April 2014
Volume 55, Issue 4
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Clinical and Epidemiologic Research  |   April 2014
Morphologic and Functional Analysis of the Optic Nerve in Premature and Term Children With OCT, HRT, and pVEP: A 10-Year Resurvey
Author Affiliations & Notes
  • Giulio Ruberto
    Ophthalmic Clinic, IRCCS San Matteo Polyclinic Hospital, Pavia, Italy
  • Raffaella Angeli
    Ophthalmic Clinic, IRCCS San Matteo Polyclinic Hospital, Pavia, Italy
  • Carmine Tinelli
    Clinical Epidemiology and Biometric Unit, IRCCS San Matteo Polyclinic Hospital, Pavia, Italy
  • Paolo Emilio Bianchi
    Ophthalmic Clinic, IRCCS San Matteo Polyclinic Hospital, Pavia, Italy
  • Giovanni Milano
    Ophthalmic Clinic, IRCCS San Matteo Polyclinic Hospital, Pavia, Italy
  • Correspondence: Giulio Ruberto, Ophthalmic Clinic IRCCS Polyclinic Hospital San Matteo, P.le Golgi 19, 27100 Pavia, Italy; rubertog@smatteo.pv.it
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2367-2375. doi:10.1167/iovs.13-13647
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      Giulio Ruberto, Raffaella Angeli, Carmine Tinelli, Paolo Emilio Bianchi, Giovanni Milano; Morphologic and Functional Analysis of the Optic Nerve in Premature and Term Children With OCT, HRT, and pVEP: A 10-Year Resurvey. Invest. Ophthalmol. Vis. Sci. 2014;55(4):2367-2375. doi: 10.1167/iovs.13-13647.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: Most studies on premature newborns have focused on infants of less than 28 weeks of gestational age (GA) due to their increased risk of developing diseases, such as premature retinopathy. Studies on premature infants born between 28 and 35 weeks GA with normal development are less frequent. The aim of our study was to identify subclinical morphologic or functional defects in these children.

Methods.: We evaluated 14 premature newborns at birth (mean gestational age, 33.45 weeks) with a neuro-ophthalmologic examination and patterned visual evoked potentials (pVEP). The same subjects were surveyed when they were young children (mean age, 7.5 ± 0.2 years) using Heidelberg retinal tomography (HRT) and optical coherence tomography (Stratus OCT). The pVEP studies were performed as transient (temporal frequency, 1.96 Hz) and steady-state (7.5-Hz temporal frequency). A complete ophthalmic examination also was performed. The data were compared to those from 15 term newborns who were examined in the same manner (mean age, 9.8 ± 0.3 years).

Results.: A statistically significant thickening of the macular temporal and inferior nerve fibers was found on OCT in premature newborns. The thickness of the superior and inferior retinal nerve fiber layer (RFNL) also was reduced. A difference also was found in rim area thickness based on HRT. Multiple significant P values were found in the VEP P100 peak time and steady-state amplitudes at the time of birth, but not at the time of morphologic analysis.

Conclusions.: Healthy, premature newborns may have morphologic abnormalities of the optic nerve. These abnormalities do not cause visual acuity or functional decreases.

Introduction
We defined premature newborns as those less than 37 weeks of gestational age (GA). Premature newborns were divided into Appropriate for GA (between the 10th and 90th percentiles) and Small for GA (under the 10th percentile), depending on their birth weight and length. Babies that are small for GA are divided into babies with low birth weight (1500–2499 g), very low birth weight (1000–1499 g), and extremely low birth weight (<999 g, <28 weeks GA). 13 The last two groups have an increased morbidity of the central vascular and nervous systems. Neonates born weighing <750 g or at 26 weeks, who are defined as micropremature, 4 represent a subpopulation that is at high risk of mortality and morbidity. A high prevalence of ophthalmologic disorders has been reported in these groups, among which the best known is retinopathy of prematurity. Late-premature births (between 34 and 36 weeks of GA) may result in subtle and specific neurocognitive deficits. 5 Optical coherence tomography (OCT) is a technology that enables the rapid and reproducible measurement of the retina and optic nerve head. 6 Normative parameters initially only referred to an adult population over 18 years of age, 7 but in the last few years, several studies have performed OCT measurements in large samples of children, including those born at term and premature infants. 812 The Heidelberg retina tomograph (HRT) is a confocal scanning laser ophthalmoscope designed for the acquisition and analysis of three-dimensional images of the posterior segment of the eye. It has been used successfully in studies of glaucomatous optic neuropathy. Previously, no control HRT data were available in child populations, and the only data available 13 on the bidimensional shape in children were obtained using fundus photography. In 2006, we gathered HRT data on 88 healthy children. 14 Visual evoked potentials (VEPs) are a well-established technique for exploring the central visual pathways from the macula to the subcortical brain. 15 Possible stimuli are a bright flash or patterns alternating on a screen. Bright flashes enable the assessment of the myelination process 16 and also are prognostic of survival rate and neurologic outcome in preterm and term newborns. 17 When using alternating patterns as stimuli, VEPs provide an index of visual maturation in a qualitative and quantitative manner. 1822 The patterns alternating at temporal frequencies high enough to generate a steady-state response have been used in some studies to determine the visual acuity resolution threshold (sweep VEP technique). 2326 We analyzed the optic disks in adolescents who were born as premature healthy newborns and who, at birth, had normal ophthalmologic, neurologic, and neurologic echography examination findings. Our aim was to determine whether the adolescents born premature exhibited optic disk anomalies, as determined by HRTIII and OCT, and VEP alterations. 
Methods
Study Patients
From 1999 to 2000, we examined 29 premature children (GA 28–35 weeks) who were considered normal according to ophthalmologic and neurologic examinations. The inclusion criteria at birth included a normal fundus, and normal neurologic and cerebral echography findings, as well as a spherical refraction between −0.50 and +2, to ensure a more homogeneous appearance of the optic nerve head, in consideration of the fact that high refractive value may influence optic disk morphology. The patterned VEP (pVEP) exam was performed at 3 and 8 months of age. Previously, 93 healthy, term newborns had been examined using the same criteria. Informed consent was obtained from the children's parents. In 2009, we asked the parents of a sample of those children for permission to resurvey the children by performing a complete ophthalmologic examination that comprised visual acuity testing with Early Treatment of Diabetic Retinopathy Study (ETDRS) charts, HRT, OCT, and pVEP. In total, 14 premature newborns (mean GA, 33.45 weeks at birth, 7.5 ± 0.2 years when reviewed) and 15 term newborns (mean GA, 39.67 weeks at birth, 9.8 ± 0.3 years when resurveyed) were examined. The parents of other children did not give their consent to be re-examined or could not be traced. Confocal scanning laser ophthalmoscopic measurements were performed using an HRT III (Heidelberg retinal tomograph; Heidelberg Engineering, Heidelberg, Germany). Three scans (15° × 15° images) of each examined eye were performed without pupil dilation. Only images with a SD of <30 were considered. The following parameters were analyzed: disc area, cup area, rim area, cup/disc area ratio, cup volume, rim volume, mean retinal nerve fiber layer (RNFL) thickness, and linear cup/disc ratio. The macula and optic disc parameters were evaluated using an optical coherence tomograph (Stratus OCT software v. 4.0.3; Carl Zeiss Meditec, Dublin, CA, USA), with pupil dilation. The RNFL thickness was evaluated with the fast RNFL thickness Stratus OCT protocol. Only good-quality images, with a signal strength of at least 7 (maximum 10) were selected for further analysis. The parameters that were considered included average RNFL thickness and RNFL thickness in four quadrants (superior, nasal, inferior, and temporal). Macular thickness was measured using six radial lines to generate a macular thickness/volume map, according to the fast macular thickness protocol. The development of the visual pathways of the babies enrolled was evaluated at birth using pVEP produced in response to a transient grating pattern stimulus administered at a temporal frequency of 1.96 Hz, and spatial frequencies of 150′ and 60′, and with a steady-state sinusoidal grating reversing at 7.5 Hz. This stimulus was administered at spatial frequencies ranging from 60′ to 3.3′ in the first year of life and from 60′ to 2′ in childhood. The stimulus display was a screen with a visual field of 28° × 21°. All the babies were examined at 3 and 8 months of postnatal life. The premature babies were examined four times, as we also chose to examine them at postmenstrual ages (pa) of 3 and 8 months, in addition to the chronological ages (cha). The pa was obtained by adding the babies' chronological ages to their gestational ages. 1 The pVEP values were recorded through an active electrode positioned on the skin of the occipital site (Oz), with the reference electrode placed on a frontal site (Fz), and the ground electrode placed on the mastoid process. The stimuli were presented to the babies in binocular vision and processed by a system used for the acquisition of electrophysiological potentials (Biomedica Mangoni 6001; Biomedica Mangoni, Pisa, Italy). In childhood, the stimuli were administered in monocular vision. The pVEP P100 wave was identified as the first large positive peak appearing after the onset of the stimulus. The steady-state pVEP signals were analyzed using Winacuità software (Biomedica Mangoni). The signal amplitude (in μV) and the phase of the second harmonic response were derived from Fourier transformation analysis. For this type of stimulation, we only considered the registrations that showed a regular sinusoid with a number of waves that was coherent with the analysis time and a regular phase to be reliable. The study adhered to the tenets of the Declaration of Helsinki. 
Statistical Analysis
The quantitative variables are presented as mean values and standard deviations, and the Shapiro-Wilk test was used to test the normality of the distribution. A Student's t-test was used to compare independent data, and the rank sum Mann-Whitney test was used to compare skewed distributions. Qualitative variables are expressed as numbers and percentages. A P value of <0.05 was considered statistically significant, and all the tests were 2-sided. Data analysis was performed using the STATA statistical package (version 12; Stata Corporation, College Station, TX, USA). 
Results
The characteristics of the children examined are summarized in Table 1
Table 1
 
Characteristics of the Examined Children
Table 1
 
Characteristics of the Examined Children
Premature, N = 13 Term, N = 14
Sex
 M 7 7
 F 6 7
Mean SD Mean SD
GA 33.45 1.22 39.64 1.41
Wt, g 1929.23 429.68 3418.57 303.49
Age, y 7.6 9.1
Visual acuity
 RE 0.004 0.034 −0.071 0.278
ETDRS
 LE 0.01 0.062 −0.069 0.279
N % N %
Optic disk
 Normal 9 69 12 86
 Increased central cup 1 8 1 7
 Increased temporal cup 1 8 1 7
 Flat 2 15 0 0
 Total 13 100 14 100
Vessels
 Normal 11 85 14 100
 Tortuous 2 15 0 0
Cover test 13 100 14 100
 Normal 6 46 8 57
 Exophoria at near 5 38 2 14
 Esophoria at near 1 8 4 29
 Esotropia 1 8 0 0
 Total 13 100 14 100
The results of the OCT scans are summarized in Table 2. The macular thickness was similar between the two groups. In the temporal and inferior inner layers, the macular thickness was significantly thinner in the premature newborns, as determined by multivariate analysis (P ≤ 0.03 and 0.02, respectively). While no significant differences were found in total RFNL thickness, the superior and temporal RNFLs were significantly thinner in the premature newborns (Table 2; Figs. 1A, 1B). The mean foveal minimum was similar in both groups. 
Figure 1
 
Optical coherence tomography in two children who were born premature in 2001 at 34 weeks GA (weight 1710 g [A]), and at 33 weeks GA (weight 1490 g [B]), respectively. The optic disk was thinner in the superior sector in both eyes.
Figure 1
 
Optical coherence tomography in two children who were born premature in 2001 at 34 weeks GA (weight 1710 g [A]), and at 33 weeks GA (weight 1490 g [B]), respectively. The optic disk was thinner in the superior sector in both eyes.
Figure 2
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CE) in a term child born in 1999. The optic disk was normal, and the P100 latencies were 100 ms at 3 months, 92 ms at 8 months, and 102 ms in childhood.
Figure 2
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CE) in a term child born in 1999. The optic disk was normal, and the P100 latencies were 100 ms at 3 months, 92 ms at 8 months, and 102 ms in childhood.
Table 2
 
Macula and RNFL Thicknesses in the Two Groups as Assessed by OCT
Table 2
 
Macula and RNFL Thicknesses in the Two Groups as Assessed by OCT
OCT Retinal Macula and Nerve Fiber Thickness Values in Premature and Term Children
Term, n = 28 Premature, n = 26 P Value
Mean SD p50 Mean SD p50
Foveal minimum, μm 163 21 162 162 27 164 0.912
A1, central macula, μm 196 20 199 196 22 190 0.994
A2, inner upper macula, μm 278 14 276 274 13 275 0.21
A3, inner temporal macula, μm 263 13 262 256 11 260 0.037
A4, inner inferior macula, μm 275 16 275 266 12 269 0.029
A5, inner nasal macula, μm 273 16 272 267 16 272 0.215
A6, outer upper macula, μm 243 14 241 241 13 239 0.701
A7, outer temporal macula, μm 224 13 223 221 13 222 0.383
A8, outer inferior macula, μm 236 14 233 236 16 232 0.42
A9, outer nasal macula, μm 263 15 261 260 13 259 0.482
Mean volume, mm3 7.00 0.3 6.97 6.90 0.3 6.92 0.296
RNFL average, μm 106 8 105 101 15.9 100 0.158
Temporal, μm 76 11 75 71 16.6 66 0.02
Superior, μm 136 15 138 122 19 124 0.026
Nasal, μm 80 13 82 76 14.5 77 0.304
Inferior, μm 131 18 132 129 19 129 0.748
The general distributions of the optic disc, disc cupping, and neural rim HRT parameters are shown in Table 3. A significant (P ≤ 0.045) difference in the rim area was found between the two groups. 
Table 3
 
The HRT Values in the Two Groups
Table 3
 
The HRT Values in the Two Groups
HRT in Premature and Term Children
Term, N = 28 Premature, N = 25 P Value
Mean SD p50 Mean SD p50
Disc area 2.51 0.71 2.18 2.34 0.68 2.23 0.392
Cup area 0.50 0.44 0.32 0.58 0.47 0.47 0.402
Rim area 2.01 0.51 1.91 1.76 0.37 1.70 0.045
Cup volume 0.11 0.15 0.05 0.13 0.15 0.07 0.458
Rim volume 0.45 0.14 0.42 0.41 0.15 0.37 0.240
C/D area ratio 0.1 8 0.12 0.15 0.23 0.14 0.21 0.265
C/D linear ratio 0.40 0.15 0.39 0.45 0.16 0.46 0.299
Mean RNFL thickness 0.20 0.07 0.20 0.22 0.21 0.18 0.721
The P100 wave results are summarized in Table 4. The P100 wave was delayed in the premature babies at 3 months after birth. This delay tended to shorten rapidly. At 8 months, the difference between the premature and full-term babies had decreased considerably. In childhood, the differences were reduced, but still were significant. The steady-state amplitudes at 3 and 8 months were significantly different between full-term and premature babies (Table 5). At 3 months after birth, the premature babies had a significantly lower VEP mean amplitude than the full-term babies at 60′ and 30′. At a corrected age of 3 months, the premature babies had a higher signal amplitude. 
Table 4
 
Patterned Visual Evoked Potentials Elicited With Transient 1.96-Hz Checkerboard Stimuli
Table 4
 
Patterned Visual Evoked Potentials Elicited With Transient 1.96-Hz Checkerboard Stimuli
Latency, msec, in Transient VEPs at 60′: P100
Term Premature P Value
N Mean SD p50 N Mean SD p50
150′ ≥ 80
 3 mo cha 14 110.78 10.68 109 7 190.57 40.96 204 0.0003
60′ ≥ 80
 3 mo pa 7 143.00 18.8 147 0.0001
60′ ≥ 80
 8 mo cha 13 100.31 6.06 102 8 117.00 14.87 113 0.0041
60′ ≥ 80
 8 mo pa 11 109.27 10.79 107 0.018
60′ ≥ 80
 Childhood 27 107.44 4.28 108 26 105.34 3.26 106 0.0507
60′ = 15% contras
 Childhood 28 115.5 6.11 115 26 118.26 6.88 120 0.1236
Table 5
 
Results of VEPs Elicited With Steady-State Stimuli in the Babies at Birth and in Childhood
Table 5
 
Results of VEPs Elicited With Steady-State Stimuli in the Babies at Birth and in Childhood
Amplitude (μV) of Steady-State VEPs
Term Premature P Value
N Mean SD p50 N Mean SD p50
60′
 3 mo cha 14 7.66 7.2 4.82 4 0.58 0.61 0.42 0.0058
 3 mo pa 2 2.03 0.8 2.03
 8 mo cha 13 5.82 4.38 3.81 3 0.42 0.5 0.22 0.0569
 8 mo pa 2 0.65 0.26 0.65 0.1303
30′
 3 mo cha 13 6.26 6.81 7.1 6 0.71 0.81 0.59 0.0014
 3 mo pa 7 4.71 3.31 3.93 0.7214
 8 mo cha 12 5.94 4.71 3.85 9 6.89 3.2 7.47 0.6104
 8 mo pa 9 4.11 3.19 4.2 0.3292
15′
 3 mo cha 6 2.49 3.43 0.64 1 1.04 1.04 0.6171
 3 mo pa 7 2.84 4.02 1 0.7751
 8 mo cha 10 3.24 2.97 2.61 6 4.35 4.72 2.83 0.5505
 8 mo pa 8 2.68 3.83 0.44 0.1551
 9 y 25 4.15 3.11 3.76 18 2.93 3.18 2.05 0.1151
10′
 3 mo cha 1 0.82 0.82 0
 3 mo pa 3 0.87 0.53 1.02
 8 mo cha 7 3.84 4.15 2.57 7 5.47 4.52 2.43 0.4062
 8 mo pa 7 2.88 2.21 2.97 0.9491
 9 y 19 4.23 2.93 3.28 18 3.42 3.52 2.16 0.3782
5′
 3 mo cha 1 0.71 0.71 0
 3 mo pa 1 2.08 2.08
 8 mo cha 8 2.57 2.33 1.39 5 1.43 1.83 0.25 0.1432
 8 mo pa 6 1.06 1.41 0.3 0.0707
 9 y 21 2.58 2.61 1.3 15 1.97 1.72 1.65 0.5106
3.3′
 9 y 16 1.80 1.22 1.51 12 2.69 2.77 1.31 0.9815
2′
 9 y 8 1.3 1.64 0.47 8 1.4 2.15 0.49 0.83
Discussion
The mean values of OCT macular thickness in the term newborns in our study are between those reported in the studies by Huynh et al. 9 and Eriksonn et al. 12 In a 2010 study, Åkerblom et al. 27 found that prematurely born children had a thicker central macula (A1) compared to full-term children. A thicker central macula was found in subjects with a history of retinopathy of prematurity. 27,28 We observed thinning of the inner temporal and inferior macula in children born preterm, as measured by OCT, but we did not observe significant differences in the central macula. The optic disk was thinner in the superior and temporal sector of the optic disk in preterm babies (Table 3; Figs. 1A, 1B). On average, compared to the study by Åkerblom et al., 27 the babies included in the present study were less premature, as they were of moderate-to-late preterm age (33.45 vs. 28.6 GA) and had a higher weight (1929.23 vs. 1299 g, Table 1). In agreement with those studies, we did not find any correlation between macular thickness and visual acuity or refraction, suggesting that these anatomic alterations are too subtle to produce a functional loss. The term and premature children in our study were European Caucasians; thus, the ethnic differences in optic disc findings recently reported by Samarawickrama et al. 10 were not evaluated. Another study with a very large sample showed that children with a low birth weight (<2500 g) had significantly thinner average, inferior, nasal, and superior RNFLs compared to those in normal-birth-weight children. 29 In our study, only the superior and temporal RNFLs were significantly different. 
In the children in our study, we observed a statistically significant difference in the rim area as analyzed by HRT. This area was thinner in the premature babies than in the term babies (Table 3). Figure 1 shows an example of a term newborn with normal HRT and VEPs. We found optic disk anomalies in four preterm newborns (Figs. 3, 4) and in two term newborns. In a previous study, we analyzed the optic disk parameters in children affected by cerebral visual impairment 14 by means of HRT and observed a smaller mean optic disk area, larger cup-to-disc ratio, reduced rim area, and thinner optic nerve fiber layer in those patients compared to normal children. The aforementioned parameters followed a similar trend in healthy, preterm babies, but the RNFL thickness was not affected. 
Figure 3
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CF) in a child who was born premature at 34 weeks GA in 2001, the same shown in Figure 1A. The optic disk was excavated, and the P100 latencies at 3 months cha and pa (C, D) at 8 months cha (E), and in childhood (F) were 208, 152, 141, and 110 ms, respectively.
Figure 3
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CF) in a child who was born premature at 34 weeks GA in 2001, the same shown in Figure 1A. The optic disk was excavated, and the P100 latencies at 3 months cha and pa (C, D) at 8 months cha (E), and in childhood (F) were 208, 152, 141, and 110 ms, respectively.
Figure 4
 
Heidelberg retinal tomography optic disk images ([A, C], right eye; [B, D], left eye; [C, D], three-dimensional) and patterned visual evoked potentials (EH) in a premature baby (33 weeks GA), the same shown in Figure 1B. The optic disk was excavated and the P100 latencies at 3 months cha and pa (E, F), 8 months pa (G), and in childhood (F) were 229, 197, 106, and 98 ms, respectively.
Figure 4
 
Heidelberg retinal tomography optic disk images ([A, C], right eye; [B, D], left eye; [C, D], three-dimensional) and patterned visual evoked potentials (EH) in a premature baby (33 weeks GA), the same shown in Figure 1B. The optic disk was excavated and the P100 latencies at 3 months cha and pa (E, F), 8 months pa (G), and in childhood (F) were 229, 197, 106, and 98 ms, respectively.
The mean ages of the preterm and term newborns in our sample were slightly different (average 2.3 years). The development of the morphologic fine retina is achieved at 4 years of age. 30 This development is reflected in the pattern of visual evoked potentials, as clearly shown by Crognale et al. 22 The latency of the positive VEP wave changes continuously with age in normal children and reaches the adult value of approximately 100 ms at approximately 3 months. Thus, the age differences observed in childhood examinations generally are irrelevant. The pVEP results in healthy, preterm infants are related to gestational or postmenstrual age. As previously reported, pVEP seems to follow a comparable developmental pattern in term and preterm children. 21 Investigations in premature children with a low risk of visual dysfunction have shown that after 8 months of postnatal age, these children have no significant latency differences compared to full-term subjects. In a recent study, O'Reilly et al. 31 did not find any differences in visual acuity between term and premature children without major neuromotor impairment, whereas they found a shorter P100 VEP latency in premature children than term children. Similarly, we found a shorter P100 latency associated with the 60′ stimulation in preterm individuals during childhood, which was not statistically significant (Table 4). Few reports have studied the steady-state VEPs in babies and children, and generally have investigated objective and subjective methods of assessing visual acuity, such as Teller Acuity Card testing. 24,25 In contrast, our objective was to obtain a steady response at different spatial frequencies. It is well known, based on previous studies, 32 that a carefully controlled stimulus train occurs approximately 12 to 20 seconds after stimulus onset, after which the average response remains approximately constant in amplitude and phase. Thus, for our steady-state stimulation, we used a protocol averaging 20 seconds for each spatial frequency, which is relatively fatiguing, especially for babies. We also took into account the possibility that the steady-state VEPs amplitudes may increase or decrease depending on spatial frequency 33 and intrasubject variability. 26 In our children, the patterned VEPs, both in transient and steady-state form, yielded significant differences between the two groups at birth, but not when they were resurveyed (Tables 4, 5). The P value of 5% can be considered a shortcoming of the study, since it could produce a high level of false positive findings. However, we considered the study as exploratory and we did not perform any multiple test correction. Exploratory studies with no prespecified hypothesis feature a great number of tests without a clear structure. Therefore, it is difficult to choose an appropriate multiple test adjustment, considering also that Bonferroni could be far too conservative and produce too many false-negative results. 34 The technologies that we utilized are in continuous development, widely used, allowing a more accurate analysis of the visual system besides the normative limits redefinition. 
In conclusion, we believed that while it is helpful to identify macular and optic disk anomalies in preterm children who otherwise are healthy, their significance should not be overestimated, as these anomalies may not significantly affect functional visual evolution, or the development of retinal and/or optic disk diseases in adulthood. At the same time, the detection of an alteration of the optic nerve in an preterm born adult should not worry clinicians, as it is congenital, it is not evolutionary, and it is not clinically relevant (as demonstrated by our study follow-up). The OCTs or VEPs repetition could be necessary only in case of progressive alteration of rim, like a thinning in case of glaucoma or optic neuritis, or a thickening in case of compression or inflammation. 
Acknowledgments
Disclosure: G. Ruberto, None; R. Angeli, None; C. Tinelli, None; P.E. Bianchi, None; G. Milano, None 
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Figure 1
 
Optical coherence tomography in two children who were born premature in 2001 at 34 weeks GA (weight 1710 g [A]), and at 33 weeks GA (weight 1490 g [B]), respectively. The optic disk was thinner in the superior sector in both eyes.
Figure 1
 
Optical coherence tomography in two children who were born premature in 2001 at 34 weeks GA (weight 1710 g [A]), and at 33 weeks GA (weight 1490 g [B]), respectively. The optic disk was thinner in the superior sector in both eyes.
Figure 2
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CE) in a term child born in 1999. The optic disk was normal, and the P100 latencies were 100 ms at 3 months, 92 ms at 8 months, and 102 ms in childhood.
Figure 2
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CE) in a term child born in 1999. The optic disk was normal, and the P100 latencies were 100 ms at 3 months, 92 ms at 8 months, and 102 ms in childhood.
Figure 3
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CF) in a child who was born premature at 34 weeks GA in 2001, the same shown in Figure 1A. The optic disk was excavated, and the P100 latencies at 3 months cha and pa (C, D) at 8 months cha (E), and in childhood (F) were 208, 152, 141, and 110 ms, respectively.
Figure 3
 
Heidelberg retinal tomography optic disk images ([A, B], left eye) and patterned visual evoked potentials (CF) in a child who was born premature at 34 weeks GA in 2001, the same shown in Figure 1A. The optic disk was excavated, and the P100 latencies at 3 months cha and pa (C, D) at 8 months cha (E), and in childhood (F) were 208, 152, 141, and 110 ms, respectively.
Figure 4
 
Heidelberg retinal tomography optic disk images ([A, C], right eye; [B, D], left eye; [C, D], three-dimensional) and patterned visual evoked potentials (EH) in a premature baby (33 weeks GA), the same shown in Figure 1B. The optic disk was excavated and the P100 latencies at 3 months cha and pa (E, F), 8 months pa (G), and in childhood (F) were 229, 197, 106, and 98 ms, respectively.
Figure 4
 
Heidelberg retinal tomography optic disk images ([A, C], right eye; [B, D], left eye; [C, D], three-dimensional) and patterned visual evoked potentials (EH) in a premature baby (33 weeks GA), the same shown in Figure 1B. The optic disk was excavated and the P100 latencies at 3 months cha and pa (E, F), 8 months pa (G), and in childhood (F) were 229, 197, 106, and 98 ms, respectively.
Table 1
 
Characteristics of the Examined Children
Table 1
 
Characteristics of the Examined Children
Premature, N = 13 Term, N = 14
Sex
 M 7 7
 F 6 7
Mean SD Mean SD
GA 33.45 1.22 39.64 1.41
Wt, g 1929.23 429.68 3418.57 303.49
Age, y 7.6 9.1
Visual acuity
 RE 0.004 0.034 −0.071 0.278
ETDRS
 LE 0.01 0.062 −0.069 0.279
N % N %
Optic disk
 Normal 9 69 12 86
 Increased central cup 1 8 1 7
 Increased temporal cup 1 8 1 7
 Flat 2 15 0 0
 Total 13 100 14 100
Vessels
 Normal 11 85 14 100
 Tortuous 2 15 0 0
Cover test 13 100 14 100
 Normal 6 46 8 57
 Exophoria at near 5 38 2 14
 Esophoria at near 1 8 4 29
 Esotropia 1 8 0 0
 Total 13 100 14 100
Table 2
 
Macula and RNFL Thicknesses in the Two Groups as Assessed by OCT
Table 2
 
Macula and RNFL Thicknesses in the Two Groups as Assessed by OCT
OCT Retinal Macula and Nerve Fiber Thickness Values in Premature and Term Children
Term, n = 28 Premature, n = 26 P Value
Mean SD p50 Mean SD p50
Foveal minimum, μm 163 21 162 162 27 164 0.912
A1, central macula, μm 196 20 199 196 22 190 0.994
A2, inner upper macula, μm 278 14 276 274 13 275 0.21
A3, inner temporal macula, μm 263 13 262 256 11 260 0.037
A4, inner inferior macula, μm 275 16 275 266 12 269 0.029
A5, inner nasal macula, μm 273 16 272 267 16 272 0.215
A6, outer upper macula, μm 243 14 241 241 13 239 0.701
A7, outer temporal macula, μm 224 13 223 221 13 222 0.383
A8, outer inferior macula, μm 236 14 233 236 16 232 0.42
A9, outer nasal macula, μm 263 15 261 260 13 259 0.482
Mean volume, mm3 7.00 0.3 6.97 6.90 0.3 6.92 0.296
RNFL average, μm 106 8 105 101 15.9 100 0.158
Temporal, μm 76 11 75 71 16.6 66 0.02
Superior, μm 136 15 138 122 19 124 0.026
Nasal, μm 80 13 82 76 14.5 77 0.304
Inferior, μm 131 18 132 129 19 129 0.748
Table 3
 
The HRT Values in the Two Groups
Table 3
 
The HRT Values in the Two Groups
HRT in Premature and Term Children
Term, N = 28 Premature, N = 25 P Value
Mean SD p50 Mean SD p50
Disc area 2.51 0.71 2.18 2.34 0.68 2.23 0.392
Cup area 0.50 0.44 0.32 0.58 0.47 0.47 0.402
Rim area 2.01 0.51 1.91 1.76 0.37 1.70 0.045
Cup volume 0.11 0.15 0.05 0.13 0.15 0.07 0.458
Rim volume 0.45 0.14 0.42 0.41 0.15 0.37 0.240
C/D area ratio 0.1 8 0.12 0.15 0.23 0.14 0.21 0.265
C/D linear ratio 0.40 0.15 0.39 0.45 0.16 0.46 0.299
Mean RNFL thickness 0.20 0.07 0.20 0.22 0.21 0.18 0.721
Table 4
 
Patterned Visual Evoked Potentials Elicited With Transient 1.96-Hz Checkerboard Stimuli
Table 4
 
Patterned Visual Evoked Potentials Elicited With Transient 1.96-Hz Checkerboard Stimuli
Latency, msec, in Transient VEPs at 60′: P100
Term Premature P Value
N Mean SD p50 N Mean SD p50
150′ ≥ 80
 3 mo cha 14 110.78 10.68 109 7 190.57 40.96 204 0.0003
60′ ≥ 80
 3 mo pa 7 143.00 18.8 147 0.0001
60′ ≥ 80
 8 mo cha 13 100.31 6.06 102 8 117.00 14.87 113 0.0041
60′ ≥ 80
 8 mo pa 11 109.27 10.79 107 0.018
60′ ≥ 80
 Childhood 27 107.44 4.28 108 26 105.34 3.26 106 0.0507
60′ = 15% contras
 Childhood 28 115.5 6.11 115 26 118.26 6.88 120 0.1236
Table 5
 
Results of VEPs Elicited With Steady-State Stimuli in the Babies at Birth and in Childhood
Table 5
 
Results of VEPs Elicited With Steady-State Stimuli in the Babies at Birth and in Childhood
Amplitude (μV) of Steady-State VEPs
Term Premature P Value
N Mean SD p50 N Mean SD p50
60′
 3 mo cha 14 7.66 7.2 4.82 4 0.58 0.61 0.42 0.0058
 3 mo pa 2 2.03 0.8 2.03
 8 mo cha 13 5.82 4.38 3.81 3 0.42 0.5 0.22 0.0569
 8 mo pa 2 0.65 0.26 0.65 0.1303
30′
 3 mo cha 13 6.26 6.81 7.1 6 0.71 0.81 0.59 0.0014
 3 mo pa 7 4.71 3.31 3.93 0.7214
 8 mo cha 12 5.94 4.71 3.85 9 6.89 3.2 7.47 0.6104
 8 mo pa 9 4.11 3.19 4.2 0.3292
15′
 3 mo cha 6 2.49 3.43 0.64 1 1.04 1.04 0.6171
 3 mo pa 7 2.84 4.02 1 0.7751
 8 mo cha 10 3.24 2.97 2.61 6 4.35 4.72 2.83 0.5505
 8 mo pa 8 2.68 3.83 0.44 0.1551
 9 y 25 4.15 3.11 3.76 18 2.93 3.18 2.05 0.1151
10′
 3 mo cha 1 0.82 0.82 0
 3 mo pa 3 0.87 0.53 1.02
 8 mo cha 7 3.84 4.15 2.57 7 5.47 4.52 2.43 0.4062
 8 mo pa 7 2.88 2.21 2.97 0.9491
 9 y 19 4.23 2.93 3.28 18 3.42 3.52 2.16 0.3782
5′
 3 mo cha 1 0.71 0.71 0
 3 mo pa 1 2.08 2.08
 8 mo cha 8 2.57 2.33 1.39 5 1.43 1.83 0.25 0.1432
 8 mo pa 6 1.06 1.41 0.3 0.0707
 9 y 21 2.58 2.61 1.3 15 1.97 1.72 1.65 0.5106
3.3′
 9 y 16 1.80 1.22 1.51 12 2.69 2.77 1.31 0.9815
2′
 9 y 8 1.3 1.64 0.47 8 1.4 2.15 0.49 0.83
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