immunocompromised patients and can include fever, malaise, anorexia,
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