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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 21  |  Issue : 3  |  Page : 194-203

Role of multifocal electroretinogram in the prediction of visual prognosis in patients with occult macular dystrophy


Department of Ophthalmology, Benha Faculty of Medicine, Benha University, Benha, Egypt

Date of Submission29-Feb-2020
Date of Decision15-Jun-2020
Date of Acceptance30-Jun-2020
Date of Web Publication23-Sep-2020

Correspondence Address:
MD Marwa Abdelshafy
1 El Amira Fawzya Street, El Vilal, Benha, El Qalubyai 13512
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/DJO.DJO_19_20

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  Abstract 


Background Occult macular dystrophy (OMD) is a rare hereditary macular dystrophy characterized by severe bilateral progressive loss of central vision with normal fundus appearance and normal fundus fluorescein angiography.
Aim The aim of this study was to assess the correlation between multifocal electroretinogram (mf-ERG) parameters and best-corrected visual acuity (BCVA) in patients with OMD.
Patients and methods In all, 20 eyes of 10 patients with OMD and 20 eyes of 10 age-matched and sex-matched normal individuals were included in this study. Full ophthalmic examination, fundus fluorescein angiography, optical coherence tomography, full-field ERG and mf-ERG were performed for all participants. The average amplitude density of P1 wave, amplitude, and implicit time of P1 and N1 waves were recorded in the five concentric hexagonal rings. Correlation between these mf-ERG parameters and BCVA (LogMAR) was analyzed.
Results There were no statistically significant differences in age, sex, and refraction between the studied groups (P=0.54, 1.0, and 0.82, respectively). Mf-ERG parameters in OMD patients showed significant central depression with less affection of peripheral rings. The average amplitude density of P1 wave and the amplitude of P1 and N1 waves were significantly reduced in the central rings (rings 1, 2, and 3), with less impairment in paracentral areas (rings 4 and 5). The implicit time of P1 and N1 waves were significantly delayed across the central rings in OMD patients. The BCVA (LogMAR) was significantly negatively correlated with the amplitude of P1 and N1 waves (P≤0.001). The BCVA (LogMAR) was significantly positively correlated with the implicit time of P1 and N1 waves (P≤0.001). Multiple regression analysis demonstrated that the amplitude and latency of P1 and N1 waves in the central rings (1 and 2) were the most important determinants for BCVA.
Conclusion Mf-ERG has a key role in the detection of OMD and can be considered as a valuable objective test for the detection of central/macular dysfunction. The amplitude and latency of P1 and N1 waves in rings 1 and 2 may be used as biomarkers for the prediction of visual prognosis in these patients.

Keywords: multifocal electroretinogram, occult macular dystrophy, optical coherence tomography, visual acuity


How to cite this article:
Abdelshafy M, Abdelshafy A. Role of multifocal electroretinogram in the prediction of visual prognosis in patients with occult macular dystrophy. Delta J Ophthalmol 2020;21:194-203

How to cite this URL:
Abdelshafy M, Abdelshafy A. Role of multifocal electroretinogram in the prediction of visual prognosis in patients with occult macular dystrophy. Delta J Ophthalmol [serial online] 2020 [cited 2020 Oct 30];21:194-203. Available from: http://www.djo.eg.net/text.asp?2020/21/3/194/295875




  Introduction Top


Occult macular dystrophy (OMD) is a rare hereditary macular dystrophy [1],[2]. It is characterized by severe bilateral progressive loss of central vision with no visible abnormalities in the fundus and normal fundus fluorescein angiography (FFA) [3],[4],[5]. It was first described by Miyake et al. [6]. Both scotopic (rod) and photopic (cone) components of the conventional full-field electroretinogram (ERG) are essentially normal in OMD patients. However, focal macular electroretinogram and multifocal electroretinogram (mf-ERG) show marked reduction of amplitude, which indicates that the dysfunction of the retina is confined to the central macula rather than the retinal periphery [7],[8]. OMD is often misdiagnosed due to the normal appearance of both fundus and FFA, which makes the diagnosis of such patients a challenging situation [2].

With advancement of spectral domain optical coherence tomography (SD-OCT), eyes with OMD were found to have structural changes even in the absence of any macular abnormalities on fundus examination [1]. SD-OCT may show disruption of the photoreceptor and/or outer nuclear layers, lost ellipsoid zone, loss of the inner segment–outer segment (IS–OS) junction and reduction of the foveal thickness. However, some cases were reported to have minimal to subtle changes in OCT in spite of macular dysfunction [9],[10],[11].

mf-ERG provides a topographic measurement of the macular function, centered on the posterior retina (20°–30°) on either side of fixation, by recording many local electroretinogram responses (61 or 103) from the cone-driven photoreceptor layer under photopic condition [12],[13].

OMD has been known to be caused by mutations in the retinitis pigmentosa 1-like 1 gene. The most common mode of inheritance is autosomal dominant. However, sporadic cases were also reported [14],[15],[16].

The aim of this study was to highlight the crucial role of mf-ERG in the diagnosis of OMD and to delineate its role in the prediction of visual prognosis in these patients by studying the correlation between mf-ERG parameters and best-corrected visual acuity (BCVA).


  Patients and methods Top


Forty eyes of 20 patients were included in this cross-sectional comparative study, which was conducted between January 2018 and February 2020. All participants were recruited from the Outpatient Clinics of Benha University Hospitals. After approval of the Local Ethics Committee of the Faculty of Medicine, Benha University, all participants or their legal guardians signed a written informed consent with the requirements of the Declaration of Helsinki to participate in the study and for publication of data before enrollment into the study.

Participants were divided into two groups: 20 eyes of 10 patients were diagnosed with OMD; six men and four women, ranging in age from 14 to 28 years (OMD group) and 20 eyes of 10 age- matchedand sex-matched normal individuals; six men and four women, ranging in age from 14 to 30 years (control group). OMD was diagnosed according to the following findings: presence of bilateral progressive loss of central vision, no visible abnormality on fundus examination, normal FFA, and normal scotopic and photopic components of the full-field ERG with marked reduction of the focal macular cone ERG. Six patients reported the presence of visual problems in other family members, while the other four patients had no positive family history. The healthy volunteers had BCVA better than 6/9, with no associated ocular diseases.

All participants had full ophthalmologic examination including slit-lamp examination, refraction, BCVA using Snellen’ s chart (expressed as LogMAR), intraocular pressure measurement by applanation tonometry, dilated fundus examination, FFA, OCT, full-field ERG, and mf-ERG.

SD-OCT scans (Topcon 3D OCT model 2000 FA, version 8.30, Topcon Corporation Company, Tokyo, Japan) was used for the analysis of macular morphology.

Full-field ERG and mf-ERG were recorded after pupil dilatation, using RETI-port/scan 21 (Roland Consult, Brandenburg, Germany) and following the International Society for Clinical Electrophysiology of Vision standards [12].

Mf-ERG was recorded using HK-loop electrodes (Hawlina-Konec electrode, HK Med; Avantia, Ljubljana, Slovenia) that were installed into the lower fornix, with the reference skin electrodes attached on the skin near the orbital rim temporally of each eye and ground skin electrodes attached on the central part of the forehead.

The mf-ERG stimulus consisted of 61 hexagons, covering a visual field of 30° and was presented on a monitor (at a viewing distance of 33 cm from the patient). Each hexagon was alternated between light and dark. Each hexagon was stimulated with the same m-sequence (frame rate: 75 Hz, hexagon luminance: 120 cd/m2 in the lighted state and <1 cd/m2 in the dark state and the contrast between white and black hexagons was 93%). Each recording session was subdivided into eight recording cycles.

The following mf-ERG parameters were recorded in the five concentric hexagonal rings: the average amplitude density of P1 wave [Amp.P1(nV/deg2)], amplitude of P1 wave [Amp.P1(mv)], amplitude of N1 wave [Amp.N1(mv)], implicit time of N1 wave [PeT.N1(ms)], and implicit time of P1 wave [PeT.P1(ms)]. Correlation between these mf-ERG parameters and visual acuity (BCVA, LogMAR) were analyzed.

Statistical analysis

The collected data were tabulated and analyzed using SPSS (the Statistical Package for Social Sciences software, version 16; SPSS Inc., Chicago, Illinois, USA). Categorical data were presented as number and percentages, and analyzed by Fisher’s exact test. Quantitative data were tested for normality using the Shapiro–Wilk test assuming normality at P value more than 0.05. Nonparametric variables were presented as median and interquartile range and were analyzed by Mann–Whitney U test (ZMWU) for two independent groups. Spearman’s correlation coefficient (rho) was used to assess nonparametric correlations. Significant factors of correlation were entered through stepwise multiple linear regression analysis to detect the significant predictors of BCVA. P value less than or equal to 0.05 was considered significant and P value less than or equal to 0.001 was considered highly significant.


  Results Top


Twenty eyes of 10 patients diagnosed with OMD; six (60%) men and four (40%) women, with a mean age of 19.2±6.0 years (OMD group) and 20 eyes of 10 age-matched and sex-matched normal individuals; six (60%) men and four (40%) women, with a mean age of 19.6±6.1 years (control group) were included in the study. There were no statistically significant differences in age, sex, and refraction between the studied groups (P=0.54, 1.0, and 0.82, respectively, [Table 1] and [Table 2]).
Table 1 Age and sex of the studied groups

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Table 2 Comparing the studied eyes regarding the studied parameters

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All patients with OMD had normal fundus picture and normal FFA. The OCT in OMD patients showed significant thinning of the central macular thickness in comparison to the control group (P<0.001, [Table 2]). The OCT findings in OMD patients varied between disruption of the photoreceptor/outer nuclear layers with lost ellipsoid zone and foveal cavitation in 12 (60%) eyes, minimal central loss of the IS–OS junction, and reduction of the foveal thickness in six (30%) eyes, while two (10%) eyes were reported to have no changes in the OCT ([Figure 1]).
Figure 1 Fundus picture and fundus fluorescein angiography of a patient with occult macular dystrophy: no visible abnormalities. Optical coherence tomography of both eyes show lost ellipsoid zone, disruption of the photoreceptor IS–OS layer, and foveal cavitation (gap in the subfoveal outer segment layer not associated with diffuse retinal thinning). IS–OS, inner segment–outer segment.

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All patients with OMD had normal scotopic and photopic responses of the full-field ERG ([Figure 2]). Mf-ERG parameters in OMD patients showed significant central depression with less affection of the peripheral rings ([Figure 3] and [Figure 4]). The average amplitude density of P1 wave, amplitude of P1 wave, and amplitude of N1 wave were significantly reduced in the central rings (rings 1, 2, and 3), with less impairment in paracentral areas (rings 4 and 5) in the OMD group in comparison to the control group ([Figure 5],[Figure 6],[Figure 7]). The implicit time of P1 and N1 waves were significantly delayed across the central rings in OMD patients ([Figure 8] and [Figure 9] and [Table 2]).
Figure 2 Normal scotopic and photopic responses of the full-field electroretinogram in a patient with occult macular dystrophy.

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Figure 3 Multifocal electroretinogram of a patient with occult macular dystrophy; there was reduction of the amplitude of P1 wave in the central rings (1 and 2) with less affection of the peripheral rings.

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Figure 4 (a) Optical coherence tomography of a patient with occult macular dystrophy (OMD) shows disruption of the IS–OS segment and decreased foveal thickness; (b) optical coherence tomography of normal individuals; (c) multifocal electroretinogram (mf-ERG) of the OMD patient with reduced amplitude of the P1 wave in the central ring and lost foveal peak in the 3D layout; and (d) mf-ERG in a normal individual. IS–OS, inner segment–outer segment.

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Figure 5 Line graph showing median average amplitude density of P1 wave among the studied groups; there were marked reduction in central rings in the occult macular dystrophy group.

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Figure 6 Line graph showing median amplitude of P1 wave among the studied groups.

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Figure 7 Line graph showing median amplitude of N1 wave among the studied groups.

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Figure 8 Line graph showing median implicit time of N1 wave among the studied groups.

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Figure 9 Line graph showing median implicit time of P1 wave among the studied groups.

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There were significant negative correlations between the amplitude of P1 and N1 waves in the central rings (rings 1, 2, and 3) with the BCVA (LogMAR). In the OMD group, the patients with the least BCVA had the markedly reduced amplitude of P1 and N1 waves in the central rings. The implicit time of P1 and N1 waves were significantly positively correlated with BCVA (LogMAR). In the OMD group, the patients with the least BCVA had the most prolonged latency of P1 and N1 waves in the central rings ([Table 3]).
Table 3 Correlation between best-corrected visual acuity and the multifocal electroretinogram parameters among the occult macular dystrophy group

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The factors that were found to be significantly correlated with BCVA were entered into the stepwise multiple linear regression model to detect its significant predictors ([Table 4]). The model showed that the average amplitude density of P1 wave in rings 1 and 2, amplitude of N1 wave in rings 1 and 2, and P1 and N1 implicit times in ring 1 were the significant predictors of BCVA (P<0.05 for all).
Table 4 Stepwise multiple linear regression analysis for the predictors of best-corrected visual acuity

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  Discussion Top


OMD is a rare type of macular dystrophy characterized by progressive loss of central vision due to macular dysfunction [1],[17]. It is usually misdiagnosed due to the associated normal fundus appearance, normal FFA, and normal full-field ERG [2],[3],[4],[5]. The ophthalmologists should keep it in mind as a possible cause of unexplained decreased visual acuity.

We report the first 10 cases with OMD in Benha University Hospital. The precise analysis of mf-ERG helped us to make the diagnosis in spite of normal fundus, FFA, and flash ERG.

Mf-ERG is considered the main diagnostic tool to distinguish OMD from other causes of decreased visual acuity with no visible fundus changes such as amblyopia, nonorganic visual loss, or optic nerve diseases [6],[18].

OMD should be also differentiated from other hereditary retinal diseases with normal fundus appearance such as congenital stationary night blindness [19],[20] and cone dysfunction syndromes [21],[22]. However, these diseases have abnormal full-field ERG with characteristic findings that help in their diagnosis.

Previous studies have reported the presence of structural changes in the macular area of OMD patients evident by OCT [9],[10],[23],[24],[25]. OCT may show reduction of foveal thickness and disrupted IS–OS junction. However, these changes may be subtle in some patients even in the presence of marked reduction in mf-ERG. This indicates that the functional changes in the macular area may precede the structural changes in these patients [1],[11]. Padhi et al. [1] in their study on two siblings with OMD reported that mf-ERG responses were markedly reduced in the central macula in spite of different OCT findings in both cases. The youngest patient had apparent mf-ERG changes with minimal OCT defect, and they concluded that the structural changes seen in OCT might not always correspond to the degree of functional loss and that functional changes might precede the appearance of structural changes.

In this study, OMD patients showed significant depression of mf-ERG responses especially in the central rings with less affection of the peripheral rings. These results reflect that the retinal dysfunction is confined to the central macula. These findings are comparable with previous studies that also reported marked central depression in mf-ERG [1],[3],[7],[8],[26].

In the present study, the correlation between various mf-ERG parameters and visual acuity was assessed. There was a significant negative correlation between the amplitude of P1 and N1 waves and the BCVA (LogMAR). In addition, there was a significant positive correlation between the implicit time of P1 and N1 waves and the BCVA (LogMAR). In the OMD group, patients with the least BCVA had markedly reduced amplitude and prolonged latency of P1 and N1 waves. A better BCVA was associated with less extensive macular dysfunction. Multiple regression analyses demonstrated that the amplitude and latency of P1 and N1 waves in the central rings (1 and 2) were the most important determinants for BCVA. These mf-ERG parameters may be used for early detection of subclinical cases with positive family history and can be used to detect minimal macular dysfunction at an early stage of OMD. It may also be a valuable biomarker in the prediction of visual prognosis in OMD patients.

One of the limitations of the current study was the small number of included patients. Further genetic studies on a larger population sample and longitudinal follow-up are needed.


  Conclusion Top


In conclusion, mf-ERG has a key role in the detection of OMD and can be considered as a valuable objective test for the detection of central/macular dysfunction, which had a profound impact on visual acuity. The amplitude and latency of P1 and N1 waves in rings 1 and 2 may be used as biomarkers for the prediction of visual prognosis in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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