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Documenta Ophthalmologica

, Volume 138, Issue 2, pp 137–145 | Cite as

Evaluation of early changes of macular function and morphology by multifocal electroretinograms in patients with nasopharyngeal carcinoma after radiotherapy

  • Haijun Gong
  • Yuanlin Tang
  • Jianhui Xiao
  • Yimin Liu
  • Rui Zeng
  • Zijing Li
  • Si Zhang
  • Yuqing LanEmail author
Original Research Article

Abstract

Objective

To assess the role of multifocal electroretinograms (mfERGs) and optical coherence tomography (OCT) for detecting early changes in macular functions of patients with nasopharyngeal carcinoma (NPC) after radiotherapy.

Methods

mfERGs and OCT were used to examine a NPC group (36 NPC patients after radiotherapy without clinically visible radiation retinopathy, 36 eyes) and a normal control group (25 healthy individuals, 25 eyes) with the same procedure and parameters. The two groups of mfERG were summarized by calculating ring averages, response density, N1 amplitude and P1 and N1 latencies were analysed. OCT scan thickness was summarized into ETDRS regions for comparison.

Results

Compared with controls, the NPC group had significantly decreased P1 response densities in 1–4 ring regions and N1 amplitudes in 1–3 rings (P < 0.01). P1 latencies were obviously prolonged in rings 1 (P < 0.01). In four quadrants (inferonasal, superonasal, inferotemporal and superotemporal) of the mfERG response waveforms, the NPC group had significantly decreased P1 response densities and N1 amplitudes mainly in the inferonasal and inferotemporal quadrants, showing statistically significant differences from the control group (P < 0.0125). But for the OCT results, there is no statistically significant difference between the NPC group and the control group.

Conclusions

In NPC patients after radiotherapy, there may be changes in the mfERGs before any visible fundus lesions appeared as radiation macular oedema. Since the global OCT macular thickness analysis cannot reveal early changes, the mfERGs can objectively and quantitatively assess the earlier changes in macular function in NPC patients.

Keywords

Multifocal electroretinograms Optical coherence tomography Nasopharyngeal carcinoma Radiation retinopathy 

Introduction

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumours in China, and the incidence rate of NPC is substantially higher in Guangdong Province than in other regions in China, e.g. 17.78/10,000 in Guangzhou City [1]. As ninety per cent of NPC cases are poorly differentiated squamous cell carcinoma that is sensitive to radiotherapy, radiotherapy has been used as the basic method for treatment of NPC. With continuous equipment updates and technical advances, the 5-year survival rate of NPC with radiotherapy has reached approximately 75% [2].

Despite the popularity of radiotherapy and the resultant improvement in patient survival, radiation damage to the eye has shown an increasing tendency, and retinal damage is one of the many complications arising from it [3]. Radiation retinopathy (RR), which was first described by Stallard in 1933, is often manifested clinically as microaneurysms, capillary telangiectasia, neovascularization, vitreous haemorrhage, hard exudate, cotton-wool spots and macular oedema [4, 5]. Macular oedema is the first clinical manifestation to present in most cases of RR. Because radiation macular oedema (RME) is the leading cause of visual acuity loss, early diagnosis and detection of macular function loss, even before its occurrence, are of great significance.

Multifocal electroretinograms (mfERGs) can be used in comprehensive examinations, and this method of visual electrophysiology was designed by Sutter in 1990 [6]. Because of its high precision, accuracy, sensitivity and correspondence for retinal disorder, mfERGs have been useful in the quantitative evaluation of subtle changes in the retina, primarily in the posterior pole region. Fundus changes in RR and diabetic retinopathy (DR) are quite similar because early onset of both RR and DR is associated with damage to retinal capillaries [7, 8, 9, 10]. Research has shown that mfERGs can detect abnormalities in visual function before DR occurs [10, 11, 12]. Yu et al. [13] observed that the P1 response density of mfERGs was decreased in the early phase of non-proliferative DR, while the latency was not significantly different from that in the normal control group.

OCT is an accurate method for detecting and quantifying macular oedema. OCT can clearly indicate the presence of intra-retinal cysts and retinal disruption. Retinal cell loss can be quantified, and the retinal thickness can be measured. Macular exudates can be measured and quantified [14]. The study by Horgan [15] demonstrated that macular oedema can be found on OCT approximately 5 months earlier than clinically detectable radiation maculopathy can be found on OCT. The subtle increase in foveal thickness and early foveal oedema, which indicates the beginning of radiation-induced damage, can be detected on OCT, while visual acuity is still preserved. However, to date, the application of mfERGs and OCT in the early detection and diagnosis of RME in NPC patients after radiotherapy has not been reported.

This study aimed to assess the efficiency of mfERGs and OCT in detecting early changes in macular function of NPC patients after radiotherapy. The normal control group of healthy individuals and the NPC group of NPC patients after radiotherapy were examined and compared using mfERGs and OCT. The results will provide reference data and an alternative method for early detection and prevention of RME.

Materials and methods

Patient selection

The study adhered to the tenets of the Declaration of Helsinki and was approved by the medical ethics committee of Sun Yat-Sen Memorial Hospital, and all patients gave informed consent. Between September 2013 and March 2015, the study was conducted, and it included the NPC group of 36 NPC patients (36 eyes) after radiotherapy and the normal control group of 25 healthy individuals (25 eyes). The time between radiation and examination ranged from 3 months to 3 years. The demographic features of patients are shown in Table 1. The radiotherapy doses of NPC patients received were within 68–71 Gy. All subjects underwent slit-lamp examination, intraocular pressure measurements and ophthalmoscopy to exclude glaucoma, high myopia, cataract, intraocular lens and retinal diseases. Those with a previous history of intraocular surgery or systemic diseases that affect the fundus (e.g. diabetes mellitus, hypertension and kidney disease) were not included in the study. The eyes under study had uncorrected or corrected visual acuity (decimal) ≥ 1.0 with refractive error controlled within the range of ± 3.00 DS (dioptre of spherical power) to ± 0.75 DC (dioptre of cylindrical power).
Table 1

Demographic features of included patients by group

Baseline characteristics

NPC

Normal

n

25 (25 eyes)

36 (36 eyes)

Age (years)

41.96 ± 8.97 years

44.03 ± 9.80 years

Sex (M/F)

13/12

20/16

Data collection

The standard mfERGs were recorded in all participants according to ISCEV guidelines [16]. Multifocal electroretinograms were recorded using a RET scan multifocal system version 3.20 (Roland Consult, Brandenburg, Germany). The stimulus pattern consisted of 61 hexagonal elements of sizes that increased with eccentricity, and a central cross was the fixation point. Pupils were maximally dilated with 0.5% tropicamide eye drops. A gold ground electrode was attached to the forehead. Retinal activity was recorded with a gold monopolar contact lens (Universo SA, La Chaux-de-Fons, Switzerland) that was placed on the anesthetized (0.4% oxybuprocaine) cornea. The contralateral eye was occluded with an eye pad. Patients were instructed to maintain fixation on the fixation spot, or on the cuneiform indicator for patients who could not see the spot. The signals were amplified 100,000 times with a band-pass filter of 5–100 Hz. The stimulus lasted 6 min 16 s, which included eight 47-s intervals. As for the kernel order, we chose the default setting (first-order kernel) of the instrument. During data recording, irregular intervals of the original waveform caused by eye movements, bubbles in the contact lens and blinking were eliminated.

According to different eccentricities, 61 original local response waveforms were divided by the computer into five ring retinal regions with evenly distributed eccentricity from the centre to the periphery. The response waveforms were then divided into four quadrants, including the superonasal, inferonasal, inferotemporal and superotemporal quadrants, and the average wave of the first-order kernel in each group was obtained. P1 response density, N1 amplitudes as well as P1 and N1 latencies in each group were finally measured. Macular thickness was measured by applying Zeiss HumPhrey OCT-4000 instruments (Carl Zeiss, Dublin, CA). The scanning protocol used for this study was the Fast Macular Thickness program, which creates a retinal map consisting of six radiating cross-sectional scans, each of 6-mm length, that produces a circular plot in which the fovea is a central circular zone of 1.00 mm diameter. Superior, nasal, inferior and temporal parafoveal zones represent annular bands in these respective sectors. Central macular thickness was analysed with the macular thickness analysis software in ETDRS nine partition mode.

Statistical analysis

SPSS version 21 (IBM SPSS, New York, NY, USA) was used for calculations. All numerical data were expressed as the mean ± SD of the mean (we measured three times at the same time for every participant, n = 3). In the two eyes of each participant, we selected the one with lower data of mfERG amplitudes for statistical analysis. Group comparisons were performed using the independent samples t test. We also corrected P values for multiple testing. For amplitudes and densities of P1, amplitudes of N1 and latencies of P1 and N1 waves, a P value less than 0.01(0.05/5) was considered statistically significant in five rings, while a P value less than 0.0125(0.05/4) was considered statistically significant in four quadrants. For macular thickness in nine districts of the OCT, a P value less than 0.0055(0.05/9) was considered statistically significant.

Results

General data

The normal control group consisted of 25 healthy individuals (25 eyes): 13 men (13 eyes) and 12 women (12 eyes) aged 29–65 years, with an average age of 41.96 ± 8.97 years. The NPC group consisted of 36 patients (36 eyes) with NPC after radiotherapy, including 20 males (20 eyes) and 16 females (16 eyes) aged 21–62 years, with an average age of 44.03 ± 9.80 years. There was no statistical difference between the NPC group and the normal control group in terms of average age (t = − 0.838, P = 0.405). Demographics are included in Table 1.

Typical responses of mfERGs

Figure 1 shows typical responses of mfERGs (traces, rings and quadrants) from one NPC patient and one normal participant. In the normal, the response was approximately equal in height. Peak implicit times vary more among the NPC patient than among the normal person. There was slight latency delay in NPC patient in rings and quadrants graphs.
Fig. 1

A typical plot of waveform trace of the control group (a) and NPC patient (b). Typical responses of mfERGs for patients from the control group (c, d) and the NPC group (e, f) in four quadrants and five rings

Comparison of P1 response densities and N1 amplitudes, as well as P1 and N1 latencies, between the control group and the NPC group in five ring regions of the mfERGs

Figure 2 shows the P1 response densities and N1 amplitudes, as well as the P1 and N1 latencies in five ring regions of the mfERGs for the control group and the NPC group. Compared with the normal control group, the NPC group had significantly decreased P1 response densities in the 1–4 ring regions and significantly decreased N1 amplitudes in the 1–3 rings (P < 0.01). In the NPC group, the P1 latencies were obviously prolonged in ring1 (P < 0.01). There were no statistically significant differences in the P1 or N1 latencies in the remaining regions between the NPC group and control group.
Fig. 2

Comparison of P1 latencies (a) and response densities (b), N1 latencies (c) and amplitudes (d) in five rings between the NPC and normal groups

Comparison of P1 amplitude densities and N1 amplitudes, as well as P1 and N1 latencies between the control group and the NPC group in four quadrants of the mfERGs

Figure 3 summarizes the P1 response densities, N1 amplitudes and P1 and N1 latencies in four quadrants of the mfERGs for the control group and NPC group. Compared with the control group, the NPC group had significantly decreased P1 response densities and N1 amplitudes in the inferonasal and inferotemporal quadrants (P < 0.0125) but had no significant difference in the superonasal and superotemporal quadrants compared to the control group. There were no significant differences between the two groups in the P1 and N1 latencies for all quadrants (P < 0.0125).
Fig. 3

Comparison of P1 latencies (a) and response densities (b), N1 latencies (c) and amplitudes (d) in four quadrants between the NPC and normal groups

Comparison of macular thickness in nine districts of the OCT between the control group and the NPC group

Table 2 shows a comparison of the macular thickness in nine districts of the OCT between the control group and the NPC group. Compared with the normal control group, in the NPC group, there were no statistically significant differences in macular thickness in all nine districts.
Table 2

Comparison of macular thickness in nine districts of the OCT between the control group and the NPC group

 

C

S1

I1

N1

T1

S2

I2

N2

T2

Normal

239.08 ± 16.35

318.72 ± 12.98

314.32 ± 10.35

321.88 ± 14.51

306.80 ± 8.96

284.44 ± 11.51

268.04 ± 10.62

300.44 ± 10.35

263.60 ± 6.71

NPC

237.39 ± 17.14

318.47 ± 21.67

317.14 ± 20.20

321.44 ± 16.79

308.86 ± 17.38

283.11 ± 14.19

268.89 ± 15.02

299.03 ± 18.86

265.47 ± 14.55

t

0.386

0.051

− 0.641

0.105

− 0.544

0.388

− 0.243

0.340

− 0.600

p

0.701

0.959

0.524

0.917

0.589

0.700

0.809

0.735

0.551

Discussion

The results obtained in this study showed that after radiotherapy, NPC patients already showed changes in the mfERGs before visible fundus changes in RME, which were mainly manifested as decreases in the P1 response densities. Kondo et al. [17] suggested that the P1 and N1 waves of the mfERGs do not correspond to negative and positive waves of a full-field ERG but may be derived from the inner retina. In the present study, the results showed that the NPC group had significant differences in the mfERGs regarding P1 wave response densities compared to the control group. Thus, we inferred that after radiotherapy, NPC patients already had abnormalities in inner retinal function before any visible fundus changes with RR appeared. We measured total macular thickness, but there were no significant differences between the NPC group and the normal control group in all nine districts. Through OCT examination, Raman et al. [18] found that patients with RR had a significantly thinner inner plexiform layer, inner nuclear layer and outer plexiform layer of the retina than normal individuals, indicating that RR-related damage is confined to the inner retina. Because our machine (Zeiss HumPhrey OCT-4000) provided entire thickness data from ILM to RPE, we cannot differentiate inner thickness and photoreceptor thickness. Thus, our further studies with a prospective study design will include inner retinal thickness analysis, even isolated retinal layer analysis.

When comparing data among the four quadrants, we found that the P1 response density, as well as the N1 amplitude, showed a significantly greater decrease in the inferonasal and inferotemporal quadrants than in the superonasal and superotemporal quadrants. We speculated that NPC patients after radiotherapy were subjected to more retinal damage by radiation in the lower part of the retina and that this is possibly related to the anatomical position of the eye. Because the lower half of the eye is close to the nasopharynx, the lower part of the eye in NPC patients receiving radiotherapy is often exposed to significantly higher radiation than the upper part of the eye.

The study by Horgan [15] demonstrated that macular oedema can be found on OCT approximately 5 months earlier than clinically detectable radiation maculopathy can be found. A subtle increase in foveal thickness and early foveal oedema, which indicates the beginning of radiation-induced damage, can be detected on OCT, while visual acuity is still preserved. However, in this study, there were no abnormalities in OCT examinations. We conclude that OCT is a morphological examination and has many advantages but that mfERG is a functional examination and is more sensitive than OCT at detecting changes in macular thickness in those NPC patients without visible retinopathy who received radiotherapy.

This study demonstrated that after radiotherapy, NPC patients already showed changes in mfERGs before any visible fundus changes and total retinal thickness at the macular changes were detected. This implies that macular function changes in NPC patients who have received radiotherapy may appear earlier than morphological changes. We suppose mfERGs may provide a good reference and tool for the early detection and prevention of RME. However, because of the limited sample size in this study, our conclusion only partially reflects the early change pattern of mfERGs in NPC patients after radiotherapy. As this study suggests inner retinal layers are more susceptible to radiation damage, segmentation of the OCT to isolate the inner retinal layer may increase the sensitivity of this test modality. Currently, OCT angiogram (OCTA) is very useful for detecting abnormalities of macular vessels, and we may perform related studies in the future. Additionally, our study is a cross-sectional study. Thus, clinical prospective studies with a larger sample size are needed to verify our results and to obtain data that could as fully as possible reflect the general pattern of early changes in the mfERGs of RME patients. Relevant work will provide more reliable reference information for the early diagnosis and prevention of RME. Because of the high incidence rate of NPC in our region, we have the resources to do relevant research, and we suppose it will be useful for the “other world”.

Notes

Compliance with ethical standards

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10633_2019_9678_MOESM1_ESM.docx (68 kb)
Supplementary material 1 (DOCX 67 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Haijun Gong
    • 1
  • Yuanlin Tang
    • 2
  • Jianhui Xiao
    • 1
  • Yimin Liu
    • 3
  • Rui Zeng
    • 1
  • Zijing Li
    • 1
  • Si Zhang
    • 1
  • Yuqing Lan
    • 1
    Email author
  1. 1.Department of Ophthalmology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina
  2. 2.Department of OphthalmologyNanhai Hospital Affiliated to Southern Medical UniversityFoshanChina
  3. 3.Department of Radiotherapy, Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina

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