LASEK is a surgical procedure that combines certain elements of both LASIK and PRK to improve the risk/benefit ratio. Diluted alcohol is used to loosen the epithelial adhesion to the corneal stroma. The loosened epithelium is moved aside from the treatment zone as a hinged sheet. Laser ablation of the subepithelial stroma is performed before the epithelial sheet is returned to its original position. The main rationale for combining elements of LASIK and PRK to LASEK is to avoid the flap-related LASIK complications and the slow visual recovery and haze risk of PRK. LASEK may avoid several of the inherent complications, including free caps, incomplete pass of the microkeratome, flap wrinkles, epithelial ingrowth, flap melt, interface debris, corneal ectasia, and diffuse lamellar keratitis, after LASIK and postoperative pain, subepithelial haze, and slow visual rehabilitation after PRK. Current ophthalmic literature does not provide the specific indications, visual outcomes, complications, and limitations of LASEK (19). Bilgihan et al. evaluated the efficacy, predictability, and safety of LASEK for treatment of high myopia with astigmatism. LASEK was performed in 61 eyes of 36 consecutive patients with myopic spherical equivalent refraction of -6.00 to -10.00 D using the Aesculap-Meditec MEL60 Еxcimer laser. Ninety-six percent of eyes achieved 20/40 or better uncorrected visual acuity (UCVA) at 1 month. At 12 months, 64% of eyes achieved 20/20 and 92% achieved 20/40 or better UCVA. Two eyes lost 2 lines of best spectacle-corrected visual acuity (BSCVA) at 6 or 12 months. Accuracy of correction was ±0.50 D from emmetropia in 82% of eyes, and ±1.00 D in 90% at 12 months (20). Taneri et al evaluated the visual outcomes and complications in low to moderate levels of myopia and astigmatism treated with LASEK. One hundred seventy-one eyes of 105 patients were studied. Preoperatively, the mean spherical equivalent was -2.99 diopters (D) ± 1.43 (SD) and the mean cylinder -0.78 ± 0.73 D. One week postoperatively, 96% of eyes had a UCVA of 20/40 or better but definitive visual recovery took more than 4 weeks in some eyes. Approximately 95% of eyes were within ±1.0 D of emmetropia after 4 to 52 weeks; the remaining 5% did not show major deviations. At 4 to 52 weeks, only 1 eye was

hyperplasia causing variable epithelial thickness (15).

**5. Laser-assisted subepithelial keratomileusis (LASEK)**

overcorrected by more than 1.0 D of manifest refraction (21).

**6. Epithelial laser in situ keratomileusis (Epi-LASIK)**

after photoablation (22).

Epi-LASIK has proved to be a suitable procedure, especially in patients with active lifestyles or occupations, eyes with thin corneas without ectatic disorders, and patients with moderate dry-eye syndrome. In epi-LASIK, an epithelial flap is created with the help of a special microkeratome. The epithelial flap is repositioned on the cornea after photoablation. It has been postulated that compared with conventional laser-assisted subepithelial keratectomy (LASEK), in which an epithelial flap is created after the epithelium is exposed to an alcohol solution, cell viability of the epithelial sheet is better in epi-LASIK surgery, in which mechanical separation is performed with a microkeratome. The quality of the epithelial separation is crucial for the success of the procedure because stromal lacerations or remaining islands of basal epithelial cells would reduce the optical quality of the cornea

The American Academy of Ophthalmology (AAO) recommended the next indications for PRK: myopia up to – 8 Dsph, hyperopia up to + 4 Dsph, and astigmatism up to 4 Dcyl (7). Large corrections (ablation depth greater than 100 µm) are considered for adjunctive 0,02% mitomycin C (MMC) because of the increased risk of postoperative haze and regression (16).

Complications of PRK include: subepithelial haze, corneal scarring, ectasia and regression.

Each candidate for PRK should be at least 21 years of age and must have a stable refractive error in the period of two years. Preoperative evaluation of each candidate includes: general and ophthalmic history; autorefractokeratometry; uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in each eye; Schirmer test; examination of the eye anterior segment on slit-lamp; applanation tonometry; examination of the eye fundus in a wide pupil; imaging of corneal topography and aberrometry. As a limit value for residual stromal thickness of the cornea (residual stromal bed) is 300 μm. The critical value for steep corneal meridian (steep K) is <39 or > 47 D and the limit value for elevation of the posterior corneal surface is 50 μm (5).

Numerous studies have investigated the effectiveness of PRK in the correction of astigmatism. Haw and Manche evaluated the safety and efficacy of PRK for the treatment of primary compound myopic astigmatism. Ninety three eyes from 56 patients with a mean spherical equivalent of −4.98 ± 1.80 diopters (range, −1.75 to −8.5) underwent photoastigmatic refractive keratectomy and were followed for 2 years. Fifty-six eyes (94.9%) had an uncorrected visual acuity of 20/40 or greater, whereas 34 eyes (57.6 %) demonstrated an uncorrected visual acuity of 20/20 or greater. One eye (1.7%) lost 2 or more lines of best spectacle-corrected visual acuity (17). Nagy et al evaluated the results of PRK using Gaussian flying spot technology in the treatment of hyperopia and hyperopic astigmatism. Two hundred eyes were evaluated with 12-month follow-up. Eyes were divided into four groups: group 1 (spherical hyperopia up to +3.50 D and astigmatism less than 1.00 D, n=62); group 2 (hyperopia up to +3.50 D and astigmatism of 1.00 D or more, n=44); group 3 (hyperopia greater than +3.50 D and astigmatism less than 1.00 D, n=56); and group 4 (hyperopia greater than +3.50 D and astigmatism of 1.00 D or more, n=38). In group 1, 82.2% (51/62 eyes) were within ±0.50 D of target refraction; 88.7% (55/62 eyes) had 20/20 or better uncorrected visual acuity; 1.6% (1/62 eye) lost two or more lines. In group 2, 68.1% (30/44 eyes) were within ±0.50 D; 77.2% (34/44 eyes) had 20/20 or better uncorrected visual acuity; 9.1% (4/44 eyes) lost two or more lines of spectacle-corrected visual acuity. In group 3, 76.8% (43/56 eyes) were within ±0.50 D; 78.6% (44/56 eyes) had 20/20 or better uncorrected visual acuity; 5.4% (3/56 eyes) lost two or more lines of spectacle-corrected visual acuity. In group 4, 42% (16/38 eyes) were within ±0.50 D; 60.5% (23/38 eyes) had 20/20 or better uncorrected visual acuity; 15.8% (6/38 eyes) lost two or more Snellen lines. In conclusion PRK was most safe and effective for low hyperopia (18).

#### **4. Trans-epithelial photorefractive keratectomy (tPRK)**

In this method, the Еxcimer laser is used to ablate the epithelium in addition to then ablating the underlying stroma. The cornea undergoes an epithelial ablation within a fixed diameter. The operating room lights are turned off as blue fluorescent light is emitted whereas epithelium is ablated. Once the blue fluorescence disappears, this indicates that the epithelium has been removed. Accuracy with this method is dependent upon regular

The American Academy of Ophthalmology (AAO) recommended the next indications for PRK: myopia up to – 8 Dsph, hyperopia up to + 4 Dsph, and astigmatism up to 4 Dcyl (7). Large corrections (ablation depth greater than 100 µm) are considered for adjunctive 0,02% mitomycin C (MMC) because of the increased risk of postoperative haze and regression (16). Complications of PRK include: subepithelial haze, corneal scarring, ectasia and regression. Each candidate for PRK should be at least 21 years of age and must have a stable refractive error in the period of two years. Preoperative evaluation of each candidate includes: general and ophthalmic history; autorefractokeratometry; uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in each eye; Schirmer test; examination of the eye anterior segment on slit-lamp; applanation tonometry; examination of the eye fundus in a wide pupil; imaging of corneal topography and aberrometry. As a limit value for residual stromal thickness of the cornea (residual stromal bed) is 300 μm. The critical value for steep corneal meridian (steep K) is <39 or > 47 D and the limit value for elevation of the posterior

Numerous studies have investigated the effectiveness of PRK in the correction of astigmatism. Haw and Manche evaluated the safety and efficacy of PRK for the treatment of primary compound myopic astigmatism. Ninety three eyes from 56 patients with a mean spherical equivalent of −4.98 ± 1.80 diopters (range, −1.75 to −8.5) underwent photoastigmatic refractive keratectomy and were followed for 2 years. Fifty-six eyes (94.9%) had an uncorrected visual acuity of 20/40 or greater, whereas 34 eyes (57.6 %) demonstrated an uncorrected visual acuity of 20/20 or greater. One eye (1.7%) lost 2 or more lines of best spectacle-corrected visual acuity (17). Nagy et al evaluated the results of PRK using Gaussian flying spot technology in the treatment of hyperopia and hyperopic astigmatism. Two hundred eyes were evaluated with 12-month follow-up. Eyes were divided into four groups: group 1 (spherical hyperopia up to +3.50 D and astigmatism less than 1.00 D, n=62); group 2 (hyperopia up to +3.50 D and astigmatism of 1.00 D or more, n=44); group 3 (hyperopia greater than +3.50 D and astigmatism less than 1.00 D, n=56); and group 4 (hyperopia greater than +3.50 D and astigmatism of 1.00 D or more, n=38). In group 1, 82.2% (51/62 eyes) were within ±0.50 D of target refraction; 88.7% (55/62 eyes) had 20/20 or better uncorrected visual acuity; 1.6% (1/62 eye) lost two or more lines. In group 2, 68.1% (30/44 eyes) were within ±0.50 D; 77.2% (34/44 eyes) had 20/20 or better uncorrected visual acuity; 9.1% (4/44 eyes) lost two or more lines of spectacle-corrected visual acuity. In group 3, 76.8% (43/56 eyes) were within ±0.50 D; 78.6% (44/56 eyes) had 20/20 or better uncorrected visual acuity; 5.4% (3/56 eyes) lost two or more lines of spectacle-corrected visual acuity. In group 4, 42% (16/38 eyes) were within ±0.50 D; 60.5% (23/38 eyes) had 20/20 or better uncorrected visual acuity; 15.8% (6/38 eyes) lost two or more Snellen lines. In conclusion

corneal surface is 50 μm (5).

PRK was most safe and effective for low hyperopia (18).

**4. Trans-epithelial photorefractive keratectomy (tPRK)**

In this method, the Еxcimer laser is used to ablate the epithelium in addition to then ablating the underlying stroma. The cornea undergoes an epithelial ablation within a fixed diameter. The operating room lights are turned off as blue fluorescent light is emitted whereas epithelium is ablated. Once the blue fluorescence disappears, this indicates that the epithelium has been removed. Accuracy with this method is dependent upon regular epithelial thickness across the diameter treatment zone and also similar epithelial thicknesses between different eyes. This technique can produce variable results when laser surface enhancement is proposed after previous refractive surgery due to areas of epithelial hyperplasia causing variable epithelial thickness (15).

#### **5. Laser-assisted subepithelial keratomileusis (LASEK)**

LASEK is a surgical procedure that combines certain elements of both LASIK and PRK to improve the risk/benefit ratio. Diluted alcohol is used to loosen the epithelial adhesion to the corneal stroma. The loosened epithelium is moved aside from the treatment zone as a hinged sheet. Laser ablation of the subepithelial stroma is performed before the epithelial sheet is returned to its original position. The main rationale for combining elements of LASIK and PRK to LASEK is to avoid the flap-related LASIK complications and the slow visual recovery and haze risk of PRK. LASEK may avoid several of the inherent complications, including free caps, incomplete pass of the microkeratome, flap wrinkles, epithelial ingrowth, flap melt, interface debris, corneal ectasia, and diffuse lamellar keratitis, after LASIK and postoperative pain, subepithelial haze, and slow visual rehabilitation after PRK. Current ophthalmic literature does not provide the specific indications, visual outcomes, complications, and limitations of LASEK (19). Bilgihan et al. evaluated the efficacy, predictability, and safety of LASEK for treatment of high myopia with astigmatism. LASEK was performed in 61 eyes of 36 consecutive patients with myopic spherical equivalent refraction of -6.00 to -10.00 D using the Aesculap-Meditec MEL60 Еxcimer laser. Ninety-six percent of eyes achieved 20/40 or better uncorrected visual acuity (UCVA) at 1 month. At 12 months, 64% of eyes achieved 20/20 and 92% achieved 20/40 or better UCVA. Two eyes lost 2 lines of best spectacle-corrected visual acuity (BSCVA) at 6 or 12 months. Accuracy of correction was ±0.50 D from emmetropia in 82% of eyes, and ±1.00 D in 90% at 12 months (20). Taneri et al evaluated the visual outcomes and complications in low to moderate levels of myopia and astigmatism treated with LASEK. One hundred seventy-one eyes of 105 patients were studied. Preoperatively, the mean spherical equivalent was -2.99 diopters (D) ± 1.43 (SD) and the mean cylinder -0.78 ± 0.73 D. One week postoperatively, 96% of eyes had a UCVA of 20/40 or better but definitive visual recovery took more than 4 weeks in some eyes. Approximately 95% of eyes were within ±1.0 D of emmetropia after 4 to 52 weeks; the remaining 5% did not show major deviations. At 4 to 52 weeks, only 1 eye was overcorrected by more than 1.0 D of manifest refraction (21).

#### **6. Epithelial laser in situ keratomileusis (Epi-LASIK)**

Epi-LASIK has proved to be a suitable procedure, especially in patients with active lifestyles or occupations, eyes with thin corneas without ectatic disorders, and patients with moderate dry-eye syndrome. In epi-LASIK, an epithelial flap is created with the help of a special microkeratome. The epithelial flap is repositioned on the cornea after photoablation. It has been postulated that compared with conventional laser-assisted subepithelial keratectomy (LASEK), in which an epithelial flap is created after the epithelium is exposed to an alcohol solution, cell viability of the epithelial sheet is better in epi-LASIK surgery, in which mechanical separation is performed with a microkeratome. The quality of the epithelial separation is crucial for the success of the procedure because stromal lacerations or remaining islands of basal epithelial cells would reduce the optical quality of the cornea after photoablation (22).

Corneal Surgical Techniques 127

performed with a mechanical microkeratome, including corneas that are too steep (likely to have buttonhole flaps), too flat (likely to have small diameter flaps), or relatively thin (more

Fig. 4. Corneal complications reported with conventional microkeratomes (24).

The femtosecond laser became available for LASIK flap formation approximately 10 years ago. Since the early femtosecond laser models were introduced, considerable progress has been made in improving flap geometry and limiting complications of LASIK performed with the laser. This has led to increasing popularity of LASIK performed with the femtosecond laser, to the point that different sources estimate that 30% to 50% of LASIK procedures in the United States in 2008 were performed using a femtosecond laser. Recently, new femtosecond laser models were introduced. These include the Femtec (20/10 Perfect Vision AG), the Femto LDV (Zeimer Group), the Visu-Max (Carl Zeiss Meditec) and commonly used IntraLase 60 kHz femtosecond laser (Abbott Medical Optics, Inc.). All 4 commercially available femtosecond laser systems use ultrashort pulses of laser and produce corneal tissue cutting using a photodisruption process. To create the lamellar flap, the IntraLase laser generates pulses of femtosecond laser at a near-infrared (1053 nm) wavelength and delivers closely spaced 3 mm spots, which are focused at variable depths to photodisrupt stromal tissue. When a high peak power is reached, hot plasma is generated, initiating a process of tissue ionization that is commonly called laser-induced optical breakdown. The hot plasma expands in shock waves and creates an intrastromal cavitation bubble composed primarily of water and carbon dioxide. Multiple cavitation bubbles coalesce, and an intrastromal cleavage plane is created. The laser delivers a series of pulses

likely to have low residual stromal bed) (Fig. 4).

Fig. 3. Widely accepted relative differences between PRK, LASEK, epi-LASIK, and LASIK (23).

#### **7. Femtosecond laser in laser in situ keratomileusis**

In the early 1960s, Barraquer introduced the concept of lamellar refractive procedures. In the 1990s, Pallikaris et al. and Buratto et al. conceived of techniques combining lamellar procedures with Еxcimer laser ablation. These advances led to the development of modern laser in situ keratomileusis (LASIK) procedures. LASIK has several advantages over PRK when performed properly in appropriate eyes. These include faster visual recovery, less discomfort after surgery, and milder and more predictable wound healing with less risk for corneal stromal opacity (haze). Lamellar corneal flap formation is the critical step in successful LASIK surgery. Improper flap formation, including improper flap geometry, decentration, irregularity of the cut, and epithelial damage, can lead to myriad LASIK complications. Considerable progress has been made over the years in producing safer instruments for LASIK flap formation since the Automated Corneal Shaper was adapted to LASIK. Thus, more reliable and safer mechanical microkeratomes contributed to the explosive growth of refractive surgery over the past 15 years. Despite these advances, complications such as incomplete or partial flaps, free flaps, buttonholes, and small irregular flaps continue to plague refractive surgeons who perform LASIK with a microkeratome. There are also significant limitations to the eyes that can safely have lamellar flap formation

Fig. 3. Widely accepted relative differences between PRK, LASEK, epi-LASIK, and LASIK

In the early 1960s, Barraquer introduced the concept of lamellar refractive procedures. In the 1990s, Pallikaris et al. and Buratto et al. conceived of techniques combining lamellar procedures with Еxcimer laser ablation. These advances led to the development of modern laser in situ keratomileusis (LASIK) procedures. LASIK has several advantages over PRK when performed properly in appropriate eyes. These include faster visual recovery, less discomfort after surgery, and milder and more predictable wound healing with less risk for corneal stromal opacity (haze). Lamellar corneal flap formation is the critical step in successful LASIK surgery. Improper flap formation, including improper flap geometry, decentration, irregularity of the cut, and epithelial damage, can lead to myriad LASIK complications. Considerable progress has been made over the years in producing safer instruments for LASIK flap formation since the Automated Corneal Shaper was adapted to LASIK. Thus, more reliable and safer mechanical microkeratomes contributed to the explosive growth of refractive surgery over the past 15 years. Despite these advances, complications such as incomplete or partial flaps, free flaps, buttonholes, and small irregular flaps continue to plague refractive surgeons who perform LASIK with a microkeratome. There are also significant limitations to the eyes that can safely have lamellar flap formation

**7. Femtosecond laser in laser in situ keratomileusis**

(23).

performed with a mechanical microkeratome, including corneas that are too steep (likely to have buttonhole flaps), too flat (likely to have small diameter flaps), or relatively thin (more likely to have low residual stromal bed) (Fig. 4).

Fig. 4. Corneal complications reported with conventional microkeratomes (24).

The femtosecond laser became available for LASIK flap formation approximately 10 years ago. Since the early femtosecond laser models were introduced, considerable progress has been made in improving flap geometry and limiting complications of LASIK performed with the laser. This has led to increasing popularity of LASIK performed with the femtosecond laser, to the point that different sources estimate that 30% to 50% of LASIK procedures in the United States in 2008 were performed using a femtosecond laser. Recently, new femtosecond laser models were introduced. These include the Femtec (20/10 Perfect Vision AG), the Femto LDV (Zeimer Group), the Visu-Max (Carl Zeiss Meditec) and commonly used IntraLase 60 kHz femtosecond laser (Abbott Medical Optics, Inc.). All 4 commercially available femtosecond laser systems use ultrashort pulses of laser and produce corneal tissue cutting using a photodisruption process. To create the lamellar flap, the IntraLase laser generates pulses of femtosecond laser at a near-infrared (1053 nm) wavelength and delivers closely spaced 3 mm spots, which are focused at variable depths to photodisrupt stromal tissue. When a high peak power is reached, hot plasma is generated, initiating a process of tissue ionization that is commonly called laser-induced optical breakdown. The hot plasma expands in shock waves and creates an intrastromal cavitation bubble composed primarily of water and carbon dioxide. Multiple cavitation bubbles coalesce, and an intrastromal cleavage plane is created. The laser delivers a series of pulses

Corneal Surgical Techniques 129

0.50 to - 2.75 D). The mean preoperative uncorrected visual acuity (UCVA) of 0.034 ± 0.016 increased to 0.35 ± 0.15 postoperatively. The mean preoperative best spectacle-corrected visual acuity (BSCVA) was 0.53 ± 0.19 and changed to 0.64 ± 0.16 postoperatively. No eye lost a line of BSCVA; 9 eyes gained 1 line, and 5 eyes gained 2 lines. No eye had + 3 haze. There were no significant complications. In conclusion, PRK was safe and effective in correcting high myopic anisometropia in children who were contact-lens intolerant (30).

Yin et al. assessed the efficacy of LASIK in facilitating amblyopia management of children from 6 to 14 years old, with high hyperopic and myopic anisometropia. Between 2000 and 2005, 42 children with high hyperopic anisometropic amblyopia and 32 children with high myopic anisometropic amblyopia underwent LASIK to reduce their anisometropia. LASIK was performed under topical or general anesthesia. Follow-up ranged from 6 months to 3 years, the averages of which were 17,45 months in the hyperopic group and 18,31 months in myopic group. Hyperopic anisometropia correction ranged from + 3.50 D to + 7.75 D, and the mean postoperative anisometropia was +0.56 ± 0.75 D at 3 years. Myopic anisometropia correction ranged from -15.75 to - 5.00 D and the mean postoperative anisometropia at 3 years was - 2.20 ± 1.05 D. The best-corrected visual acuity for distance and reading in the myopic group improved from 0.4 ± 0.25 and 0.58 ± 0.27, respectively, before surgery to 0.59 ± 0.28 and 0.96 ± 0.35, respectively, 3 years after surgery. In the hyperopic group, bestcorrected visual acuity for distance and reading improved from 0.23 ± 0.21 and 0.34 ± 0.32, respectively, before surgery to 0.53 ± 0.31 and 0.80 ± 0.33, respectively, 3 years after surgery. Study shows that LASIK is an alternative method for correcting high hyperopic and myopic anisometropia. The proportion of patients who had stereopsis increased from 19.1% preoperatively to 46.7% postoperatively in the hyperopic group and from 19% to 89% in the myopic group. In conclusion, LASIK reduced high hyperopic and myopic anisometropia in children, thus facilitating amblyopia management and improving their visual acuity and

Astle et al. assessed the refractive, visual acuity, and binocular results of LASEK for anisomyopia, anisohyperopia, and anisoastigmatia in children with various levels of amblyopia secondary to the anisometropic causes. Retrospective review was of 53 children with anisometropia who had LASEK to correct the refractive difference between eyes. All LASEK procedures were performed using general anesthesia. Patients were divided into 3 groups according to their anisometropia as follows: myopic difference greater than 3.00 diopters (D), astigmatic difference greater than 1.50 D, and hyperopic difference greater than 3.50 D. The children were followed for at least 1 year. The mean age at treatment was 8.4 years (range 10 months to 16 years). The mean preoperative anisometropic difference was 6.98 D in the entire group, 9.48 D in the anisomyopic group, 3.13 D in the anisoastigmatic group, and 5.50 D in the anisohyperopic group. One year after LASEK, the mean anisometropic difference decreased to 1.81 D, 2.43 D, 0.74 D, and 2.33 D, respectively, and 54% of all eyes were within ± 1.00 D of the fellow eye, 68% were within ± 2.00 D, and 80% were within ± 3.00 D. Preoperative visual acuity and binocular vision could be measured in 33 children. Postoperatively, 63.6% of children had an improvement in best corrected visual acuity (BCVA) and the remainder had no noted change. No patient had a reduction in BCVA or a loss in fusional ability after LASEK. Of the 33 children, 39.4% had positive stereopsis preoperatively and 87.9% had positive stereopsis 1 year after LASEK. In conclusion, LASEK is an effective surgical alternative to improve visual acuity in

stereopsis (31).

in a specified pattern to create the lamellar intrastromal cut and then extends the cleavage to the surface with a side cut to complete the flap (25). Stonecipher et al. reported the refractive results after LASIK for high myopia and cylinder at one center with one surgeon comparing two laser platforms. A total of 206 eyes of 121 patients were treated for –6.00 to –12.00 diopters (D) of spherical equivalent refractive error with up to 3.00 D of cylinder. All eyes underwent LASIK with the ALLEGRETTO WAVE 200-Hz (n=141) or 400-Hz (n=65) laser (Alcon Laboratories Inc). Corneal flaps were created with the IntraLase femtosecond laser (Abbott Medical Optics) at an intended thickness of 100 or 110 µm in all cases. At 3- and 6 month follow-up in the 200-Hz group, 77% (109/141) and 86% (121/141) of eyes, respectively, were within ±0.50 D of intended correction. In the 400-Hz group, 98.5% (64/65) and 100% (65/65) of eyes were within ±50 D of intended correction at 3 and 6 months postoperatively. At 3- and 6-month follow-up, 84% (119/141) and 77% (109/141) of eyes, respectively, in the 200-Hz group and 80% (52/65) and 92% (60/65) of eyes, respectively, in the 400-Hz group had 20/20 or better uncorrected distance visual acuity. At 6-month followup, refractive predictability and visual acuity were statistically superior in eyes in the 400- Hz group (chi square, P<.01). No eyes underwent retreatment as a secondary procedure during the time of analysis (26).

#### **8. Refractive laser surgery in children**

The use of Еxcimer laser vision correction in children is controversial because their eyes and refractive state continue to change. More studies on the growing eye and the effect of Еxcimer laser on the pediatric corneal endothelium are needed before the effect of refractive surgery in the pediatric age group can be fully understood (27).

Traditional methods of correcting and rehabilitating the refractive status of children with high myopia, myopic anisometropic amblyopia, hyperopia, hyperopic anisometropic amblyopia or significant astigmatism include glasses and contact lenses combined with some form of occlusion or optical penalization therapy. However, some children may not improve with these traditional forms of treatment because of aniseikonia, compliance issues, or both. This is especially true when children have concurrent medical diagnoses such as autism, cerebral palsy, developmental delay, Down syndrome, or other associated ocular disorders (eg, corneal, retinal, and optic nerve problems). So, in such children traditional optical refractive correction is often not successful (28, 29).

In the past ten years, refractive laser surgery techniques have been shown to be a good lastresort treatment in children who have failed with traditional treatment approaches. There are numerous reports of the successful performance of PRK, LASIK and LASEK in children when conventional therapy failed.

Autrata and Rehurek evaluated the visual and refractive results of multizonal PRK for high myopic anisometropia and contact-lens intolerance in children. Twenty-one patients aged 7 to 15 years with high myopic anisometropia had multizonal PRK in the more myopic eye and were retrospectively analyzed. The scanning-slit Nidek EC-5000 Еxcimer laser was used. The safety, efficacy, predictability, and stability of the procedure were evaluated. Long-term binocular vision outcome was analyzed. All patients completed a 4-year followup. The mean preoperative spherical equivalent (SE) refraction was - 8.93 diopters (D) ± 1.39 (SD) (range - 6.75 to - 11.75 D) and the mean postoperative SE was – 1.66 ± 0.68 D (range -

in a specified pattern to create the lamellar intrastromal cut and then extends the cleavage to the surface with a side cut to complete the flap (25). Stonecipher et al. reported the refractive results after LASIK for high myopia and cylinder at one center with one surgeon comparing two laser platforms. A total of 206 eyes of 121 patients were treated for –6.00 to –12.00 diopters (D) of spherical equivalent refractive error with up to 3.00 D of cylinder. All eyes underwent LASIK with the ALLEGRETTO WAVE 200-Hz (n=141) or 400-Hz (n=65) laser (Alcon Laboratories Inc). Corneal flaps were created with the IntraLase femtosecond laser (Abbott Medical Optics) at an intended thickness of 100 or 110 µm in all cases. At 3- and 6 month follow-up in the 200-Hz group, 77% (109/141) and 86% (121/141) of eyes, respectively, were within ±0.50 D of intended correction. In the 400-Hz group, 98.5% (64/65) and 100% (65/65) of eyes were within ±50 D of intended correction at 3 and 6 months postoperatively. At 3- and 6-month follow-up, 84% (119/141) and 77% (109/141) of eyes, respectively, in the 200-Hz group and 80% (52/65) and 92% (60/65) of eyes, respectively, in the 400-Hz group had 20/20 or better uncorrected distance visual acuity. At 6-month followup, refractive predictability and visual acuity were statistically superior in eyes in the 400- Hz group (chi square, P<.01). No eyes underwent retreatment as a secondary procedure

The use of Еxcimer laser vision correction in children is controversial because their eyes and refractive state continue to change. More studies on the growing eye and the effect of Еxcimer laser on the pediatric corneal endothelium are needed before the effect of refractive

Traditional methods of correcting and rehabilitating the refractive status of children with high myopia, myopic anisometropic amblyopia, hyperopia, hyperopic anisometropic amblyopia or significant astigmatism include glasses and contact lenses combined with some form of occlusion or optical penalization therapy. However, some children may not improve with these traditional forms of treatment because of aniseikonia, compliance issues, or both. This is especially true when children have concurrent medical diagnoses such as autism, cerebral palsy, developmental delay, Down syndrome, or other associated ocular disorders (eg, corneal, retinal, and optic nerve problems). So, in such children traditional

In the past ten years, refractive laser surgery techniques have been shown to be a good lastresort treatment in children who have failed with traditional treatment approaches. There are numerous reports of the successful performance of PRK, LASIK and LASEK in children

Autrata and Rehurek evaluated the visual and refractive results of multizonal PRK for high myopic anisometropia and contact-lens intolerance in children. Twenty-one patients aged 7 to 15 years with high myopic anisometropia had multizonal PRK in the more myopic eye and were retrospectively analyzed. The scanning-slit Nidek EC-5000 Еxcimer laser was used. The safety, efficacy, predictability, and stability of the procedure were evaluated. Long-term binocular vision outcome was analyzed. All patients completed a 4-year followup. The mean preoperative spherical equivalent (SE) refraction was - 8.93 diopters (D) ± 1.39 (SD) (range - 6.75 to - 11.75 D) and the mean postoperative SE was – 1.66 ± 0.68 D (range -

during the time of analysis (26).

when conventional therapy failed.

**8. Refractive laser surgery in children**

surgery in the pediatric age group can be fully understood (27).

optical refractive correction is often not successful (28, 29).

0.50 to - 2.75 D). The mean preoperative uncorrected visual acuity (UCVA) of 0.034 ± 0.016 increased to 0.35 ± 0.15 postoperatively. The mean preoperative best spectacle-corrected visual acuity (BSCVA) was 0.53 ± 0.19 and changed to 0.64 ± 0.16 postoperatively. No eye lost a line of BSCVA; 9 eyes gained 1 line, and 5 eyes gained 2 lines. No eye had + 3 haze. There were no significant complications. In conclusion, PRK was safe and effective in correcting high myopic anisometropia in children who were contact-lens intolerant (30).

Yin et al. assessed the efficacy of LASIK in facilitating amblyopia management of children from 6 to 14 years old, with high hyperopic and myopic anisometropia. Between 2000 and 2005, 42 children with high hyperopic anisometropic amblyopia and 32 children with high myopic anisometropic amblyopia underwent LASIK to reduce their anisometropia. LASIK was performed under topical or general anesthesia. Follow-up ranged from 6 months to 3 years, the averages of which were 17,45 months in the hyperopic group and 18,31 months in myopic group. Hyperopic anisometropia correction ranged from + 3.50 D to + 7.75 D, and the mean postoperative anisometropia was +0.56 ± 0.75 D at 3 years. Myopic anisometropia correction ranged from -15.75 to - 5.00 D and the mean postoperative anisometropia at 3 years was - 2.20 ± 1.05 D. The best-corrected visual acuity for distance and reading in the myopic group improved from 0.4 ± 0.25 and 0.58 ± 0.27, respectively, before surgery to 0.59 ± 0.28 and 0.96 ± 0.35, respectively, 3 years after surgery. In the hyperopic group, bestcorrected visual acuity for distance and reading improved from 0.23 ± 0.21 and 0.34 ± 0.32, respectively, before surgery to 0.53 ± 0.31 and 0.80 ± 0.33, respectively, 3 years after surgery. Study shows that LASIK is an alternative method for correcting high hyperopic and myopic anisometropia. The proportion of patients who had stereopsis increased from 19.1% preoperatively to 46.7% postoperatively in the hyperopic group and from 19% to 89% in the myopic group. In conclusion, LASIK reduced high hyperopic and myopic anisometropia in children, thus facilitating amblyopia management and improving their visual acuity and stereopsis (31).

Astle et al. assessed the refractive, visual acuity, and binocular results of LASEK for anisomyopia, anisohyperopia, and anisoastigmatia in children with various levels of amblyopia secondary to the anisometropic causes. Retrospective review was of 53 children with anisometropia who had LASEK to correct the refractive difference between eyes. All LASEK procedures were performed using general anesthesia. Patients were divided into 3 groups according to their anisometropia as follows: myopic difference greater than 3.00 diopters (D), astigmatic difference greater than 1.50 D, and hyperopic difference greater than 3.50 D. The children were followed for at least 1 year. The mean age at treatment was 8.4 years (range 10 months to 16 years). The mean preoperative anisometropic difference was 6.98 D in the entire group, 9.48 D in the anisomyopic group, 3.13 D in the anisoastigmatic group, and 5.50 D in the anisohyperopic group. One year after LASEK, the mean anisometropic difference decreased to 1.81 D, 2.43 D, 0.74 D, and 2.33 D, respectively, and 54% of all eyes were within ± 1.00 D of the fellow eye, 68% were within ± 2.00 D, and 80% were within ± 3.00 D. Preoperative visual acuity and binocular vision could be measured in 33 children. Postoperatively, 63.6% of children had an improvement in best corrected visual acuity (BCVA) and the remainder had no noted change. No patient had a reduction in BCVA or a loss in fusional ability after LASEK. Of the 33 children, 39.4% had positive stereopsis preoperatively and 87.9% had positive stereopsis 1 year after LASEK. In conclusion, LASEK is an effective surgical alternative to improve visual acuity in

Corneal Surgical Techniques 131

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[17] Haw WW, Manche EE. Photorefractive keratectomy for compound myopic

[18] Nagy ZZ, Munkacsy G, Popper M. Photorefractive Keratectomy Using the Meditec

[19] Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes and

[20] Bilgihan K, Hondur A, Hasanreisoglu B. Laser subepithelial keratomileusis for myopia

[21] Taneri S, Feit R, Azar DT. Safety, efficacy, and stability indices of LASEK correction in moderate myopia and astigmatism. J Cataract Refract Surg 2004; 30: 2130-2137. [22] Herrmann WA, Hillenkamp J, Hufendiek K et al*.* Epilaser in situ keratomileusis:

[23] Taneri S, Weisberg M, Azar DT. Surface ablation techniques. J Cataract Refract Surg

[24] Binder PS. One thousand consecutive IntraLase laser in situ keratomileusis flaps. J

[25] Saloma MQ, Wilson SE. Femtosecond laser in laser in situ keratomileusis. J Cataract

[26] Stonecipher KG, Kezirian GM, Stonecipher M. LASIK for -6.00 to -12.00 D of myopia

results with the 200- and 400-Hz platforms. J Refract Surg 2010; 26: 814-818. [27] American Academy of Ophthalmology. Refractive Surgery in Ocular and Systemic

[29] Astle WF, Fawcett SL, Huang PT, Alewenah O, Ingram A. Long-term outcomes of

[30] Autrata R, Rehurek J. Clinical results of excimer laser photorefractive keratectomy for

[31] Yin ZQ, Wang H, Yu T, Ren Q, Chen Li. Facilitation of amblyopia management by laser

with up to 3.00 D of cylinder using the ALLEGRETTO WAVE: 3- and 6-month

Disease. In: American Academy of Ophthalmology. Refractive surgery, Section 13, 2010-2011. Singapore: American Academy of Ophthalmology; 2010. p. 203-222. [28] Astle WF, Huang PT, Ereifej I, Paszuk A. Laser-assisted subepithelial keratectomy for

bilateral hyperopia and hyperopic anisometropic amblyopia in children. J Cataract

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anisometropic children unable to tolerate conventional methods of treatment or in whom these methods fail (32).

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[5] Vukosavljević M, Milivojević M, Resan M, Cerović V. Laser in situ keratomyleusis

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[9] Probst LE. Intraoperative complications. In: Probst LE. Lasik: a color atlas and surgical

[10] Probst LE. Early and late postoperative complications. In: Probst LE. Lasik: a color atlas and surgical synopsis. Thorofare, NJ: Slack Incorporated; 2001. p. 257-297. [11] Stojanovic A, Nitter TA. 200 Hz flying-spot technology of the LaserSight LSX excimer

[12] Ditzen K, Fiedler J, Pieger S. Laser in situ Keratomileusis for Hyperopia and Hyperopic

[13] Albarran-Diego C, Munoz G, Montes-Mico R, Alio JL. Bitoric laser in situ keratomileusis

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these methods fail (32).

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**9. References**

**Part 3**

**Refraction and Refractive Correction**

[32] Astle WF, Rahmat J, Ingram AD, Huang PT. Laser-assisted subepithelial keratectomy for anisometropic amblyopia in children: Outcomes at 1 year. J Cataract Refract Surg 2007; 33: 2028–2034.

## **Part 3**

## **Refraction and Refractive Correction**

132 Advances in Ophthalmology

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Surg 2007; 33: 2028–2034.

for anisometropic amblyopia in children: Outcomes at 1 year. J Cataract Refract

**8**

**Incidence of Refractive**

*1Department of Ophthalmology,*

*2Department of Pharmacology,*

*Pakistan*

*Baqai Medical University, Karachi Sindh,*

**Error and Amblyopia Among**

*Liaquat University Eye Hospital, Hyderabad Sindh,*

Ashok Kumar Narsani1, Shafi Muhammad Jatoi1, Mohan Perkash Maheshwari2 and Khairuddin Shah1

**Young Adults – A Hospital Based Study**

Visual impairment remains a major public health problem world wide, with an estimated 161 million people with visual impairment, of whom 37 million are blind.1 Uncorrected or inadequately corrected refractive errors have been shown to be a major cause of visual impairment in population-based studies2-6. While amblyopia is a significant cause of

Genetic factors are thought to play a role in development of refractive errors. It has been established that myopia clusters within families, and familial high myopia (refraction of -6 diopter {D} or less) has been linked to long arm regions on chromosomes 7, 12 and 188,9. Environmental risk factors have also been associated with refractive errors, myopia or hypermetropia. Education10,11 and near-work12 are both strongly associated with increasing

In different parts of Asia such as in India, the Andhra Pradesh Eye Disease Study shows 15.2%13 prevalence rate of myopia (spherical equivalent {SE} at least -1.0D). While study in a 15,068 Singapore military recruits aged 16 to 25 years, the prevalence rates of myopia (SE at least -0.5 D) were much higher with some racial variation, 82.2% in Chinese, 68.8% in Indians, and 65.0% in Malays14. Similar high rates of myopia (SE at least -0.25 D; 84%) were present in 16 to 18 years old Chinese children in Taiwan15. In Pakistan the prevalence rates of myopia, hypermetropia, astigmatism (with SE worse than –0.5 D, greater than +0.5D, and greater than 0.75D respectively) was 36.5%, 27.1%, and 37%, respectively in adults aged 30 years or more in the National Blindness and Visual

In United states, the Baltimore eye survey17 and Beaver Dam study18 showed the prevalence rates of myopia (SE at least -0.5 D) were 28.1% in white adults aged 40 years or more and

unilateral reduced visual acuity in a population aged 40 years and older.7

**1. Introduction**

severity of myopia.

Impairment Survey.16

26.2% in adults aged 43 to 84 years respectively.

### **Incidence of Refractive Error and Amblyopia Among Young Adults – A Hospital Based Study**

Ashok Kumar Narsani1, Shafi Muhammad Jatoi1, Mohan Perkash Maheshwari2 and Khairuddin Shah1 *1Department of Ophthalmology, Liaquat University Eye Hospital, Hyderabad Sindh, 2Department of Pharmacology, Baqai Medical University, Karachi Sindh, Pakistan*

#### **1. Introduction**

Visual impairment remains a major public health problem world wide, with an estimated 161 million people with visual impairment, of whom 37 million are blind.1 Uncorrected or inadequately corrected refractive errors have been shown to be a major cause of visual impairment in population-based studies2-6. While amblyopia is a significant cause of unilateral reduced visual acuity in a population aged 40 years and older.7

Genetic factors are thought to play a role in development of refractive errors. It has been established that myopia clusters within families, and familial high myopia (refraction of -6 diopter {D} or less) has been linked to long arm regions on chromosomes 7, 12 and 188,9. Environmental risk factors have also been associated with refractive errors, myopia or hypermetropia. Education10,11 and near-work12 are both strongly associated with increasing severity of myopia.

In different parts of Asia such as in India, the Andhra Pradesh Eye Disease Study shows 15.2%13 prevalence rate of myopia (spherical equivalent {SE} at least -1.0D). While study in a 15,068 Singapore military recruits aged 16 to 25 years, the prevalence rates of myopia (SE at least -0.5 D) were much higher with some racial variation, 82.2% in Chinese, 68.8% in Indians, and 65.0% in Malays14. Similar high rates of myopia (SE at least -0.25 D; 84%) were present in 16 to 18 years old Chinese children in Taiwan15. In Pakistan the prevalence rates of myopia, hypermetropia, astigmatism (with SE worse than –0.5 D, greater than +0.5D, and greater than 0.75D respectively) was 36.5%, 27.1%, and 37%, respectively in adults aged 30 years or more in the National Blindness and Visual Impairment Survey.16

In United states, the Baltimore eye survey17 and Beaver Dam study18 showed the prevalence rates of myopia (SE at least -0.5 D) were 28.1% in white adults aged 40 years or more and 26.2% in adults aged 43 to 84 years respectively.

Incidence of Refractive Error and Amblyopia Among Young Adults – A Hospital Based Study 137

phakic ametropic patients. While for amblyopia all patients who met the criteria were

There were 341 (64.95% of phakic ametropic patients) male and 184 (35.05%) were female. The age range from 20 to 40 years **(Table 1),** mean age being 26±3.9 years. The mean age of men and women was 28±3.9 and 24±6.3 years respectively (statistically significant at

Hypermetropia was found in 185 (35.24% of phakic ametropic) patients (Table 1). The mean age of hypermetropia was 26.31±4.51 years. Which was not significantly different from that of entire population (P=0.5476). There were 121 men (23.04% of total ametropic) and 64 women (12.19%). Man had significantly higher prevalence of hypermetropia than women (P<0.001). Three hundred and fifteen (60% of phakic ametropic) patients had myopia (Table 1). The mean age of myopes was 23.69±3.98 years. Which was significantly lower than the entire population (P<0.001). There were 205 (39.05%) men and 110 (20.95%) women. The man had

Twenty five (4.76%) patients of the study population were high myopes (Table 1). Among which 15 patients were males and 10 were females. The mean age among high myopes was 22. 50±3.25 years. Which was also significantly lower than the entire population (P<0.0002). However there was no significant different between the mean age of myopes and high

Two hundred and fifteen (25.38 % of phakic ametropic) patients had astigmatism worse than –0.5 DC. The males were 134 (62.32%) of total astigmatic patients and remaining were females. The man had a significantly higher prevalence of astigmatism than women (P<0.001). One hundred and forty two (66.04%) patients had ATR astigmatism, 52 (24.18%) had WTR astigmatism and 21 (9.76%) had oblique astigmatism. The prevalence of against

The incidence of associated unilateral amblyopia was in 19 (3.62%) of phakic ametropic patients (Table 2). Ten (52.63%) patients were male and 09 (47.37%) were females. Amblyopia was not found to be significantly different by age (p=0.1312) group and gender (p=0.1211). Anisometropia was more common in amblyopic cases (41.75%) compared to the normal population (5.91%), and 69% of amblyopic eyes had visual acuity worse than 20/60. However, two amblyopic patients had strabismus in addition to anisometropia, but the prime reason of both conditions was anisometropia. While none of the case of bilateral

Age (yrs) Hypermetropia Myopia High myopia Total (%) M F M F M F

21-25 38 21 48 25 7 4 143 (27.23) 26-30 29 17 65 27 5 4 147 (28.00) 31-35 27 10 49 32 0 1 119 (22.68) 36-40 27 16 43 26 3 1 116 (22.09) Total 121 64 205 110 15 10 525 (100)

a significantly higher prevalence of myopia than did the women (P<0.001)

the rule astigmatism increased significantly with age (P=0.007).

evaluated.

myopes (P=0.1632).

amblyopia were seen in this study.

Table 1. Age and type of refractive error

P<0.001). The mean refractive error was 0.75D.

Amblyopia is a frequent cause of unilateral or bilateral blindness. The prevalence of amblyopia ranges from 0.73% to 3.06%7 in previous studies. However, the epidemiology of amblyopia among this region of Asia is not well described and may be different from other because of difference in distribution of refractive error or strabismus.

**AIM:** To assess the incidence of refractive error and associated amblyopia among young adult.

#### **2. Methodology**

#### **2.1 Subjects**

This six months study was conducted from June 2008 to November 2008 at tertiary referral center Liaquat University Eye Hospital, Hyderabad Sindh, Pakistan. Three thousand four hundred fifty two patients were included and examined in out patients department with age ranged from 20-40 years. The proportion of men and women was 1:0.54. Both rural and urban residents were evaluated. After taking written consent all subjects underwent a comprehensive ophthalmic examination, and a standardized form was used to extract the data, including the following variables: demographic information, best corrected visual acuity, types of refractive error including myopia, hypermetropia, astigmatism and amblyopia.

#### **2.2 Methods**

Monocular visual acuity was determined with current spectacle prescription if any. Pinhole acuity was assessed in eyes with presenting visual acuity <20/20. Non-cycloplegic autorefraction followed by subjective refinements was performed in all subjects. The best corrected visual acuity was recorded. Refraction data was based on subjective refraction. Only the right phakic eye of each subject was considered for refractive error evaluation and amblyopia evaluated bilaterally.

Amblyopia was defined as best-corrected visual acuity of 20/40 or worse in the absence of any pathological cause. Hypermetropia was defined as a SE greater than +0.5 diopter sphere (DS)17-21. Emetropia was defined as a SE between -0.50 and +0.50 DS20. Myopia was defined as a SE worse than -0.50 DS17--21 and a SE or worse than -5.00 DS19 was classified as high myopia. Astigmatism correction was prescribed in minus cylinder format, and astigmatism was defined as cylindrical error worse than -0.50 diopter cylinder (DC) in any axis. The axis of any cylinder component was classified as with the rule (WTR) if the minus cylinder axis was within 15o of 180o, against the rule (ATR) for minus cylinder axis within 15o of 90o, or oblique (other than WTR or ATR)22.

#### **3. Results**

Of the 3452 patients, 847 (24.54 %) patients had best corrected visual acuity 20/40 or better and remaining 2605 (75.46%) had less than 20/40 due to different anterior and posterior segment eye pathologies, or amblyopia.

Out of the 847 patients 525 (15.20 %) were phakic in right eye, and remaining 322 (9.32%) were pseudophakic. For refractive error the result was analyzed for only 15.20%

Amblyopia is a frequent cause of unilateral or bilateral blindness. The prevalence of amblyopia ranges from 0.73% to 3.06%7 in previous studies. However, the epidemiology of amblyopia among this region of Asia is not well described and may be different from other

**AIM:** To assess the incidence of refractive error and associated amblyopia among young

This six months study was conducted from June 2008 to November 2008 at tertiary referral center Liaquat University Eye Hospital, Hyderabad Sindh, Pakistan. Three thousand four hundred fifty two patients were included and examined in out patients department with age ranged from 20-40 years. The proportion of men and women was 1:0.54. Both rural and urban residents were evaluated. After taking written consent all subjects underwent a comprehensive ophthalmic examination, and a standardized form was used to extract the data, including the following variables: demographic information, best corrected visual acuity, types of refractive error including myopia, hypermetropia, astigmatism and

Monocular visual acuity was determined with current spectacle prescription if any. Pinhole acuity was assessed in eyes with presenting visual acuity <20/20. Non-cycloplegic autorefraction followed by subjective refinements was performed in all subjects. The best corrected visual acuity was recorded. Refraction data was based on subjective refraction. Only the right phakic eye of each subject was considered for refractive error evaluation and

Amblyopia was defined as best-corrected visual acuity of 20/40 or worse in the absence of any pathological cause. Hypermetropia was defined as a SE greater than +0.5 diopter sphere (DS)17-21. Emetropia was defined as a SE between -0.50 and +0.50 DS20. Myopia was defined as a SE worse than -0.50 DS17--21 and a SE or worse than -5.00 DS19 was classified as high myopia. Astigmatism correction was prescribed in minus cylinder format, and astigmatism was defined as cylindrical error worse than -0.50 diopter cylinder (DC) in any axis. The axis of any cylinder component was classified as with the rule (WTR) if the minus cylinder axis was within 15o of 180o, against the rule (ATR) for minus cylinder axis within 15o of 90o, or

Of the 3452 patients, 847 (24.54 %) patients had best corrected visual acuity 20/40 or better and remaining 2605 (75.46%) had less than 20/40 due to different anterior and posterior

Out of the 847 patients 525 (15.20 %) were phakic in right eye, and remaining 322 (9.32%) were pseudophakic. For refractive error the result was analyzed for only 15.20%

because of difference in distribution of refractive error or strabismus.

adult.

**2. Methodology**

**2.1 Subjects**

amblyopia.

**2.2 Methods**

**3. Results**

amblyopia evaluated bilaterally.

oblique (other than WTR or ATR)22.

segment eye pathologies, or amblyopia.

phakic ametropic patients. While for amblyopia all patients who met the criteria were evaluated.

There were 341 (64.95% of phakic ametropic patients) male and 184 (35.05%) were female. The age range from 20 to 40 years **(Table 1),** mean age being 26±3.9 years. The mean age of men and women was 28±3.9 and 24±6.3 years respectively (statistically significant at P<0.001). The mean refractive error was 0.75D.

Hypermetropia was found in 185 (35.24% of phakic ametropic) patients (Table 1). The mean age of hypermetropia was 26.31±4.51 years. Which was not significantly different from that of entire population (P=0.5476). There were 121 men (23.04% of total ametropic) and 64 women (12.19%). Man had significantly higher prevalence of hypermetropia than women (P<0.001).

Three hundred and fifteen (60% of phakic ametropic) patients had myopia (Table 1). The mean age of myopes was 23.69±3.98 years. Which was significantly lower than the entire population (P<0.001). There were 205 (39.05%) men and 110 (20.95%) women. The man had a significantly higher prevalence of myopia than did the women (P<0.001)

Twenty five (4.76%) patients of the study population were high myopes (Table 1). Among which 15 patients were males and 10 were females. The mean age among high myopes was 22. 50±3.25 years. Which was also significantly lower than the entire population (P<0.0002). However there was no significant different between the mean age of myopes and high myopes (P=0.1632).

Two hundred and fifteen (25.38 % of phakic ametropic) patients had astigmatism worse than –0.5 DC. The males were 134 (62.32%) of total astigmatic patients and remaining were females. The man had a significantly higher prevalence of astigmatism than women (P<0.001). One hundred and forty two (66.04%) patients had ATR astigmatism, 52 (24.18%) had WTR astigmatism and 21 (9.76%) had oblique astigmatism. The prevalence of against the rule astigmatism increased significantly with age (P=0.007).

The incidence of associated unilateral amblyopia was in 19 (3.62%) of phakic ametropic patients (Table 2). Ten (52.63%) patients were male and 09 (47.37%) were females. Amblyopia was not found to be significantly different by age (p=0.1312) group and gender (p=0.1211). Anisometropia was more common in amblyopic cases (41.75%) compared to the normal population (5.91%), and 69% of amblyopic eyes had visual acuity worse than 20/60. However, two amblyopic patients had strabismus in addition to anisometropia, but the prime reason of both conditions was anisometropia. While none of the case of bilateral amblyopia were seen in this study.

Table 1. Age and type of refractive error

Incidence of Refractive Error and Amblyopia Among Young Adults – A Hospital Based Study 139

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vision impairment. *Arch Ophthalmol.* 2000;118:264–269.

**5. References**

2002;120:613–619.

332.

*Ophthalmology.* 2001;108:960–967.

Australia. *Ophthalmic Epdimol* .2000;7:249-58.

chromosome7q36. *J Med Genet*. 2002;39:118–124.

*Invest Ophthalmol Vis Sci*. 1994;35:4344–4347.

Norway. *Acta Ophthalmol*. 1992;70:317-322.

in Singapore. *Optom Vis Sci.* 2001;78:234–239.

Taiwan in 1995. *Optom Vis Sci*. 1999;76:275–281.

chromosome 18p. *Am J Hum Genet.*1998;63:109–119.

Study. *Invest Ophthalmol Vis Sci.* 1999;40:2810–2818.

Table 2. Demography of amblyopia

#### **4. Discussion**

The incidence of hypermetropia in this study was 35.24% of total 525 phakic ametropic patients. In contrast to Andhra Paeye disease study (APEDS)**13**, Barbados eye study**20**, and several other studies**17,18** hypermetropia decrease with increasing age in our study

The incidence of myopia and high myopia in this study was 60% and 4.76% of the phakic ametropic patients and decreased with age. The Attebok et al**18**, Wang et al**11**, Katz et al**<sup>17</sup>** reported a significant trends of decreasing myopia with age. However the Chennai glaucoma study**3**, Barbodos**20** study reported increase of myopia with age and also have an association of nuclear sclerosis with myopia. Saw**22**, Guggenheim et al**23** and Dan et al**<sup>24</sup>** reported environmental influence such as near work, night lighting and ultraviolet exposure may be responsible for ageing of the crystalline lens and associated myopia. In contrast to population based studies from Australia**18**, Singapore**19**, and Indonesia**25**, the incidence of myopia was more in males than females in our study.

The incidence of astigmatism in this study was 25.38% and increased significantly with age. The same has been reported from Chenni**3**, Australia**18**, Singapore**19**, and Indonesia**25**. ATR astigmatism in this study was predominant that made the 66.04% of the total ametropic patients. In relation to the Chennai**3** study the incidence of ATR astigmatism significantly increased with age and WTR astigmatism decreased with age in our study. Gudmundsdottir et al**26**, Pensyl et al**22** and Goss et al**28** reported same and the reason for this could be increased lid laxity with age causing flattening of vertical corneal meridian thereby decreasing WTR astigmatism and increased ATR astigmatism.

In this study the incidence, of associated amblyopia was 3.62% of phakic ametropic patients, which was less than Goel B.S**29** study in which amblyopia was reported 5.97%. One thing common in both were higher rate of amblyopia in ametropic then general population. In contrast to Karki JKD**30** study amblyopia was not found significantly different by age and gender in this study.

In conclusion, 15.20% of people had refractive error and 3.62% has the amblyopia. The prevalence of myopia was 60% and decreased with age. Hypermetropia was more common among men. The prevalence of astigmatism was 25.38%. It was interesting to note that against the rule astigmatism in contrast to other studies was observed more often (66.04%) in this study. Though the above study represent the regional population of limited age (20- 40 years), but the differences in the pattern of refractive error in this study leads us to believe that genetic, racial, environmental and occupational influences may play an important role.

#### **5. References**

138 Advances in Ophthalmology

Age (yrs) Frequency of amblyopia Total ( %) Male Female

21 -25 2 2 4 (21.04) 26 -30 3 2 5 (26.32) 31 -35 2 3 5 (26.32) 36 -40 3 2 5 (26.32) Total 10 9 19 (100)

The incidence of hypermetropia in this study was 35.24% of total 525 phakic ametropic patients. In contrast to Andhra Paeye disease study (APEDS)**13**, Barbados eye study**20**, and

The incidence of myopia and high myopia in this study was 60% and 4.76% of the phakic ametropic patients and decreased with age. The Attebok et al**18**, Wang et al**11**, Katz et al**<sup>17</sup>** reported a significant trends of decreasing myopia with age. However the Chennai glaucoma study**3**, Barbodos**20** study reported increase of myopia with age and also have an association of nuclear sclerosis with myopia. Saw**22**, Guggenheim et al**23** and Dan et al**<sup>24</sup>** reported environmental influence such as near work, night lighting and ultraviolet exposure may be responsible for ageing of the crystalline lens and associated myopia. In contrast to population based studies from Australia**18**, Singapore**19**, and Indonesia**25**, the incidence of

The incidence of astigmatism in this study was 25.38% and increased significantly with age. The same has been reported from Chenni**3**, Australia**18**, Singapore**19**, and Indonesia**25**. ATR astigmatism in this study was predominant that made the 66.04% of the total ametropic patients. In relation to the Chennai**3** study the incidence of ATR astigmatism significantly increased with age and WTR astigmatism decreased with age in our study. Gudmundsdottir et al**26**, Pensyl et al**22** and Goss et al**28** reported same and the reason for this could be increased lid laxity with age causing flattening of vertical corneal meridian thereby

In this study the incidence, of associated amblyopia was 3.62% of phakic ametropic patients, which was less than Goel B.S**29** study in which amblyopia was reported 5.97%. One thing common in both were higher rate of amblyopia in ametropic then general population. In contrast to Karki JKD**30** study amblyopia was not found significantly different by age and

In conclusion, 15.20% of people had refractive error and 3.62% has the amblyopia. The prevalence of myopia was 60% and decreased with age. Hypermetropia was more common among men. The prevalence of astigmatism was 25.38%. It was interesting to note that against the rule astigmatism in contrast to other studies was observed more often (66.04%) in this study. Though the above study represent the regional population of limited age (20- 40 years), but the differences in the pattern of refractive error in this study leads us to believe that genetic, racial, environmental and occupational influences may play an

several other studies**17,18** hypermetropia decrease with increasing age in our study

Table 2. Demography of amblyopia

myopia was more in males than females in our study.

decreasing WTR astigmatism and increased ATR astigmatism.

**4. Discussion**

gender in this study.

important role.

**9**

*New Zealand*

**Myopia, Light and Circadian Rhythms**

John R. Phillips, Simon Backhouse and Andrew V. Collins *Department of Optometry and Vision Science, The University of Auckland*

Myopia has been investigated scientifically for over a century but the search for an effective remedy has been manifestly unsuccessful. The prevalence of myopia in developed societies has now risen to about 30% in USA (Vitale, Sperduto et al. 2009) and up to 70% in some Asian centres (Lin, Shih et al. 2004). In addition to the socio-economic burden of providing optical corrections for myopia, common myopia limits career choice and increases the risk of glaucoma and cataract. High myopia also increases the risk of retinal detachment, chorioretinal degeneration and subsequent visual impairment (Saw, Gazzard et al. 2005). Both genetic and environmental factors have been implicated in the aetiology of myopia. Children with myopic parents have a higher than normal risk of developing myopia (Mutti, Mitchell et al. 2002) and twin studies show a higher level of concordance of common myopia in monozygotic compared to dizygotic twins (Dirani, Chamberlain et al. 2006). However, the rapid rise in myopia prevalence over recent decades argues strongly that changing

In the early 1900s Fuchs asserted '*The following means are advised to put a stop to the extension of myopia in schools. First, the excess of work which many scholars have at present to struggle with should be reduced'*…. '*Instruction ought not to begin too early (if possible not before the completion of the sixth year) and more time should be allotted to bodily exercise, especially in the open air, than has hitherto been the case.*' (Duane 1919). Although the long-held view that myopia primarily results from too much near-work is now regarded as an over-simplification, several recent studies support Fuchs's idea that outdoor activity may have an important role in protecting

There have been many attempts to inhibit the progression of myopia in children. More recently, these have included treatment with antimuscarinic agents such as atropine eyedrops (Chua, Balakrishnan et al. 2006) and optical devices including multifocal spectacle lenses (Gwiazda, Hyman et al. 2003), dual-focus contact lenses (Anstice and Phillips 2011) and orthokeratology (Kakita, Hiraoka et al. 2011). However, none of these approaches entirely arrests myopia progression in the long term and the vast majority of myopia is managed by optical correction alone. Although conventional optical corrections including refractive surgery restore acuity, they do not prevent the abnormal enlargement of the myopic eye, so children with myopia remain at increased risk of ocular disease later in life. In this review we examine evidence from human and animal studies that one aspect of outdoor activity, namely exposure to natural light, may reduce the prevalence and

environmental factors also play an important role in the aetiology of myopia.

**1. Introduction**

against myopia.

### **Myopia, Light and Circadian Rhythms**

John R. Phillips, Simon Backhouse and Andrew V. Collins *Department of Optometry and Vision Science, The University of Auckland New Zealand*

#### **1. Introduction**

140 Advances in Ophthalmology

[18] Attebo K, Ivers RQ, Mitchell P. Refractive errors in an older population: The Blue

[19] Wong TY, Foster PJ, Hee J, Pin Ng T, Tielsch JM, Chew SJ, Johnson GJ and Seah SKL.

[20] Wu SY, Nemesure B, Leske MC. Refractive errors in a black adult population: The

[21] Gwiazda J, Scheiman M, Mohindra I, Held R. Astigmatism in children: changes in axis and amount from birth to six years. *Invest Ophthalmol Vis Sci.* 1984;25:88–92. [22] Saw SM. A synopsis of the prevalence rates and enviromental risk factors for myopia.

[23] Guggenheim JA, Hill C, Yam TF. Myopia, genetics and ambient lighting at night in a

[24] Dong X, Dong, Ayala M, Lofgren S, Soderberg PG. Ultraviolet radiation induced

[25] Saw SM, Gazzard G,Koh D, Farook M, Widjaja D, Lee J, Donald T. H. Tan DTH .

[26] Gudmundsdottir E, Jonasson F, Jonsson V, Stefansson E, Sasaki H, Sasaki K. "With the rule" astigmatism is not the rule in the elderly. *Acta Ophthalmol.* 2000;78:642-646. [27] Pensyl CD, Harrson RA, Simpson P, Waterbor JW. Distribution of astigmatism among

[28] Goss DA. Meridonial Analysis of with the rule astigmatism in Oklahoma *Indians.*

[29] Goel.B.S, Amblyopia: modern concept and management. In current topics in

[30] Karki KJD Prevalence of Amblyopia in ametropia in clinical set up. *Katmandu*

ophthalmology. I Gupta, A.K (ED), B.I Churchil Livingstone New Dehli, 1993, p

sioux Indians in South Dakota. *J Am Optom Assoc*. 1997;68:425-431.

catract: age and maximum acceptable dosage. *Invest Ophthalmol Vis Sci*.

Prevalence rates of refractive errors in Sumarta, Indonesia. *Invest Ophthalmol Vis*

Barbados Eye Study. *Invest Ophthalmol Vis Sci.* 1999;40:2179–2184.

Prevalence and risk factors of refractive errors in adult Chinese in Singapore. *Invest*

Mountains eye study. *Ophthalmology.* 1999;106:1066–1072.

*Ophthalmol Vis Sci.* 2000;41:2486–2494.

*Clin Exp Optom*. 2003;86:289-294.

2003;44:1150-1154.

145.

*Sci.* 2002;43:3174-3180.

*Optom Vis Sci.* 1989;66:281-287.

*University Medical Journal*. 2006;4;470-73.

UK sample. *Br J Ophthalmol*. 2003;87:580-582.

Myopia has been investigated scientifically for over a century but the search for an effective remedy has been manifestly unsuccessful. The prevalence of myopia in developed societies has now risen to about 30% in USA (Vitale, Sperduto et al. 2009) and up to 70% in some Asian centres (Lin, Shih et al. 2004). In addition to the socio-economic burden of providing optical corrections for myopia, common myopia limits career choice and increases the risk of glaucoma and cataract. High myopia also increases the risk of retinal detachment, chorioretinal degeneration and subsequent visual impairment (Saw, Gazzard et al. 2005). Both genetic and environmental factors have been implicated in the aetiology of myopia. Children with myopic parents have a higher than normal risk of developing myopia (Mutti, Mitchell et al. 2002) and twin studies show a higher level of concordance of common myopia in monozygotic compared to dizygotic twins (Dirani, Chamberlain et al. 2006). However, the rapid rise in myopia prevalence over recent decades argues strongly that changing environmental factors also play an important role in the aetiology of myopia.

In the early 1900s Fuchs asserted '*The following means are advised to put a stop to the extension of myopia in schools. First, the excess of work which many scholars have at present to struggle with should be reduced'*…. '*Instruction ought not to begin too early (if possible not before the completion of the sixth year) and more time should be allotted to bodily exercise, especially in the open air, than has hitherto been the case.*' (Duane 1919). Although the long-held view that myopia primarily results from too much near-work is now regarded as an over-simplification, several recent studies support Fuchs's idea that outdoor activity may have an important role in protecting against myopia.

There have been many attempts to inhibit the progression of myopia in children. More recently, these have included treatment with antimuscarinic agents such as atropine eyedrops (Chua, Balakrishnan et al. 2006) and optical devices including multifocal spectacle lenses (Gwiazda, Hyman et al. 2003), dual-focus contact lenses (Anstice and Phillips 2011) and orthokeratology (Kakita, Hiraoka et al. 2011). However, none of these approaches entirely arrests myopia progression in the long term and the vast majority of myopia is managed by optical correction alone. Although conventional optical corrections including refractive surgery restore acuity, they do not prevent the abnormal enlargement of the myopic eye, so children with myopia remain at increased risk of ocular disease later in life.

In this review we examine evidence from human and animal studies that one aspect of outdoor activity, namely exposure to natural light, may reduce the prevalence and

Myopia, Light and Circadian Rhythms 143

completed by parents of children aged 2-16 years (median 8 years) on their child's nighttime light-exposure, reported a strong, dose-dependent association between the prevalence of myopia at the time of the study and night-time lighting conditions experienced by the children before the age of 2 years. Remarkably, 55% of children who slept with the room lights on developed myopia whereas 34% of children who slept with night-lights, and 10% of children who slept in darkness, had developed myopia at the time of the study. On the statistical strength of their findings, the authors suggested that the absence of a daily period of darkness could be a precipitating factor in the later development of myopia. A similar study (Czepita, Goslawski et al. 2004) also reported increased prevalence of myopia in children who had experienced ambient light at night before the age of 2 years. However, several studies in different parts of the world, also based on parental questionnaires, have reported no difference in prevalence of myopia in children sleeping in darkness or with ambient light at night before the age of 2 years (USA (Gwiazda, Ong et al. 2000; Zadnik, Jones et al. 2000), Asia (Saw, Zhang et al. 2002), UK (Guggenheim, Hill et al. 2003)). Both studies from the USA found associations between the number of myopic parents in the family and nursery lighting experienced by the child before the age of 2 years, suggesting that the results obtained by Quinn et al. may have been confounded by the uncontrolled effect of parental myopia. However, exposure to light at night may also affect the refractive development of young adults. A study of law students (Loman, Quinn et al. 2002) reported an association between increased myopia progression during law school with less daily

Further evidence for the influence of light exposure early in life on later refractive error comes from studies on the effect of season of birth (and by implication perinatal photoperiod) on adult refractive status. In a study population of 276,911 adolescents born in Israel (Mandel, Grotto et al. 2008), moderate and severe myopia prevalence varied by birth month, with the summer months (June/July) being associated with a higher myopia prevalence than the winter months (December/January). Moreover, increasing photoperiod was associated with increasing myopia prevalence in a dose-dependent pattern. Mild myopia was not associated with either season of birth or photoperiod. Birth during the summer was also found to be significantly associated with high myopia in a UK study (McMahon, Zayats et al. 2009) but no association was found between postnatal photoperiod and prevalence of myopia in adulthood. Seasonal variations in photoperiod are particularly extreme above the Arctic Circle. However, in a study of Finnish military conscripts (Vannas, Ying et al. 2003) no associations between myopia prevalence and birth month, global irradiance at birth month or daily hours of darkness during the birth month were found, although there was a trend towards higher prevalence of myopia among conscripts living

The human data on light exposure and refractive development suggest that increased daytime outdoor light exposure is associated with reduced myopia prevalence whereas increased night-time exposure to artificial light may be associated with increased myopia development – a case of day-light good, night-light bad. The remainder of this review examines the underlying processes which could explain why perturbations in the daily

light-dark cycle may affect eye growth and refractive development.

exposure to darkness (i.e. more artificial light at night).

**2.3 Season of birth**

above the Arctic Circle.

progression of myopia. We focus on the timing of light exposure in relation to the circadian cycle and on the potential roles of dopamine and melatonin in control of ocular growth and refractive development.

#### **2. Human myopia and light**

#### **2.1 Outdoor activity**

Current epidemiological research, as quantified by validated surveys, supports the idea that time spent in outdoor activities has a beneficial effect in reducing myopia prevalence in children and young adults (Jones, Sinnott et al. 2007; Rose, Morgan et al. 2008a; Rose, Morgan et al. 2008b). Whether the effect derives predominantly from increased natural light exposure or increased activity (e.g. sport) or from greater viewing distances outdoors has yet to be ascertained. An association between greater physical activity and reduced myopia progression has been reported in university students (Jacobsen, Jensen et al. 2008) although this association may have been confounded by other factors in the outdoor environment where much of the activity took place. Other studies have found an association between increased outdoor hours and lower myopia even when time spent playing sport outdoors was excluded (Rose, Morgan et al. 2008a). Moreover, indoor sport appears to have no beneficial effect (Rose, Morgan et al. 2008a; Dirani, Tong et al. 2009) suggesting that physical activity alone cannot account for the effect of outdoor activity. Whether the increased viewing distance typically associated with being outdoors has a positive effect in reducing myopia is unknown. The idea that time spent outdoors may act beneficially by substituting for time spent in near and mid-working distance activities seems not to be the case (Rose, Morgan et al. 2008a). In relation to distance viewing outdoors, the accommodative demand for viewing beyond about 6 metres is minimal. Indoor environments, particularly in city apartments, inevitably restrict viewing distance and typically include low dioptric stimuli for accommodation over the peripheral visual field (Charman 2011). However, the most obvious difference between spending time outdoors and time indoors is in light exposure. The spectral composition of light outdoors includes large amounts of ultraviolet (UV) and infrared (IR) in addition to light in the visible spectrum. Indoors, the UV portion of the spectrum is largely absent and if incandescent lighting is used the composition of the light is often biased towards the red end of the spectrum. Light intensity indoors is rarely more than 800 lux, whereas outdoor light intensity is around 50,000 lux on a sunny, blue-sky day and is rarely less than 5,000 lux, even when overcast. The cumulative light exposure for one hour spent outdoors is thus very much greater than for one hour spent indoors (Backhouse, Ng et al. 2011). This increased light exposure during the day is generally believed to be the most likely basis for the beneficial effect of outdoor activity in reducing myopia prevalence (Rose, Morgan et al. 2008a).

#### **2.2 Light at night**

Between birth and 2 years of age, the normal eye grows very rapidly, with axial length increasing at a rate of about 2 mm/year before slowing to about 0.1 mm/year until the eye reaches adult size (Larsen 1971). It has been suggested that environmental influences acting in this early period of rapid eye growth may potentially affect refractive development later in life. Quinn et al. (Quinn, Shin et al. 1999) investigated the effects of light exposure early in life on refractive status later in childhood. Their study, which was based on a questionnaire

progression of myopia. We focus on the timing of light exposure in relation to the circadian cycle and on the potential roles of dopamine and melatonin in control of ocular growth and

Current epidemiological research, as quantified by validated surveys, supports the idea that time spent in outdoor activities has a beneficial effect in reducing myopia prevalence in children and young adults (Jones, Sinnott et al. 2007; Rose, Morgan et al. 2008a; Rose, Morgan et al. 2008b). Whether the effect derives predominantly from increased natural light exposure or increased activity (e.g. sport) or from greater viewing distances outdoors has yet to be ascertained. An association between greater physical activity and reduced myopia progression has been reported in university students (Jacobsen, Jensen et al. 2008) although this association may have been confounded by other factors in the outdoor environment where much of the activity took place. Other studies have found an association between increased outdoor hours and lower myopia even when time spent playing sport outdoors was excluded (Rose, Morgan et al. 2008a). Moreover, indoor sport appears to have no beneficial effect (Rose, Morgan et al. 2008a; Dirani, Tong et al. 2009) suggesting that physical activity alone cannot account for the effect of outdoor activity. Whether the increased viewing distance typically associated with being outdoors has a positive effect in reducing myopia is unknown. The idea that time spent outdoors may act beneficially by substituting for time spent in near and mid-working distance activities seems not to be the case (Rose, Morgan et al. 2008a). In relation to distance viewing outdoors, the accommodative demand for viewing beyond about 6 metres is minimal. Indoor environments, particularly in city apartments, inevitably restrict viewing distance and typically include low dioptric stimuli for accommodation over the peripheral visual field (Charman 2011). However, the most obvious difference between spending time outdoors and time indoors is in light exposure. The spectral composition of light outdoors includes large amounts of ultraviolet (UV) and infrared (IR) in addition to light in the visible spectrum. Indoors, the UV portion of the spectrum is largely absent and if incandescent lighting is used the composition of the light is often biased towards the red end of the spectrum. Light intensity indoors is rarely more than 800 lux, whereas outdoor light intensity is around 50,000 lux on a sunny, blue-sky day and is rarely less than 5,000 lux, even when overcast. The cumulative light exposure for one hour spent outdoors is thus very much greater than for one hour spent indoors (Backhouse, Ng et al. 2011). This increased light exposure during the day is generally believed to be the most likely basis for the beneficial effect of outdoor activity in reducing myopia prevalence

Between birth and 2 years of age, the normal eye grows very rapidly, with axial length increasing at a rate of about 2 mm/year before slowing to about 0.1 mm/year until the eye reaches adult size (Larsen 1971). It has been suggested that environmental influences acting in this early period of rapid eye growth may potentially affect refractive development later in life. Quinn et al. (Quinn, Shin et al. 1999) investigated the effects of light exposure early in life on refractive status later in childhood. Their study, which was based on a questionnaire

refractive development.

**2.1 Outdoor activity**

(Rose, Morgan et al. 2008a).

**2.2 Light at night**

**2. Human myopia and light**

completed by parents of children aged 2-16 years (median 8 years) on their child's nighttime light-exposure, reported a strong, dose-dependent association between the prevalence of myopia at the time of the study and night-time lighting conditions experienced by the children before the age of 2 years. Remarkably, 55% of children who slept with the room lights on developed myopia whereas 34% of children who slept with night-lights, and 10% of children who slept in darkness, had developed myopia at the time of the study. On the statistical strength of their findings, the authors suggested that the absence of a daily period of darkness could be a precipitating factor in the later development of myopia. A similar study (Czepita, Goslawski et al. 2004) also reported increased prevalence of myopia in children who had experienced ambient light at night before the age of 2 years. However, several studies in different parts of the world, also based on parental questionnaires, have reported no difference in prevalence of myopia in children sleeping in darkness or with ambient light at night before the age of 2 years (USA (Gwiazda, Ong et al. 2000; Zadnik, Jones et al. 2000), Asia (Saw, Zhang et al. 2002), UK (Guggenheim, Hill et al. 2003)). Both studies from the USA found associations between the number of myopic parents in the family and nursery lighting experienced by the child before the age of 2 years, suggesting that the results obtained by Quinn et al. may have been confounded by the uncontrolled effect of parental myopia. However, exposure to light at night may also affect the refractive development of young adults. A study of law students (Loman, Quinn et al. 2002) reported an association between increased myopia progression during law school with less daily exposure to darkness (i.e. more artificial light at night).

#### **2.3 Season of birth**

Further evidence for the influence of light exposure early in life on later refractive error comes from studies on the effect of season of birth (and by implication perinatal photoperiod) on adult refractive status. In a study population of 276,911 adolescents born in Israel (Mandel, Grotto et al. 2008), moderate and severe myopia prevalence varied by birth month, with the summer months (June/July) being associated with a higher myopia prevalence than the winter months (December/January). Moreover, increasing photoperiod was associated with increasing myopia prevalence in a dose-dependent pattern. Mild myopia was not associated with either season of birth or photoperiod. Birth during the summer was also found to be significantly associated with high myopia in a UK study (McMahon, Zayats et al. 2009) but no association was found between postnatal photoperiod and prevalence of myopia in adulthood. Seasonal variations in photoperiod are particularly extreme above the Arctic Circle. However, in a study of Finnish military conscripts (Vannas, Ying et al. 2003) no associations between myopia prevalence and birth month, global irradiance at birth month or daily hours of darkness during the birth month were found, although there was a trend towards higher prevalence of myopia among conscripts living above the Arctic Circle.

The human data on light exposure and refractive development suggest that increased daytime outdoor light exposure is associated with reduced myopia prevalence whereas increased night-time exposure to artificial light may be associated with increased myopia development – a case of day-light good, night-light bad. The remainder of this review examines the underlying processes which could explain why perturbations in the daily light-dark cycle may affect eye growth and refractive development.

Myopia, Light and Circadian Rhythms 145

produced is approximately double that of normal chicks by 42 days. In contrast, tree shrews placed in continuous darkness eventually exhibit a myopic shift in refraction (Norton, Amedo et al. 2006). Although the animals initially stabilise at a low degree of hyperopia following 16 days of normal visual experience after eye opening, a subsequent period of 10 days of continuous darkness results in vitreous elongation and a myopic refraction (Norton, Amedo et al. 2006). While both chicks and tree shrews exhibit ocular growth under constant darkness, the significant corneal flattening which produces hyperopia in chicks does not occur in the tree shrew. Conversely, raising rhesus monkeys in continuous darkness appears to interfere with the emmetropisation process such that they retain their relatively high

Gottlieb et al. (Gottlieb, Fugate-Wentzek et al. 1987) proposed that two mechanisms may combine under dark-rearing in chicks to produce the hyperopic outcome: a visual deprivation mechanism which triggers enlargement of the eye, as occurs in formdeprivation myopia, and a second photoperiod-related mechanism which results in corneal

A phase advance in the cycle of eye growth is found in chicks raised under constant darkness which is associated with an overall increase in axial growth and choroidal thinning (Nickla, Wildsoet et al. 2001). As the rhythms in choroidal thinning and axial growth persist under constant darkness, they must be circadian in origin, rather than simply diurnal in response to external light-dark cycles (Nickla, Wildsoet et al. 2001). Nickla (Nickla 2006) provides further evidence for the role of a phase shift in the temporal relationship between axial length and choroidal thickness cycles in the control of ocular growth in a study comparing recovery from form-deprivation, myopic defocus and hyperopic defocus in chicks. It appears that where the treatment requires a decrease in ocular growth (such as recovery from form-deprivation) the axial length and choroidal rhythms shift into phase. The mechanism by which such a phase shift might influence ocular growth is not certain, although it has been proposed that the variation in thickness of the choroid may regulate diffusion of a signal molecule from the retina to the sclera, or may act as a mechanical scaffolding against the influence of diurnal intra-ocular pressure changes on the sclera

In order to determine the minimum period of darkness within the diurnal light:dark cycle that is required for normal eye growth, Li et al. (Li, Howland et al. 2000) investigated the effect of various periods of darkness from zero (constant light) to a standard 12:12 h light:dark cycle in chicks. They found that at least 4 hours darkness per diurnal cycle produced a normal emmetropisation response in the chick (Li, Howland et al. 2000). Further investigations demonstrated that the 4 hours of darkness was most effective in blocking the effects of excess light exposure when presented in a single period at the same time of day, rather than at random times or as multiple periods totalling 4 hours (Li, Howland et al. 2000). Li et al. (Li, Howland et al. 2000) concluded that this period of darkness may be sufficient to entrain the intrinsic circadian clock of the avian retina (Morgan and Boelen 1996). The requirement for periods of darkness during a diurnal cycle in order to produce normal eye growth in chicks has a potential corollary in humans. As noted earlier, the use of night lights in children's bedrooms under the age of 2 years has been associated with the

hyperopic neonatal refractions (Guyton, Greene et al. 1989).

flattening.

(Nickla 2006).

**3.3 Diurnal modulation of illumination**

development of myopia in later life (Quinn, Shin et al. 1999).

#### **3. Light and animal models of myopia**

Animal studies have shown that a diurnal light:dark photoperiod is required for the normal refractive development of the eye in chicks (Li, Troilo et al. 1995; Stone, Lin et al. 1995), tree shrews (Norton, Amedo et al. 2006) and Rhesus monkeys (Smith, Bradley et al. 2001). In normal chick eyes there is a diurnal growth rhythm in which greatest eye elongation occurs during the day with reduced growth rates at night (Weiss and Schaeffel 1993; Nickla, Wildsoet et al. 1998). The choroid also demonstrates a similar diurnal rhythm in which the choroid thins during the day and thickens at night (Papastergiou, Schmid et al. 1998). In eyes deprived of form vision in order to induce myopia, a phase shift occurs in the relationship between the axial length and choroidal rhythms such that peak axial growth occurs earlier than in normal eyes (Nickla, Wildsoet et al. 1998).

#### **3.1 Effect of constant light**

Rearing chicks under constant light with open eyes produces hyperopia, due to corneal flattening resulting in shallow anterior chambers (Li, Troilo et al. 1995; Stone, Lin et al. 1995). While the anterior chamber becomes shallower, the vitreous chamber lengthens, resulting in no net change in axial length at 2 weeks of age. Continued rearing of chicks in constant light beyond 2 weeks produces macrophthalmos (Oishi, Lauber et al. 1987). The final refractive state may be hyperopic despite the development of significantly deeper vitreous chambers (Li, Troilo et al. 1995). In form-deprived eyes, constant light also produces hyperopia despite overall longer axial lengths and enlarged vitreous chambers in both axial and equatorial directions; (Stone, Lin et al. 1995).

While rearing chicks under continuous light produces hyperopia, the effect is dependent on the level of ambient illumination. Thus, higher light intensities are correlated with higher degrees of hyperopia, lower corneal power and increased vitreous chamber depth. Cohen et al. (Cohen, Belkin et al. 2008) reported that chicks raised under continuous illumination at 10,000 lux for 90 days developed a hyperopic mean refraction of +11.97D, while those raised under 50 lux resulted in an emmetropic mean refraction of +0.63D. An illumination level of 500 lux also produced a relatively high hyperopic outcome of +7.90D. While vitreous chamber depth was positively correlated with light intensity, overall axial length did not vary significantly between groups due to the corneal flattening associated with increasing light intensity, resulting in an overall hyperopic refraction at the moderate and high illumination levels (Cohen, Belkin et al. 2008).

Monkeys raised under continuous light conditions (Smith, Bradley et al. 2001) do not exhibit the increase in ocular growth typically found in the chick. Rhesus monkeys raised under continuous light for 6 months developed hyperopic refractions similar in magnitude to animals raised under normal diurnal light cycles. However, the refractions were more variable in outcome, with some animals developing axial anisometropia and low myopia (Smith, Bradley et al. 2001). The authors cautioned that the animals may have been able to re-establish at least a partial diurnal cycle by shielding their eyes during sleep with their arms, although no significant difference in behaviour was observed (Smith, Bradley et al. 2001).

#### **3.2 Effect of constant darkness**

Rearing chicks in complete darkness also produces hyperopia irrespective of whether a diffusing goggle is worn (Gottlieb, Fugate-Wentzek et al. 1987). The degree of hyperopia

Animal studies have shown that a diurnal light:dark photoperiod is required for the normal refractive development of the eye in chicks (Li, Troilo et al. 1995; Stone, Lin et al. 1995), tree shrews (Norton, Amedo et al. 2006) and Rhesus monkeys (Smith, Bradley et al. 2001). In normal chick eyes there is a diurnal growth rhythm in which greatest eye elongation occurs during the day with reduced growth rates at night (Weiss and Schaeffel 1993; Nickla, Wildsoet et al. 1998). The choroid also demonstrates a similar diurnal rhythm in which the choroid thins during the day and thickens at night (Papastergiou, Schmid et al. 1998). In eyes deprived of form vision in order to induce myopia, a phase shift occurs in the relationship between the axial length and choroidal rhythms such that peak axial growth

Rearing chicks under constant light with open eyes produces hyperopia, due to corneal flattening resulting in shallow anterior chambers (Li, Troilo et al. 1995; Stone, Lin et al. 1995). While the anterior chamber becomes shallower, the vitreous chamber lengthens, resulting in no net change in axial length at 2 weeks of age. Continued rearing of chicks in constant light beyond 2 weeks produces macrophthalmos (Oishi, Lauber et al. 1987). The final refractive state may be hyperopic despite the development of significantly deeper vitreous chambers (Li, Troilo et al. 1995). In form-deprived eyes, constant light also produces hyperopia despite overall longer axial lengths and enlarged vitreous chambers in

While rearing chicks under continuous light produces hyperopia, the effect is dependent on the level of ambient illumination. Thus, higher light intensities are correlated with higher degrees of hyperopia, lower corneal power and increased vitreous chamber depth. Cohen et al. (Cohen, Belkin et al. 2008) reported that chicks raised under continuous illumination at 10,000 lux for 90 days developed a hyperopic mean refraction of +11.97D, while those raised under 50 lux resulted in an emmetropic mean refraction of +0.63D. An illumination level of 500 lux also produced a relatively high hyperopic outcome of +7.90D. While vitreous chamber depth was positively correlated with light intensity, overall axial length did not vary significantly between groups due to the corneal flattening associated with increasing light intensity, resulting in an overall hyperopic refraction at the moderate and high

Monkeys raised under continuous light conditions (Smith, Bradley et al. 2001) do not exhibit the increase in ocular growth typically found in the chick. Rhesus monkeys raised under continuous light for 6 months developed hyperopic refractions similar in magnitude to animals raised under normal diurnal light cycles. However, the refractions were more variable in outcome, with some animals developing axial anisometropia and low myopia (Smith, Bradley et al. 2001). The authors cautioned that the animals may have been able to re-establish at least a partial diurnal cycle by shielding their eyes during sleep with their arms, although no

Rearing chicks in complete darkness also produces hyperopia irrespective of whether a diffusing goggle is worn (Gottlieb, Fugate-Wentzek et al. 1987). The degree of hyperopia

significant difference in behaviour was observed (Smith, Bradley et al. 2001).

**3. Light and animal models of myopia**

**3.1 Effect of constant light**

occurs earlier than in normal eyes (Nickla, Wildsoet et al. 1998).

both axial and equatorial directions; (Stone, Lin et al. 1995).

illumination levels (Cohen, Belkin et al. 2008).

**3.2 Effect of constant darkness**

produced is approximately double that of normal chicks by 42 days. In contrast, tree shrews placed in continuous darkness eventually exhibit a myopic shift in refraction (Norton, Amedo et al. 2006). Although the animals initially stabilise at a low degree of hyperopia following 16 days of normal visual experience after eye opening, a subsequent period of 10 days of continuous darkness results in vitreous elongation and a myopic refraction (Norton, Amedo et al. 2006). While both chicks and tree shrews exhibit ocular growth under constant darkness, the significant corneal flattening which produces hyperopia in chicks does not occur in the tree shrew. Conversely, raising rhesus monkeys in continuous darkness appears to interfere with the emmetropisation process such that they retain their relatively high hyperopic neonatal refractions (Guyton, Greene et al. 1989).

Gottlieb et al. (Gottlieb, Fugate-Wentzek et al. 1987) proposed that two mechanisms may combine under dark-rearing in chicks to produce the hyperopic outcome: a visual deprivation mechanism which triggers enlargement of the eye, as occurs in formdeprivation myopia, and a second photoperiod-related mechanism which results in corneal flattening.

A phase advance in the cycle of eye growth is found in chicks raised under constant darkness which is associated with an overall increase in axial growth and choroidal thinning (Nickla, Wildsoet et al. 2001). As the rhythms in choroidal thinning and axial growth persist under constant darkness, they must be circadian in origin, rather than simply diurnal in response to external light-dark cycles (Nickla, Wildsoet et al. 2001). Nickla (Nickla 2006) provides further evidence for the role of a phase shift in the temporal relationship between axial length and choroidal thickness cycles in the control of ocular growth in a study comparing recovery from form-deprivation, myopic defocus and hyperopic defocus in chicks. It appears that where the treatment requires a decrease in ocular growth (such as recovery from form-deprivation) the axial length and choroidal rhythms shift into phase. The mechanism by which such a phase shift might influence ocular growth is not certain, although it has been proposed that the variation in thickness of the choroid may regulate diffusion of a signal molecule from the retina to the sclera, or may act as a mechanical scaffolding against the influence of diurnal intra-ocular pressure changes on the sclera (Nickla 2006).

#### **3.3 Diurnal modulation of illumination**

In order to determine the minimum period of darkness within the diurnal light:dark cycle that is required for normal eye growth, Li et al. (Li, Howland et al. 2000) investigated the effect of various periods of darkness from zero (constant light) to a standard 12:12 h light:dark cycle in chicks. They found that at least 4 hours darkness per diurnal cycle produced a normal emmetropisation response in the chick (Li, Howland et al. 2000). Further investigations demonstrated that the 4 hours of darkness was most effective in blocking the effects of excess light exposure when presented in a single period at the same time of day, rather than at random times or as multiple periods totalling 4 hours (Li, Howland et al. 2000). Li et al. (Li, Howland et al. 2000) concluded that this period of darkness may be sufficient to entrain the intrinsic circadian clock of the avian retina (Morgan and Boelen 1996). The requirement for periods of darkness during a diurnal cycle in order to produce normal eye growth in chicks has a potential corollary in humans. As noted earlier, the use of night lights in children's bedrooms under the age of 2 years has been associated with the development of myopia in later life (Quinn, Shin et al. 1999).

Myopia, Light and Circadian Rhythms 147

deprivation myopia in chicks (Ashby and Schaeffel 2010) further supporting the hypothesis that this neurotransmitter is intrinsically involved in the control of the emmetropisation mechanism (Ashby and Schaeffel 2010; Mao, Liu et al. 2010; Nickla, Totonelly et al. 2010).

The contribution of the chromatic component of light to refractive development has been investigated in a number of animal models including chicks (Rucker and Wallman 2009), fish (Kroger and Wagner 1996) and guinea pigs (Long, Chen et al. 2009). Guinea pigs raised under long-wavelength light (peak at 760 nm) reportedly develop a significant degree of myopia, associated with a significant increase in vitreous chamber depth, over a period of 4 weeks when compared to animals raised under mixed-wavelength light (unfiltered halogen lamps) (Long, Chen et al. 2009). The myopiagenic effect of long-wavelength light was reversed by allowing the animals to recover under mixed-wavelength light conditions for two weeks, after which there was no significant difference in refraction (Long, Chen et al.

One possible explanation for the effect of wavelength on refractive outcome is based on the intrinsic chromatic aberration of the vertebrate eye (Mandelman and Sivak 1983) which could provide a sign-of-defocus signal for emmetropisation (Flitcroft 1990) as the long and short wavelength components would produce relative hyperopic and myopic defocus of the retinal image respectively. For example, in a comparison of the effects of raising guinea pigs under equiluminant short wavelength light (430 nm) or middle wavelength light (530 nm), Liu et al. (Liu, Qian et al. 2011) demonstrated that after 12 weeks the 530 nm group was less hyperopic due to faster vitreous elongation, while the 430 nm group was more hyperopic following slower vitreous elongation. The difference in refraction between the groups (4.50 D) exceeded the longitudinal chromatic aberration of the guinea pig eye (approximately 1.5 D) at the selected wavelengths, which was possibly due to additional accommodative effects produced by the monochromatic illumination (Seidemann and Schaeffel 2002), or by wavelength-dependent alteration of retinal or retinal pigment epithelium growth signals

The role of illumination level and the requirement for periodic light:dark cycles during normal refractive development points to a role for the intrinsic circadian clock and the associated dopamine-melatonin cycle in the control of eye growth (Cahill and Besharse 1995; Witkovsky 2004; Iuvone, Tosini et al. 2005). The presumed role of circadian rhythms, which persist in constant darkness independent of the diurnal light:dark cycle, is to regulate the timing of biological events so as to optimise the metabolic function and energy use of the

Although the control of the circadian rhythm is a complex, multivariate process, it has been known for some time that light plays a pivotal role (Iuvone, Tosini et al. 2005). The underlying circadian rhythm is controlled by a circadian clock, through the expression of "clock genes" and their products, and entrainment cues known as zeitgebers ("time givers")

organism (Roenneberg and Foster 1997; Levi and Schibler 2007).

**3.5 Chromaticity and refractive development**

2009).

(Liu, Qian et al. 2011).

**4. Light and circadian rhythms**

**4.1 The circadian pacemaker**

Diurnal modulation of ambient illumination rather than the need for periods of total darkness may be the significant requirement for normal emmetropisation in chicks. Liu et al. (Liu, Pendrak et al. 2004) reared chicks under light:dark, light:dim and constant light cycles with the aim of investigating the effect of ambient lighting at night on emmetropisation. The irradiance of the light phase was 1500 W/cm2, while the dim phase varied between 0.01 and 500 W/cm2. The eyes of chicks raised under light:dark and light:dim cycles had comparable ocular refractions and dimensions. Conversely, rearing under constant light levels from 1 W/cm2 (~0.3 lux) to 1500 W/cm2 (~500 lux) produced the typical shallow anterior chamber and hyperopic shift in refraction as found previously in chicks. These results imply that the modulation of light levels during a diurnal cycle may be of more importance in the maintenance of the normal emmetropisation response than the absolute light (or dark) levels. Consequently, the use of light:dim diurnal cycles may be a more pertinent paradigm for study as it more closely approximates the typical urban environment with artificial lighting at night (Liu, Pendrak et al. 2004).

#### **3.4 Amplitude modulation of illumination**

Recent animal investigations support the fundamental hypothesis that light exposure is the mediator of the antimyopiagenic effect of outdoor activity (Rose, Morgan et al. 2008a). Experiments in chicks have shown that exposure to high ambient light levels, either artificial or natural, modifies the development of experimental myopia due to either visual form deprivation using translucent occluders, or induced defocus using spectacle lenses (Ashby, Ohlendorf et al. 2009; Ashby and Schaeffel 2010). While exposure to high illumination levels of 15,000 lux for 5 hours per day significantly reduced form-deprivation myopia by around 60%, in lens-induced myopia the rate of compensation for the induced defocus was modified, but not the final degree of refractive error produced (Ashby and Schaeffel 2010). The normal emmetropisation process in chicks can also be directly influenced by ambient light levels: raising animals under low light levels (50 lux) produced myopic refractive outcomes on average, while high light levels (10,000 lux) produced hyperopic refractive outcomes (Cohen, Belkin et al. 2011).

In form-deprivation experiments in chicks, exposure to high artificial light (15,000 lux) indoors or natural light (30,000 lux) outdoors for 15 minutes per day with occluders removed was sufficient to produce a statistically significant decrease in axial myopia beyond that produced by the removal of the occluders under normal laboratory light levels (500 lux) (Ashby, Ohlendorf et al. 2009). The antimyopiagenic effect of high illumination levels was also demonstrated under constant occluder wear conditions where a significant decrease in axial myopia development was also demonstrated in chicks raised under 15,000 lux for 6 hours per day when compared to animals raised under 50 or 500 lux (Ashby, Ohlendorf et al. 2009). As the antimyopiagenic effect occurred during continuous occluder wear the authors conclude that the effect cannot be due to a reduction in image blur resulting from pupil constriction as these animals did not receive clear form vision at any time in the occluded eye. It has been suggested that high ambient illumination levels may affect the diurnal variation in retinal dopamine, which is disrupted in form-deprivation in chicks (Weiss and Schaeffel 1993), with the proposal that the chick retina has a graded release of dopamine under high illumination levels which results in a retardation of myopia development (Ashby, Ohlendorf et al. 2009). The intra-vitreal administration of a dopamine antagonist (spiperone) blocked the protective effect of high illumination levels against form-

Diurnal modulation of ambient illumination rather than the need for periods of total darkness may be the significant requirement for normal emmetropisation in chicks. Liu et al. (Liu, Pendrak et al. 2004) reared chicks under light:dark, light:dim and constant light cycles with the aim of investigating the effect of ambient lighting at night on emmetropisation. The irradiance of the light phase was 1500 W/cm2, while the dim phase varied between 0.01 and 500 W/cm2. The eyes of chicks raised under light:dark and light:dim cycles had comparable ocular refractions and dimensions. Conversely, rearing under constant light levels from 1 W/cm2 (~0.3 lux) to 1500 W/cm2 (~500 lux) produced the typical shallow anterior chamber and hyperopic shift in refraction as found previously in chicks. These results imply that the modulation of light levels during a diurnal cycle may be of more importance in the maintenance of the normal emmetropisation response than the absolute light (or dark) levels. Consequently, the use of light:dim diurnal cycles may be a more pertinent paradigm for study as it more closely approximates the typical urban environment

Recent animal investigations support the fundamental hypothesis that light exposure is the mediator of the antimyopiagenic effect of outdoor activity (Rose, Morgan et al. 2008a). Experiments in chicks have shown that exposure to high ambient light levels, either artificial or natural, modifies the development of experimental myopia due to either visual form deprivation using translucent occluders, or induced defocus using spectacle lenses (Ashby, Ohlendorf et al. 2009; Ashby and Schaeffel 2010). While exposure to high illumination levels of 15,000 lux for 5 hours per day significantly reduced form-deprivation myopia by around 60%, in lens-induced myopia the rate of compensation for the induced defocus was modified, but not the final degree of refractive error produced (Ashby and Schaeffel 2010). The normal emmetropisation process in chicks can also be directly influenced by ambient light levels: raising animals under low light levels (50 lux) produced myopic refractive outcomes on average, while high light levels (10,000 lux) produced hyperopic refractive

In form-deprivation experiments in chicks, exposure to high artificial light (15,000 lux) indoors or natural light (30,000 lux) outdoors for 15 minutes per day with occluders removed was sufficient to produce a statistically significant decrease in axial myopia beyond that produced by the removal of the occluders under normal laboratory light levels (500 lux) (Ashby, Ohlendorf et al. 2009). The antimyopiagenic effect of high illumination levels was also demonstrated under constant occluder wear conditions where a significant decrease in axial myopia development was also demonstrated in chicks raised under 15,000 lux for 6 hours per day when compared to animals raised under 50 or 500 lux (Ashby, Ohlendorf et al. 2009). As the antimyopiagenic effect occurred during continuous occluder wear the authors conclude that the effect cannot be due to a reduction in image blur resulting from pupil constriction as these animals did not receive clear form vision at any time in the occluded eye. It has been suggested that high ambient illumination levels may affect the diurnal variation in retinal dopamine, which is disrupted in form-deprivation in chicks (Weiss and Schaeffel 1993), with the proposal that the chick retina has a graded release of dopamine under high illumination levels which results in a retardation of myopia development (Ashby, Ohlendorf et al. 2009). The intra-vitreal administration of a dopamine antagonist (spiperone) blocked the protective effect of high illumination levels against form-

with artificial lighting at night (Liu, Pendrak et al. 2004).

**3.4 Amplitude modulation of illumination**

outcomes (Cohen, Belkin et al. 2011).

deprivation myopia in chicks (Ashby and Schaeffel 2010) further supporting the hypothesis that this neurotransmitter is intrinsically involved in the control of the emmetropisation mechanism (Ashby and Schaeffel 2010; Mao, Liu et al. 2010; Nickla, Totonelly et al. 2010).

#### **3.5 Chromaticity and refractive development**

The contribution of the chromatic component of light to refractive development has been investigated in a number of animal models including chicks (Rucker and Wallman 2009), fish (Kroger and Wagner 1996) and guinea pigs (Long, Chen et al. 2009). Guinea pigs raised under long-wavelength light (peak at 760 nm) reportedly develop a significant degree of myopia, associated with a significant increase in vitreous chamber depth, over a period of 4 weeks when compared to animals raised under mixed-wavelength light (unfiltered halogen lamps) (Long, Chen et al. 2009). The myopiagenic effect of long-wavelength light was reversed by allowing the animals to recover under mixed-wavelength light conditions for two weeks, after which there was no significant difference in refraction (Long, Chen et al. 2009).

One possible explanation for the effect of wavelength on refractive outcome is based on the intrinsic chromatic aberration of the vertebrate eye (Mandelman and Sivak 1983) which could provide a sign-of-defocus signal for emmetropisation (Flitcroft 1990) as the long and short wavelength components would produce relative hyperopic and myopic defocus of the retinal image respectively. For example, in a comparison of the effects of raising guinea pigs under equiluminant short wavelength light (430 nm) or middle wavelength light (530 nm), Liu et al. (Liu, Qian et al. 2011) demonstrated that after 12 weeks the 530 nm group was less hyperopic due to faster vitreous elongation, while the 430 nm group was more hyperopic following slower vitreous elongation. The difference in refraction between the groups (4.50 D) exceeded the longitudinal chromatic aberration of the guinea pig eye (approximately 1.5 D) at the selected wavelengths, which was possibly due to additional accommodative effects produced by the monochromatic illumination (Seidemann and Schaeffel 2002), or by wavelength-dependent alteration of retinal or retinal pigment epithelium growth signals (Liu, Qian et al. 2011).

#### **4. Light and circadian rhythms**

The role of illumination level and the requirement for periodic light:dark cycles during normal refractive development points to a role for the intrinsic circadian clock and the associated dopamine-melatonin cycle in the control of eye growth (Cahill and Besharse 1995; Witkovsky 2004; Iuvone, Tosini et al. 2005). The presumed role of circadian rhythms, which persist in constant darkness independent of the diurnal light:dark cycle, is to regulate the timing of biological events so as to optimise the metabolic function and energy use of the organism (Roenneberg and Foster 1997; Levi and Schibler 2007).

#### **4.1 The circadian pacemaker**

Although the control of the circadian rhythm is a complex, multivariate process, it has been known for some time that light plays a pivotal role (Iuvone, Tosini et al. 2005). The underlying circadian rhythm is controlled by a circadian clock, through the expression of "clock genes" and their products, and entrainment cues known as zeitgebers ("time givers")

Myopia, Light and Circadian Rhythms 149

for the production of melatonin are active within the pineal gland, which is the main site of production (Axelrod 1974; Zawilska, Skene et al. 2009). The first step is the conversion of the dietary amino acid tryptophan to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase (TPH); the second step involves the conversion of 5-hydroxytryptophan to serotonin via the enzyme aromatic L-amino acid decarboxylase (AADC); serotonin is converted in the third step to N-acetylserotonin by the enzyme arylalkylamine-Nacetyltransferase (AANAT); the final step is the O-methylation of N-acetylserotonin to melatonin by the enzyme hydroxyindole-O-methyltransferase (HIOMT). The rate limiting enzyme in the production of melatonin is widely thought to be AANAT, although recent work suggests that HIOMT may be the crucial limiting factor (Liu and Borjigin 2005). The precursor components of melatonin synthesis also show inherent circadian rhythms of production (Axelrod 1974). The retina is another significant producer of melatonin in some animals, providing the basis for a peripheral clock in addition to the central clock of the

Fig. 1. Melatonin production pathway showing the precursor compounds and the enzymes

In the majority of species studied to date, whether they are diurnally or nocturnally active, there is a circadian secretion pattern of melatonin with high levels present at night and low levels during the day (Zawilska, Skene et al. 2009). The onset of darkness following a period

pineal gland (Iuvone, Tosini et al. 2005)

involved.

**4.4 Circadian melatonin rhythms**

which influence the timing of these rhythms (Roenneberg and Foster 1997; Iuvone, Tosini et al. 2005). The primary, central time keeping clock in the body is the suprachiasmatic nucleus (SCN) of the hypothalamus (Roenneberg and Foster 1997). The primary input to the SCN is from the retina via the retinohypothalamic tract (RHT) (Simonneaux and Ribelayga 2003), which makes light the primary zeitgeber for entrainment of the circadian rhythm (Roenneberg and Foster 1997). While input via the RHT is not necessary for the generation of a circadian rhythm (evidenced by the free running nature of the SCN rhythm), it is necessary for the entrainment of the circadian rhythm to the normal light:dark cycle (Inouye and Kawamura 1979).

#### **4.2 The light entrainment pathway**

The traditional view of the photosensitive retinal organisation is of a dual photoreceptor system comprising both rods and cones. However, circadian entrainment has been found to originate from a small subset of retinal ganglion cells, the intrinsically photosensitive retinal ganglion cells (ipRGCs) (Berson, Dunn et al. 2002; Hattar, Liao et al. 2002). The photopigment melanopsin, first described in melanophores on frog skin and subsequently found in the inner retina of a number of mammals including humans, provides the ipRGCs with this photosensitivity (Provencio, Rodriguez et al. 2000; Hattar, Liao et al. 2002). Melanopsin has an action spectrum that peaks around 480 nm (Berson, Dunn et al. 2002). However, studies in melanopsin-knockout mice showed that melanopsin is not essential for light entrainment of the circadian pacemaker, but improves the magnitude of the response (Ruby, Brennan et al. 2002). It transpires that the melanopsin-containing ipRGCs also receive input from the traditional rod and cone photoreceptors (Perez-Leon, Warren et al. 2006). There is a loss of photo-entrainment, but a persistence of pattern vision, in animals without functional ipRGCs providing definitive support for the role of the ipRGCs in the entrainment of the circadian system by light (Guler, Ecker et al. 2008). The entrainment of the circadian system in mammals is thus mediated by the ipRGCs as a balance between intrinsic photoreception enabled by melanopsin and input from the traditional retinal photoreceptors. In chicks melanopsin is found in both the retina and the pineal gland, indicating light can entrain the circadian pacemaker through both retinal (via ipRGCs) and direct pineal routes (Torii, Kojima et al. 2007; Neumann, Ziegler et al. 2008).

The SCN, working as a central master clock, controls the circadian timing of the organism through a multisynaptic pathway. The SCN projects to neurones in the paraventricular hypothalamic nucleus, which synapse preganglionic sympathetic neurons in the intermediolateral cell column, stimulating postganglionic sympathetic neurons in the superior cervical ganglion, before finally providing sympathetic input to the pineal gland (Larsen, Enquist et al. 1998). The main circadian mediator from the pineal gland is melatonin, a hormone first isolated from bovine pineal glands and named for its ability to lighten the melanocytes in frog skin (Lerner, Case et al. 1958). Melatonin acts through melatonin receptors in a diverse range of tissues, performing a variety of roles in circadian entrainment, endocrine functions, cardiovascular responses, the immune system, and ocular physiology (Alarma-Estrany and Pintor 2007).

#### **4.3 Melatonin precursors**

Melatonin (N-acetyl-5-methoxytryptamine) is a circadian hormone produced through a pathway involving four precursor intermediaries (Fig. 1.). All of the components necessary

which influence the timing of these rhythms (Roenneberg and Foster 1997; Iuvone, Tosini et al. 2005). The primary, central time keeping clock in the body is the suprachiasmatic nucleus (SCN) of the hypothalamus (Roenneberg and Foster 1997). The primary input to the SCN is from the retina via the retinohypothalamic tract (RHT) (Simonneaux and Ribelayga 2003), which makes light the primary zeitgeber for entrainment of the circadian rhythm (Roenneberg and Foster 1997). While input via the RHT is not necessary for the generation of a circadian rhythm (evidenced by the free running nature of the SCN rhythm), it is necessary for the entrainment of the circadian rhythm to the normal light:dark cycle (Inouye