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International Ophthalmology

, Volume 38, Issue 1, pp 233–239 | Cite as

The assessment of macular electrophysiology and macular morphology in patients with vitiligo

  • Rukiye Aydin
  • Mustafa Ozsutcu
  • Sevil Karaman Erdur
  • Funda Dikkaya
  • Ali Balevi
  • Merve Ozbek
  • Fevzi Senturk
Original Paper

Abstract

Purpose

We aimed to analyze the electrophysiologic function and morphology of macula in vitiligo patients.

Methods

Seventeen patients with vitiligo and 11 healthy subjects were studied. All participants underwent multifocal electroretinography (mfERG) and spectral domain optical coherence tomography (SD-OCT) evaluations. The mfERG (P1 mfERG responses central and peripheral) and retinal layer segmentation parameters (nine ETDRS subfields) were compared in vitiligo and control groups.

Results

The mean P1 response amplitudes were significantly decreased in central and peripheral rings of the fovea in patients with vitiligo compared with controls (p = 0.002 and p = 0.006, respectively). There was a tendency toward a prolonged mean implicit time for both central and peripheral in patients with vitiligo compared to controls, however, with no statistical significance (p = 0.453 and p = 0.05, respectively). There was no statistically significant difference in all retinal layers thickness between two groups.

Conclusion

In patients with vitiligo, while photoreceptor segment preserved in SD-OCT, mfERG reduced showing potential decline in central retinal function. This study showed a potential decline in central retinal function in patients with vitiligo even if they have normal fundus appearance and SD-OCT findings.

Keywords

Vitiligo Multifocal electroretinography Photoreceptor function Spectral domain optical coherence tomography 

Introduction

Vitiligo is a disease characterized by depigmentation in different parts of the skin secondary to melanocyte destruction with unknown etiopathogenesis [1].

Various ocular abnormalities may be presented in patients with vitiligo. Uveal melanocytes and pigment epithelium of the eye also contain melanin pigment and these ocular tissues may also be destroyed as cutaneous melanocytes. Hypopigmented spots on the iris and retina, atrophic changes in the peripapillary area and retinal pigment epithelium, and chorioretinal degeneration have been noted in previous studies [2, 3, 4].

There are some animal and human studies reporting electrophysiologic changes both in vitiligo. Impairment in overall retinal electrophysiologic function is observed in patients with vitiligo [5, 6, 7, 8].

Multifocal electroretinography (mfERG) is an objective method in the evaluation of retinal function. Full-field electroretinography (ERG) quantifies the electrical responses of the retina entirely, where mfERG quantifies multiple responses at distinct retinal regions simultaneously. So topographic mapping of retinal activity in the central 40°–50° of the retina can be maintained by mfERG. The mfERG could be more sensitive than the conventional ERG to the subclinical retinal changes as mfERG responses were obtained via multiple frequencies of stimulation [9, 10].

Optical coherence tomography (OCT) is a noninvasive method that enables to evaluate retinal morphology in vivo. Spectral domain optical coherence tomography (SD-OCT) with its high resolution gives chance of evaluation of retinal layers including the macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), inner nuclear layer (INL), inner plexiform layer (IPL), outer plexiform layer (OPL) and outer nuclear layer (ONL). External limiting membrane (ELM), ellipsoid zone (EZ—ellipsoid portion of the inner photoreceptor segments) and interdigitation zone (IZ—interdigitation of the apical processes of the RPE with the cone outer segments) are hyperreflective bands in the outer retina which are used to evaluate the photoreceptor segments. Some animal studies showed a good correlation between retinal histology and cross-sectional retinal images provided by OCT [11].

Histopathologic changes including degeneration of photoreceptor cells and disruption of the outer segment/RPE interdigitation similar to retinitis pigmentosa have been shown in studies with vitiligo mutant mice [6, 7, 8, 9, 10, 11, 12]. In retinitis pigmentosa patients, integrity of IZ, EZ and ELM gets disrupted and ONL thickness decreases in OCT analysis [13, 14]. Menghini et al. [15] were found correlation between ONL thickness and cone density in both normal subjects and patients with retinitis pigmentosa.

In this study, we aimed to analyze the electrophysiologic function of the macula with mfERG and morphology of macula with SD-OCT in vitiligo patients based on the association between retinitis pigmentosa and vitiligo.

Methods

We recorded mfERG responses simultaneously from both eyes of 17 patients diagnosed with vitiligo and 11 healthy individuals. Patients with any retinal diseases that could influence ERG responses such as genetic retinal diseases, retinal detachment, uveitis, macular diseases or history of consumption of oral treatment or topical eye drops that affect retinal function were also excluded. Informed consent was obtained from all subjects before their participation. Procedures followed the tenets of the Declaration of Helsinki, and the protocol was approved by the review board and ethical committee of Istanbul Medipol University.

The patients underwent complete ophthalmic examination, including corrected visual acuity measurement (with Snellen chart), slit lamp biomicroscopy and indirect ophthalmoscopy.

Multifocal ERG recording was performed in all subjects. The mfERGs were recorded using the RETI scan (Roland Consult, Weisbaden, Germany). Thirty degree of central retina was stimulated with a stimulus array of 61 hexagons. The luminance of the stimulus was 120 cd/m2 for the bright flashes and 1 cd/m2 for the dark flashes.

Tropicamide 5 mg/mL and cyclopentolate hydrochloride 10 mg/mL drops were administered to fully dilate the pupil before testing. All patients were stayed in room light for 15 min for light adaptation before testing. Gold foil scleral electrodes were used for mfERG recording. Room lights were maintained throughout the recordings. The mfERG recordings were divided into eight segments, and any unsuitable records were discarded and recorded again. Retinal signals were filtered with low-frequency and high-frequency cutoffs of 10 and 300 Hz, respectively, and amplified with a gain of 100,000.

The first-order kernel mfERG responses were analyzed. The mfERG provides detection of the spatial variations in mfERG responses that localize retinal damage to discrete regions of retina: the macula, paramacular or discrete peripheral areas [16]. Therefore, individual mfERG responses for the hexagons were grouped into the two concentric areas centered on the fovea, with a central ring of 0°–7° (central group) and a peripheral ring 7°–25° (peripheral group). The first positive peak (P1) response amplitudes and P1 peak latencies for the central and peripheral groups were then measured. Results were compared between study group and controls.

After mfERG, SD-OCT was performed with the Spectralis (Heidelberg Engineering, Heidelberg, Germany) which has software that allows the segmentation of individual layers of the retina including the mRNFL, GCL, INL, IPL, OPL and ONL. Nine ETDRS subfields were used in the analysis; central fovea (CF), inner superior (IS), inner nasal (IN), inner inferior (II), inner temporal (IT), outer superior (OS), outer nasal (ON), outer inferior (OI) and outer temporal (OT). Results for ONL and total macular thickness were compared with study and control groups.

Optical coherence tomography also enables to evaluate the ELM, EZ and IZ which are hyperreflective bands in the outer retina showing integrity of the photoreceptor segments. We also evaluate the integrity of ELM, EZ and IZ for all subjects.

Results

The mean subject age was 33.5 ± 13.5 years (range 15–60 years) in vitiligo group (nine females, eight males) and 32 ± 9 years (range 15–45 years) in control group (seven females and four males). There were no significant differences between two groups with respect to age or sex (p = 0.747 and p = 0.576, respectively). All patients had a visual acuity of 20/20.

Clinical characteristics of patients with vitiligo are shown in Table 1. The mean mfERG-c P1 and mfERG-p P1 amplitudes were significantly lower in vitiligo group compared with control group (p = 0.002 and p = 0.006, respectively). There was no significant difference in mfERG-c P1 and mfERG-p P1 peak times between two groups (p = 0.453 and p = 0.05). Figure 1 shows a normal mfERG response of a control subject, whereas Fig. 2 shows affected mfERG traces of left eye of 16 years old vitiligo patient. Summary statistics are shown in Table 2.
Table 1

Clinical characteristics of patients with vitiligo

Patient

Age (years)

mfERG-c P1 amplitude (nV/°2)

mfERG-p P1 amplitude (nV/°2)

mfERG-c P1 peak time (ms)

mfERG-p P1 peak time (ms)

1

16

26.55

12.81

45.20

41.30

2

34

62.26

22.95

44.30

42.30

3

16

63.80

23.33

44.30

42.30

4

41

67.94

23.63

43.30

41.30

5

26

43.62

19.09

40.30

43.30

6

60

43.49

18.13

43.30

43.30

7

45

26.93

14.99

41.30

43.30

8

49

39.41

16.04

42.30

43.30

9

16

71.93

22.33

46.20

42.30

10

45

53.48

18.59

42.30

42.30

11

40

53.58

20.77

46.20

43.30

12

39

59.03

21.67

45.20

43.30

13

28

53.47

26.23

42.30

44.30

14

45

12.54

11.65

35.40

42.30

15

15

55.33

21.47

43.30

41.30

16

24

61.44

25.40

41.30

41.30

17

31

43.05

19.14

48.20

43.30

mfERG-c mfERG-central, mfERG-p mfERG-peripheral

Fig. 1

Normal multifocal electroretinogram response of a control subject

Fig. 2

Multifocal electroretinogram of the right eye of patient showing decreased mean mfERG-c P1 and mfERG-p P1 amplitudes

Table 2

Comparisons of the multifocal electroretinography parameters between groups

Parameters

Vitiligo group

Mean ± SD

Control group

Mean ± SD

p* value

mfERG-c P1 amplitude (nV/°2)

49.3 ± 16.1

67.7 ± 7.5

0.002

mfERG-p P1 amplitude (nV/°2)

19.9 ± 4.2

24.3 ± 3.2

0.006

mfERG-c P1 peak time (ms)

43.2 ± 2.9

42.5 ± 1.7

0.453

mfERG-p P1 peak time (ms)

42.6 ± 1

41.8 ± 1

0.05

SD standard deviation, mfERG-c mfERG-central, mfERG-p mfERG-peripheral

* Independent t test

In OCT images of patients, ELM, EZ and IZ which are used to evaluate photoreceptor segments were intact. There was no statistically significant difference in thickness of ONL and total macular thickness between two groups (Table 3; Fig. 3). Also there was no statistically significant difference in the thickness of mRNFL, GCL, INL, IPL, OPL in all nine ETDRS subfields between two groups.
Table 3

Comparisons of the total retinal and ONL thickness between groups

 

Vitiligo patients

Mean ± SD

Control group

Mean ± SD

p

Retina central

268.76 ± 21.5

274.65 ± 17.2

0.387

Retina nasal inner

349.29 ± 16.4

351.59 ± 15.2

0.676

Retina nasal outer

322.76 ± 18.4

326.82 ± 14

0.475

Retina superior inner

350.53 ± 16.5

349.65 ± 15.7

0.875

Retina superior outer

308.82 ± 13.9

307.65 ± 12.5

0.797

Retina inferior inner

347.65 ± 16

346.53 ± 29.7

0.892

Retina inferior outer

295.65 ± 15.7

298.47 ± 11.9

0.560

Retina temporal inner

333.35 ± 14.9

335.35 ± 13.5

0.685

Retina temporal outer

292.94 ± 12.8

299.35 ± 25.4

0.361

ONL central thickness

91.94 ± 11

92.82 ± 13.8

0.838

ONL nasal inner

76.94 ± 10.1

77.94 ± 8.7

0.761

ONL nasal outer

61.65 ± 8.5

60.88 ± 7.1

0.779

ONL superior inner

67.94 ± 13.2

66.94 ± 14.1

0.833

ONL superior outer

61.47 ± 8.9

61.18 ± 8.4

0.922

ONL inferior inner

65.82 ± 14.2

71.42 ± 11.5

0.219

ONL inferior outer

53.47 ± 7.2

55.12 ± 5.8

0.471

ONL temporal inner

74.53 ± 7.1

74 ± 9.7

0.858

ONL temporal outer

59.53 ± 6.7

60.29 ± 7

0.749

Fig. 3

Normal topographic results of retinal layer segmentation of a vitiligo patient with abnormal mfERG

Discussion

Although visual acuity is still the gold standard in visual function assessment in routine clinic practice, there are some other aspects of visual function, such as contrast sensitivity, color discrimination, dark adaptation in some cases. Therefore, we need some other tests to have a more detailed assessment of visual function. One of those established tests is mfERG. Multifocal ERG changes might be more pervasive than predicted based on the healthy fundus appearance of a patient with 20/20 visual acuity in both eyes.

In mfERG technique, local electric activities from distinct locations of the retina are recorded. Therefore, in patients with normal fundus appearance mfERGs may help to discriminate between retinal and central etiology of visual problems. This technique allows obtaining multiple local ERG responses, obtained simultaneously from the cone-driven retina under photopic conditions. Similar to traditional full-field ERG recording, a corneal electrode is used to record electrical responses from the retina. What differs between two techniques is the style of the stimulus and the type of the analysis. In this way, local electrical activity of the retina topographically could be quantified [9, 10].

Generally, an abnormal mfERG shows that the foveal cones and/or bipolar cell layers are dysfunctional which leads to vision loss. The precise distribution of the retinal dysfunction may also be reported by mfERG, but flash ERG does not give this information.

Tang et al. [6] reported abnormal flash ERG findings secondary to histopathologic abnormalities in mutant mice with vitiligo. Similar with retinitis pigmentosa, the authors found reduced and delayed a- and b-ERG waves. Additionally, they observed short and disoriented rod outer segments and dissociation between rod segments and pigment epithelium [6]. The apoptosis of the photoreceptors in vitiligo mice was shown in the morphologic and biochemical studies. In another study by Smith et al. [17], photoreceptor cell apoptosis was reported depend on morphologic and biochemical data. Bora et al. [12] found weak adhesion connections between the neural retina and RPE in a Mitf vitiligo mutant mouse.

Perossini et al. [7] observed that electro-oculography and pattern visual evoked potential tests were varied in patients with vitiligo. Shoeibi et al. [5] assessed the retinal electrophysiology in patient with psoriasis and vitiligo. They found significantly reduced mean rod response b-wave, standard combined a- and b-waves, single flash cone response b-wave and the 30-Hz flicker (N1-P1) amplitudes in the study group compared with controls in the same range of age. They reported significant impairment in overall retinal electrophysiologic function in patients with vitiligo and psoriasis [5].

Based on RPE photoreceptor atrophy, ERG abnormalities and dark adaptation results were reported in a vitiligo subject by Albert et al. [8]. They claimed that there might be association between retinitis pigmentosa and vitiligo. Electrophysiologic and histopathologic studies with vitiligo mutant mice also suggested RPE and photoreceptor changes similar to the retinitis pigmentosa [6, 7, 8, 9, 10, 11, 12, 17].

Earliest histopathologic change in retinitis pigmentosa is distortion in the outer segments of the rod and cone photoreceptors, and loss of photoreceptors following these changes [18]. Current spectral domain OCT devices with their high resolution enables in vivo detailed evaluation of retinal structure and measurement of the thickness of the all segments of retina. In the literature, there are studies showing loss of IZ and EZ band, ELM and decrease in ONL thickness in retinitis pigmentosa patients which are consistent with histopathologic change [13, 14].

There are a few studies which investigate relation between mfERG and OCT changes. Sugita et al. [19] reported relation between macular volume and length of the IS/OS line with amplitude of the mfERGs in retinitis pigmentosa patients. They found weak correlation between the mfERG amplitude and macular structure by OCT. They reported some patients with severely reduced mfERG amplitude had normal total macular volume and relatively preserved IS/OS line. This result indicated that electrophysical changes might precede structural changes. Contrary to it, Wolsley et al. [20] showed loss of mfERG amplitude correlated with photoreceptor layer thinning in retinitis pigmentosa patients with good visual acuity and central visual fields.

In our study, we found that the mean P1 amplitude for both central and peripheral groups was significantly lower in vitiligo group compared to control group. However, mean P1 peak latencies for both groups were not significantly different from control group. Our results are compatible with the previous studies. However, full-field ERG was used in those. The major contribution of our study is the usage of mfERG. The mfERG shows that the amplitude of the cone ERG signal generated focal responses by the central 30° area of the macula is decreased in vitiligo patients relative to normal adults. Because the mfERG response is closely relative with the density profile of cone photoreceptors, the reduced ERG signal in vitiligo proposes a decrease in macular cone photoreceptor density. Although we found decreased mean P1 response amplitude, there was no disruption in ELM, EZ and IZ band, also there was no difference in thickness of outer nuclear and other layer between vitiligo and control group. This result made us to think that functional abnormality could occur in vitiligo patients which were detected with electrophysical tests without any structural changes.

In conclusion, in this study we reported mfERG abnormalities in eyes of patients with vitiligo who have healthy fundus appearance with good visual acuity in both eyes. In patients with vitiligo, while photoreceptor segment preserved in OCT, P1 amplitude of the first-order kernel mfERG reduced showing potential decline in central retinal function. These findings should be kept in mind when evaluating the vision and retinal function of vitiligo patients.

Notes

Funding

No funding was received for this research.

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.

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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Rukiye Aydin
    • 1
  • Mustafa Ozsutcu
    • 1
  • Sevil Karaman Erdur
    • 1
  • Funda Dikkaya
    • 1
  • Ali Balevi
    • 2
  • Merve Ozbek
    • 1
  • Fevzi Senturk
    • 1
  1. 1.Department of OphthalmologyIstanbul Medipol UniversityBagcılar, IstanbulTurkey
  2. 2.Department of DermatologyIstanbul Medipol UniversityIstanbulTurkey

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