FP1211 : Long term outcome of treatment with diode laser therapy for retinopathy of prematurity

Dr.SASIKALA ELIZBETH ANILKUMAR, Dr.vinut Anandi

Long term outcome of treatment with Diode laser therapy for retinopathy of prematurity

Abstract:

Purpose:Advancements in infant health care has led to an increased survival of prematurely born infant. There is a rising trend of ocular morbidities such as high refractive error, strabismus, and amblyopia in laser treated retinopathy of prematurity(ROP) children.Long term optical status and refractive outcome are less investigated in these children. The purpose of our study is to evaluate long term outcome (refractive, biometric profile, sensory) of treatment for ROP using Diode laser.

Methods: This study is a retrospective, cross sectional, observational, interventional study in children age 6-15 years who underwent Diode laser for ROP with a minimum of 6 year follow up.

Results: 80 lasered eyes of 41 children were assessed. Mean age 9.71 years. 73 eyes (91.2 %) achieved visual acuity better than 20/40. The mean visual acuity in LogMAR was 0.18(20/30). The mean spherical equivalence was -5.29 D± 4.9. Mean astigmatism measured was -1.53 DC( range:+0.50 DC to -4.5DC). 53 eyes(66.25%) had  significant astigmatism. The mean axial length 23.5 mm ±1.35(21-26). Mean lens thickness 3.76mm± 0.30(3.03-4.34). Correlation analysis among the low and high spherical equivalence group signified that axial length (p-value =0.001), visual acuity (p-value = 0.0002) and myopic shift (p-value = 0.0006) were found to be statistically significant. (41%) had stereopsis better than 480 sec of arc for near. Structural posterior pole sequelae developed in 3 eyes(3.75%). Conclusion: Significant number of children in our study had high myopia and astigmatism with satisfactory visual outcome, warranting a mandatory close long term follow up.

Key words: Diode laser, Myopia, Retinopathy of prematurity, refractive outcome, ocular biometry, Sensory outcome

Introduction

Retinopathy of prematurity (ROP) is a widely recognized cause of visual impairment in premature infants. ROP occurs due to abnormal retinal vasculature at the boundary of vascularized and avascular peripheral retina¹. Gilbert.C et al. in 2005 reported the prevalence of ROP related blindness in India to be about 0.2% of the world wide burden². Advancements in infant health care has led to an increased survival of prematurely born infants in the middle income countries. Severe ROP is often encountered in babies weighing greater than 1250 g at birth in developing countries³.

Blencowe et al. in 2010 estimated about 20,000 premature survivors with severe visual impairment and blindness world-wide⁴. It is well established that prematurity, low birth weight and ROP increases the risk for myopia. Laser photocoagulation reduces the morbidity arising from ROP and results in successful anatomical outcome. It acts by killing abnormal retinal tissue and stops release of angiogenic factor⁵. There is a rising trend of ocular morbidities such as refractive error, strabismus and amblyopia in this subset of children. Long term optical status and refractive outcome are less investigated in ROP children undergoing laser treatment. Hence we aimed to analyse the long term refractive, ocular biometric profile and sensory outcome among the children with a minimum of 6 years follow up who were treated for ROP with Diode laser therapy.

Material and methods

This is a retrospective, cross sectional, interventional and observational study in children age 6-15 years who underwent Diode laser for ROP. This study was conducted in a tertiary eye centre in South India. The study was approved by the institutional ethics committee and has adhered to the provisions of the declaration of Helsinki. We reviewed the case records of all the children who visited our paediatric ophthalmology clinic between December 2017 and May 2018 with a history of Diode laser treatment for ROP with a minimum of 6 years follow up. We excluded patients who had spontaneously regressed and who underwent surgery. Data collection included sex, gestational age at birth(GA), birth weight, oxygen exposure, stage and zone of ROP involvement, the presence of aggressive posterior ROP (APROP), plus disease, post conception age at laser treatment, unilateral or bilateral treatment, the type of treatment received, age at regression of disease and the spherical equivalence at 1 year of age.

At presentation, all patients aged 6 years and above underwent a complete ophthalmological evaluation including best corrected uniocular visual acuity and refraction assessed using Snellen’s chart. Sensory evaluation included binocular single vision and stereopsis.Measurement of ocular deviation was done using prism bar cover test. Colour vision and Contrast sensitivity(CS) were assessed. The refractive error was checked after dilatation with 1% cyclopentolate. The refractive error was converted to spherical equivalent (SE) and defined as spherical error + half cylindrical error. Negligible refractive error was SE of ±0.5D. Anisometropia was defined as the difference of SE between the eyes being ≥ 1.5 D.

Following cycloplegia, ocular biometry was done using IOL master (Carl Zeiss Germany) in which the corneal diameter, corneal power (average of the K1 and K2 reading), anterior chamber depth, axial length and lens thickness were measured. The anterior and posterior segment were examined for structural sequelae.The stage and severity of ROP were classified according to the International Classification of ROP⁶. The indication for laser treatment was as per the Early Treatment for Retinopathy of Prematurity Cooperative Group (ET-ROP)^7. 

Statistical analysis

Data from each eye were taken as an independent variable. Mean, median, range and standard deviations were calculated for the demographic, refractive, biometric and sensory outcome data. Spearman correlation was used to correlate quantitative variables. P-value less than 0.05 considered as statistically significant. Student’s t-test/ Mann-Whitney U test was used to find out the significant difference between two quantitative variables.

Results:

Characteristics of study group:

80 lasered eyes of 41 children met the inclusion criteria. They presented at a mean age 9.71(±3.39)years (range 6-15 years). No sex difference among the study group(M: F -51.2% :48.8%). 39(95.1%) children had undergone laser photocoagulation for ROP on both eyes, while 2(4.9%) children underwent unioculary. Their mean gestational age was 30.51 weeks ±2.01 (26-35) weeks and mean birth weight was 1430.37±318.11(800-2250) grams. Our study group comprised of 48.7% babies with gestational age ≤30 weeks, while 51.3% were > 30weeks of gestation. 61.3% had a birth weight ≤1500 grams and 38.7 % had a birth weight >1,500 gms. Among the study group 78% infants were exposed to oxygen therapy.

Of the 80 eyes evaluated, Zone I involvement was present in 28(35%) and Zone II in 52(65 %). APROP was present in 26(32.5%) and plus disease in 50(62.5%) patients.  Their mean post conceptional age at which laser photocoagulation was performed was 35.39(range: 30-42) weeks. The mean number of laser spots applied was 2262(range-743 to 5623) spots. The mean time for regression of ROP following treatment was 28.60 (range: 7-112) days.

Refractive outcome:

At the time of study, the mean visual acuity in LogMAR was 0.18(20/30) (range: 20/125- 20/20). 73 eyes (91.2 %) had visual acuity better than or equal to 20/40 and 25 eyes (31.25%) had visual acuity of 20/20. Seven eyes (8.8 %) had satisfactory visual acuity between 20/40 and 20/200. None of the patients had unsatisfactory visual acuity worse than 20/ 200. 73 eyes(91.25%) had refractive error. The mean spherical equivalence was-5.29 D± 4.9(range: +0.75 to -18.5 D). 71 eyes(88.75%) had a myopic refraction. 40(50%) eyes had low myopia (≤6 D) while high myopia (>6.0 D) was seen in 31 eyes(38.75%). Two (2.5%) eyes had hyperopia.

Mean astigmatism measured was -1.53 DC( range:+0.50 DC to -4.5DC). 53 eyes(66.25%) had  significant astigmatism. With the rule astigmatism, against the rule astigmatism and oblique astigmatism were present in 62.5%, 8.75% and 16.25% eyes respectively. Fifteen eyes(36.58 %)had an anisometropia (range:1.5D -7.5D). Seven (8.8%) eyes had emmetropia. The mean CS was 1.64 log CS units. Colour vision was normal in 77(96.25 %) children. The mean SE at 1 year of age was -2.28(range: +4 to -12.5), the mean myopic change was –2.99D (range +0.25 to -17.50D) in the study group. Mean myopic shift per year -0.29D / year (IQR: 0.17D – 0.53D).

Ocular biometric profile:

The mean axial length 23.5 mm ±1.35(21-26). Mean lens thickness 3.76mm± 0.30(3.03-4.34). The mean corneal refractive power was 46.3 D and the mean corneal diameter was 11.8 mm. The mean anterior chamber depth was 3.1 mm.

Correlation of gestational age and birth weight with refractive components was analysed using spearman rank order correlation. There was a correlation between gestational age and spherical equivalent (rho = 0.22, p-value = 0.045) suggesting that lower gestational age children had higher SE. Also there was correlation between gestational age and axial length (rho = -0.22, p-value = 0.048) indicating that lower gestational age children developed longer eyes. While correlating between birth weight and visual acuity (rho = -0.23, p-value = 0.040) suggests that higher the birth weight, better the visual acuity.

Mann-Whitney U test when applied showed a correlation between gestational age(≤ 30 weeks and >30 weeks) with SE(p-value= 0.038) and myopic shift per year (p-value = 0.016) denoting that there is a significant difference between the gestational age groups. This indicates that high myopia refraction is seen among the children with low gestational age and they had a higher myopic shift. Similar analysis between birth weight (≤1500 g and >1500 g )showed that the p-value had significant difference in SE(p-value = 0.035)  and logMAR visual acuity (p-value = 0.012) denoting lower birth weight group had  higher SE and higher logMAR. Student’s t-test when performed between eyes with APROP and without APROP showed that lens thickness (p-value 0.050) was statistically significant. (Table-1)

Mean axial length among the low(≤ 6D, )  and high(>6D) SE group are 22.73 mm and 24.79 mm respectively. Student’s t-test and Mann-Whitney U test when performed between low SE groups and high SE groups signified that axial length (p-value <0.001), visual acuity (p-value = 0.0002) and myopic shift (p-value = 0.0006) were found to be statistically significant. 

Sensory outcome:

Fifteen children(36.5%) had strabismus[1(2.4 %)esotropia ,13(31.7%)exotropia and 1(2.4 %) hypertropia]. Of them six had anisometropia associated with amblyopia. In total nine eyes(10.6%) had amblyopia. In the study group 34 children(82.9%)  and 28 children(68%) had binocular single vision for near and distance respectively. Seventeen children(41%) had stereopsis better than 480 sec of arc for near. Six(14.6%) had a best stereopsis of 60 sec of arc.

Structural outcome:

Structural sequelae developed in 3 eyes(3.75%). Of them one had peripheral traction membrane and developed very high myopia and strabismus with satisfactory visual acuity of 20/63.  One child (both eyes) had visually insignificant cataract with high myopia and ametropic amblyopia with a visual acuity of 20/80. Patient was kept on observation as the density of cataract was not contributing to the vision loss.

Discussion:

Our study presents the long term outcome in children treated for ROP with Diode laser therapy. Comparison among the studies about the patient characteristics are tabulated inTable 2^8,9,10,11. All the studies including the present study had much higher mean birth weight and mean gestational age compared to ETROP cohort [(703 g)& (25 weeks)]⁷. Yang et al reported mean LogMAR visual acuity of 0.20 (20/32) similar to our results⁸.  In a study done by Shah P.K et al on zone 1 APROP reported 10.41% with 20/20¹².

The reasons for our good visual outcome could be due to early referral, timely management and faster regression of disease (mean regression of disease being 28 days) which in turn also resulted in a good structural outcome. Katoch et al in their study concluded that the risk factors for myopia were a greater number of clock hours of ROP, greater number of laser spots, and a longer time to regression of ROP¹³. Prematurely born infants gestational age and birth weight cannot be controlled. Only by providing strict neonatal care, early treatment for ROP, timely referral can control the severity of disease, reduce myopia and provide good visual outcome.

Similar to other studies ours also shows a significant number of eyes with predominantly high myopic SE and astigmatism. (Table -3)^9,10,12,14. Many authors have concluded myopia to be associated with ROP laser treated than non ROP infants and spontaneously regressed ROP cohort ^9,10,,15.Choi et al concluded in their study that myopia begins to appear at 6 months of age and its severity increases between the ages of 6 months and 3 years andeyes with cicatricial retinopathy tended towards myopia¹⁶. ETROP findings suggest that increased myopia in fact is due to more severe ROP rather than any direct effect of the laser treatment¹⁷.

The reason for developing myopia in laser treated eyes seems to be controversial.It is proposed that high myopia is due to steep keratometry, greater lens thickness, forward position of the lens centre and shallower anterior chamber ^8,10,11,16. Fielder et al in their study have suggested that the ROP insult retards that part of the globe which is undergoing maximal growth, and this effect will in turn, mechanically inhibit anterior segment development¹⁸. It is also argued that the ablated retina following laser therapy hampers ocular growth in the posterior segment. This could trigger overcompensation of the anterior chamber. Yang et al based on their findings hypothesize that there is incomplete postnatal development of the cornea, anterior sclera, and anterior segment in the premature infants.⁸

Our biometric outcomes when compared with other reports in literature and the age matched controls shows increased axial length, shallow anterior chamber depth and increased lens thickness (Table-4)^8,10,11,19. Laws et al report finding a negative correlation between the severity of ROP and axial length, suggesting that changes in the axial length are not caused by the ROP but by prematurity²⁰. Choi et al in their study found an average axial length in emmetrope, low myopia and high myopia as 21.96 mm, 22.74 mm 24.77 mm which are much similar to our study reports¹⁶.Lee et al report the average axial length in emmetropia of 6 year olds to be 22.18 mm²¹.

It is not possible to directly correlate statistically with the results of Lee et al, still our study shows that there is an increased axial length among the premature laser treated infants and was statistically significant (p =0.001) with a significant myopic shift (p= 0.0006 ). Majority of the studies report the increased lens thickness to be contributory factor for myopia in laser treated ROP eyes^10,22.Connolly et al found that laser-treated eyes were significantly less myopic than cyrotherapy-treated eyes and that the lens power seemed to be the predominant factor contributing to the excess myopia¹⁹.

Subtle colour vision and contrast sensitivity deficits are found among preterm and severe ROP babies²³.  It was reported as 1.28 log CS units according to Kaur et al¹⁰. In a study by Bonotto et al on preschool laser treated ROP children, normal CS among 66.67% and 100 % normal colour vision²⁴.Majority of our children had best CS and colour vision. There is a paucity among studies about the sensory outcome in children laser treated for ROP^9,10.  Lower stereoscopic resolution and binocularity was observed among premature infants after ROP treatment and it varied with ROP severity. Bonotto et.al reported that none had good stereopsis²⁴.Our study also reported excellent sensory outcome. Authors report the percentage of strabismus among laser treated ROP eyes ranging between 10% and 30.5%^8,9,10. Our study showed exotropia in majority of the children.

The limitations of our study lies in the retrospective nature that induces inherent sampling and observational bias. Our study lacks a control group. Longer prospective comparative studies would provide more light into the unknown aspects of why high myopia is common in these eyes.

Conclusion

Our study has shown a good refractive outcome in terms of best corrected visual acuity, spherical equivalence and satisfactory sensory outcome indicating binocularity and effective treatment of amblyopia and a favourable structural outcome in ROP children treated with laser. Very few studies in literature focus on analysing theses parameters and provide long term results. In line with other studies our report shows high myopia and astigmatism in laser treated eyes. With the third epidemic the burden of ROP is on a steady rise with similar reporting among larger premature babies in developing countries like India. There is lack of awareness among paediatricians in many parts of India about ROP. We need to emphasize the need for increased awareness about the long term challenges in regard to refractive error. A lower threshold for spectacle prescription for this category of children is recommended. Timely and meticulous long term follow up is mandatory in these children.

References

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Table 1: Comparison of Gestational age, birth weight, Zones involved and presence of APROP with refractive and biometric outcomes.

Outcomes	Mean or median	Gestational Age P-value	Birth weight P-value	Zone P-value	APROP P-value
Visual acuity in (Median logMAR)	0.18(6/9)	0.099 b	0.012 b	0.149 b	0.086 b
Spherical equivalent Mean(SD)	-5.28(4.72)	0.038 b	0.035 b	0.224 b	0.488 b
Astigmatism (range)	-1.53 (0.5 to -4.5DC)	0.457 c	0.261 c	0.423 c	0.331 c
Myopic shift ( median)	0.29	0.016 b	0.325 b	0.250 b	0.655 b
Axial length Mean(SD)	23.50(1.40)	0.127 a	0.710 a	0.445 a	0.948 a
Lens thickness Mean(SD)	3.81(0.31)	0.322 a	0.964 a	0.252 a	0.050 a

^a independent t-test, ^b Mann-Whitney U test, ^c Fisher’s exact test 

Table: 2 Comparison between studies based on patient characteristics

Comparison study	Study conducted period	No. of study participant	Mean birth weight (g)	Mean gestational age ( weeks)	Mean age at study (years)
Yang C.S et al8	2012	24	1256	28.8	9.2
Nguyen P.H et al9	2015	50	1426	29.88	5
Kaur C.S et al10	2017	36	1262	29.01	7.37
Mcloone E.M et al11	2006	8	890	26.6	11.1
Present study	2018	41	1430	30.51	9.71

 Table 3: Comparison between studies based on refractive and visual outcome.

Study	No of eyes	Mean spherical equivalence (SE) D	Dominant refractive error		BCVA better than 20/40 (%)	astigmatism
			Myopia (%)	Hyperopia(%)		Mean astigmatism (D)	%
Stoica F etal14	96	-4.12	70.83	–	72.9	–	20.83
Shah P K et al12	48	-5.62	93.75	–	81	-2.08	48.8
Nguyen et al9	100	-2.87	59	21		1.63	49
Kaur et al10	72	-4.50	75	20	75	-2.7	30.5
Our study	80	-5.29	88.75	2.5	91.2	-1.53	66.25

 Table: 4 Comparison between studies and age matched controls based on the Biometric outcomes.

Study	Follow up years	Number of eyes	Mean axial length* mm	Mean AC depth* mm	Mean corneal power* D	Mean lens thickness* mm
McLoone et al11	11.1	16	22.81	3.38	45.24	–
Connolley et al19	9.9	20	22.89	3.44	46.68	3.95
Kaur et al10	7.37	72	20.35	2.95	45.8	4.33
Yang CS et al8	9.2	46	23.32	2.91	–	3.94
Yang C.S et al [age matched control]8	–	1021	23.24	3.58	–	3.39
Present study	9.77	80	23.5	3.1	46.3	3.76