Introduction: Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, optic neuropathy. The typical symptoms include reduced visual acuity and central scotoma. Despite the presence of deep central scotoma, some patients with LHON are able to perform daily activities. This study aimed to investigate the correlation between the residual visual field and visual acuity, critical flicker frequency, and fixation ellipse in patients with chronic LHON. Methods: Residual visual function (defined as sensitivity points where patients sensed the size V stimulus) of both eyes was evaluated in 10 patients with LHON carrying the m.11778 mitochondrial DNA mutation and with median age of onset and disease duration of 29 and 16.5 years, respectively. The central visual field was measured as static perimetry using the Humphrey visual field testing 30-2 program with the size III or V stimulus. Moreover, best-corrected visual acuity, critical flicker frequency, and the correlation between fixation ellipse and residual central visual fields were determined. The analysis was performed through a linear mixed-effects model. Results: The residual visual sensitivity in the inferior nasal visual field was significantly correlated with the logMAR (p < 0.05). The fixation ellipse fell within the residual visual field region with higher sensitivity. Conclusions: Patients with chronic LHON tended to retain the sensitivity detectable with the size V stimulus at the central inferior nasal visual field regions, where the fixation ellipse fell. Visual acuity, which influences daily activity, was spatially correlated with residual visual sensitivity.

Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, bilateral optic neuropathy associated with point mutations in the mitochondrial DNA. Three point mutations, i.e., m.3460G > A, m.11778G > A, and m.14484T > C, account for more than 90% of LHON cases [1]. This optic neuropathy usually emerges in men during adolescence up until their 30s [2]. The typical symptoms include a marked reduction in corrected visual acuity and central scotoma. In most cases, the corrected decimal visual acuity declines to approximately 0.1 [3]. LHON develops in one eye and subsequently in the other eye within weeks or months. Although some patients with LHON spontaneously recover their visual function [4], most of them retain the visual defects.

The central 10° and 30° visual fields have exceptionally high sensitivity and are essential in maintaining visual acuity [5‒7], and a defect in these fields leads to a significant loss of visual function. For example, the sensitivity of the central 10° visual field is strongly correlated with visual acuity, affecting the quality of vision of patients with glaucoma. Additionally, there is a correlation between the sensitivity of the central 30° visual field and best-corrected visual acuity, and the residual visual field is critical in predicting changes in visual acuity [6].

Despite the development of deep central scotoma, clinicians have occasionally reported patients with LHON who can manage school activities or delicate jobs that comprise visual tasks, suggesting that they may retain a residual visual sensitivity within the scotoma and adapt to visual impairment through this residual visual field. In this regard, studies have shown that, when the size V stimulus is used instead of the routine size III stimulus in the Humphrey visual field test, residual sensitivity is detected within the visual field defect; thus, the actual scotoma size decreases in patients with glaucoma and retinitis pigmentosa [8, 9]. Our previous study reported that the scotoma detected in patients with LHON using the size V stimulus was also smaller than that detected using the size III stimulus [10].

This study aimed to investigate the spatial correlation between the residual visual field detected using the Humphrey visual field test with the size V stimulus and other visual functional variables, namely, visual acuity, form perception, critical flicker frequency (CFF), motion perception, and fixation ellipse measured via MP-3 microperimetry. Elucidating these correlations facilitates the understanding of the unique features that characterize LHON-induced visual impairment and the ways in which patients adapt to it.

Study Design and Measurements

This retrospective observational study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the Institutional Review Board of the Kobe University Graduate School of Medicine (B200115), which waived the acquisition of written informed consent because of the retrospective and observational nature of this study. However, patients could withdraw consent any time after reviewing information about this study by accessing the hospital homepage and selecting the opt-out option. Written informed consents were also obtained from all patients about using their examination results for publication, that do not identify individuals.

Japanese patients diagnosed with LHON at Kobe University Hospital were recruited, and data on their latest best-corrected visual acuity (measured using the Landolt ring chart) and CFF (RE Medical, Inc., Osaka, Japan) were retrospectively collected. The patients included in this study were at least 18 years old and did not receive any LHON-related treatments, such as idebenone or gene therapy, with the exception of supplements. This is not because we have selected patients, but unfortunately, idebenone is not approved in Japan and none of the patients participated in clinical studies involving gene therapy or trans-electrical stimulation therapy. In addition, we defined inclusion criteria as patients diagnosed with LHON based on the criteria for LHON [11] and who underwent static visual field testing using size V. Briefly, LHON is diagnosed when mitochondrial gene mutation is detected and other optic nerve diseases can be ruled out. Visual acuity test was performed by Landolt C using K-3435 Inami Wireless Remote Control Vision Screening Device (Inami & Co., Ltd.). Based on the recommendations of the Japanese Association of Certified Optometrists, illuminance of the room was set at at least 50 lux and not exceeding the optotype surface illuminance, and the luminance of the background of the optotype was set at 500 ± 125 radlux. Visual acuity was converted to the logarithm of the minimal angle of resolution (logMAR) and “counting fingers” was converted to 2.0, as previously described [12]. As previously reported [13], CFF measures the temporal resolution of vision and is deemed to reflect optic nerve function, specifically, the magnocellular pathway-related motion perception. Patients were instructed to look at a flashing light visible in an eyepiece with a diameter of 10 mm located 30 cm away. The CFF “disappear” threshold was defined as the minimum flicker frequency at which patients detected the incremental flickering of light pulse as a continuous light beam, whereas the CFF “appear” threshold was defined as the maximum flicker frequency at which patients noticed the decremental frequency of light as flickering light. Both measurements were repeated three times, and the average values were used for the analysis.

The central visual field was measured using a Humphrey field analyzer (HFA; Carl Zeiss Meditec, Inc.) and the Swedish Interactive Thresholding Algorithm program 30-2 with size III or V stimulus. The 72 visual field points measured using the HFA were grouped into five areas: four points were assigned to the central area and the superior nasal, inferior nasal, superior temporal, and inferior temporal areas; 34 points to the superior and inferior nasal areas (17 per area); and 32 points to the superior and inferior temporal areas (16 points per area) excluding the Mariotte blind spot.

The reliability of the Humphrey visual field test is indicated by three parameters: stability of fixation, false positives, and false negatives. During each visual field test, the optometrist checked the patient’s gaze directly on the monitor and guided the patient to ensure that the fixation position did not shift. The test is determined extremely unreliable when false positives and false negatives exceed 15% and 33%, respectively. In this study, false negatives were not detected in any patient, and false positives were detected only in the right eye of 1 patient (No. 10). Based on these results, we concluded that the reliability of patient testing was assured.

The fixation ellipse was examined using an MP-3 microperimeter (Nidek, Co., Ltd., Aichi, Japan). A cross-shaped target of 2° viewing angle was visualized at the center of the monitor, and patients were instructed to look at the target at a retinal location where the target was most clearly visible. If patients could not find it, its size was increased to 10° and its shape was changed to a circle, or the orthoptists guided the patients to look at an appropriate position based on the visual field test results. After the fixation position was identified, the patients were instructed to keep staring at it for 1 min during which the MP-3 continuously recorded the fixation point. During the examination, the fixation points were measured 30 times per second, for a total of 1,800 times. The fixation frequency of each patient was treated as normally distributed data, with the highest portion of the distribution displayed in purple and the surrounding areas in a light blue gradation (shown in Fig. 1). The spatial correlation between the residual visual field with the highest sensitivity and other visual functions tested, i.e., logMAR, CFF “appear” and “disappear” threshold values, and fixation ellipse position, was evaluated.

Fig. 1.

Spatial correlation of fixation ellipses and central visual field areas. a, b Representative image of the superimposition of the grayscale image of the Humphrey visual field test on a fixation ellipse detected with MP-3 for cases 1 and 5. The individual’s fixation frequency was treated as normally distributed data, with the highest part of the distribution displayed in purple and the surrounding areas in a light blue gradation.

Fig. 1.

Spatial correlation of fixation ellipses and central visual field areas. a, b Representative image of the superimposition of the grayscale image of the Humphrey visual field test on a fixation ellipse detected with MP-3 for cases 1 and 5. The individual’s fixation frequency was treated as normally distributed data, with the highest part of the distribution displayed in purple and the surrounding areas in a light blue gradation.

Close modal

Statistical Analysis

A linear mixed-effects model was used to analyze the association between the residual visual field and other visual functions tested. An analysis program was developed and run using the freely available EZR software (http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/download.html). Statistical significance was set at a p value <0.05.

This study examined the visual function of 10 patients (both eyes were tested) that carried the m.11778 mtDNA mutation. The average age of onset of LHON was 46.3 years (age range, 5–52 years), and the average disease duration was 28.4 years (range, 7–36 years). Except for 2 cases (case 1 and case 9), the latest best-corrected decimal visual acuity of the patients was <0.1 (Table 1).

Table 1.

Patient information

No.SexOnset ageDurationLatest decimal visual acuity (R, L)CFF appear (R, L)CFF disappear (R, L)
36 (0.6, 0.6) (36, 41) (34, 39) 
15 31 (0.04, 0.05) (50, 52) (44, 47) 
25 28 (0.02, 0.03) (21, 20) (18, 18) 
46 22 (0.02, 0.02) (20, 17) (15, 11) 
52 20 (0.01, 0.01) (17, NA) (16, NA) 
41 (0.03, 0.02) (37, 37) (33, 33) 
33 16 (0.04, 0.03) (30, 35) (21, 25) 
44 17 (30 cm/c.f., 30 cm/c.f.) (21, 23) (19, 21) 
18 13 (0.01, 0.01) (55, 50) (45, 41) 
10 37 10 (0.2, 0.3) (32, 19) (23, 13) 
11 11 (0.01, 0.01) (27, 46) (23, 40) 
12 14 (0.02, 0.02) (46, 40) (34, 27) 
No.SexOnset ageDurationLatest decimal visual acuity (R, L)CFF appear (R, L)CFF disappear (R, L)
36 (0.6, 0.6) (36, 41) (34, 39) 
15 31 (0.04, 0.05) (50, 52) (44, 47) 
25 28 (0.02, 0.03) (21, 20) (18, 18) 
46 22 (0.02, 0.02) (20, 17) (15, 11) 
52 20 (0.01, 0.01) (17, NA) (16, NA) 
41 (0.03, 0.02) (37, 37) (33, 33) 
33 16 (0.04, 0.03) (30, 35) (21, 25) 
44 17 (30 cm/c.f., 30 cm/c.f.) (21, 23) (19, 21) 
18 13 (0.01, 0.01) (55, 50) (45, 41) 
10 37 10 (0.2, 0.3) (32, 19) (23, 13) 
11 11 (0.01, 0.01) (27, 46) (23, 40) 
12 14 (0.02, 0.02) (46, 40) (34, 27) 

Onset age, years old; duration, years; CFF, Hz. M, male; F, female; R, right eye; L, left eye; CFF, critical flicker frequency; c.f., counting fingers.

The linear mixed-effects model (Table 2) showed that the inferior nasal visual field was significantly correlated with the logMAR-derived visual acuity. The shape or range of the residual visual field detected via the size V stimulus varied among individuals but exhibited a similar pattern in left and right eyes within the same patients (shown in Fig. 1, 2). Figure 1a and b depicts the fixation ellipses on the fundus photograph of cases 1 and 5, respectively, which were superimposed on the grayscale image measured using the HFA 30-2 program with size V stimulus. Case 1 seemed to have a central fixation, probably due to the relatively good residual central sensitivity. In comparison, the fixation ellipse in case 5 hovered eccentrically downward, probably due to the reduced sensitivity in the upper hemifield.

Table 2.

Spatial relationship between regions with highest residual sensitivity and logMAR and CFF appear and disappear thresholds

Region with the highest residual visual sensitivity
centralsuperior nasalinferior nasalsuperior temporalinferior temporal
LogMAR 
 B −0.0068 0.0053 −0.0223 −0.0036 −0.0059 
 SE 0.0066 0.0030 0.0093 0.0035 0.0043 
 p value 0.3011 0.0754 0.0163* 0.3065 0.1652 
CFF appear 
 B −0.0265 −0.2025 0.1543 0.0509 0.1477 
 SE 0.1573 0.2564 0.0765 0.2042 0.2132 
p value 0.8660 0.4296 0.0437* 0.8030 0.4880 
CFF disappear 
 B −0.0827 −0.3828 0.1484 0.0320 0.1099 
 SE 0.1479 0.2335 0.0674 0.1964 0.2328 
p value 0.5760 0.1011 0.0277* 0.8710 0.6646 
Region with the highest residual visual sensitivity
centralsuperior nasalinferior nasalsuperior temporalinferior temporal
LogMAR 
 B −0.0068 0.0053 −0.0223 −0.0036 −0.0059 
 SE 0.0066 0.0030 0.0093 0.0035 0.0043 
 p value 0.3011 0.0754 0.0163* 0.3065 0.1652 
CFF appear 
 B −0.0265 −0.2025 0.1543 0.0509 0.1477 
 SE 0.1573 0.2564 0.0765 0.2042 0.2132 
p value 0.8660 0.4296 0.0437* 0.8030 0.4880 
CFF disappear 
 B −0.0827 −0.3828 0.1484 0.0320 0.1099 
 SE 0.1479 0.2335 0.0674 0.1964 0.2328 
p value 0.5760 0.1011 0.0277* 0.8710 0.6646 

The linear mixed-effects model was used for statistical analyses.

B, estimate; SE, standard error.

*p < 0.05.

Fig. 2.

Typical example of a measured visual field in which the stimulus size was changed in the same patient. Changing the stimulus size from III to V allowed the detection of the residual visual field. Note the similar pattern of the residual visual field between the right and left eyes.

Fig. 2.

Typical example of a measured visual field in which the stimulus size was changed in the same patient. Changing the stimulus size from III to V allowed the detection of the residual visual field. Note the similar pattern of the residual visual field between the right and left eyes.

Close modal

Figure 3 schematically illustrates the spatial relationship between the fixation viewpoints and residual visual fields measured using the size III or V stimulus. Seven of 10 patients had concurrent visual field test in size III. The sensitivity detected at each measurement point was higher when using the size V stimulus as the residual visual field, and the fixation ellipses were located toward the sensitive area or direction.

Fig. 3.

Schematic diagrams of the spatial relationship between fixation ellipses and visual field regions measured via size III and V stimulus in 10 patients with LHON carrying the m.11778 mutation.

Fig. 3.

Schematic diagrams of the spatial relationship between fixation ellipses and visual field regions measured via size III and V stimulus in 10 patients with LHON carrying the m.11778 mutation.

Close modal

In this study, the sensitivity of the central inferior nasal visual field, which corresponds to the superior temporal retinal area, exhibited a significant correlation with visual acuity in the examined patients with LHON carrying the m.11778 mutation. The average age of LHON onset in this study was higher than typical LHON. In recent years, with the aging of the population, there has been a gradual increase in reports of newly developed cases in the elderly patients. We estimate that this situation has led to a discrepancy between the previous reports and the result of the present study.

Additionally, the patients exhibited a similar visual field defect pattern in their right and left eyes. A previous report that, in the early stages of LHON, visual field defects occur in the central superior temporal field even in cases where visual acuity is good [14] supports the present findings.

To evaluate visual function in the LHON, we consider visual acuity, CFF, visual field test, and fixation point to be very useful indicators. The results of subjective testing are important indicators of how the patient is using the remaining visual field. On the other hand, it is difficult to analyze the results of structural examinations such as OCT, especially in patients with chronic LHON, because the inner retinal layers are completely thinned, and it is difficult to observe changes over time and differences in findings between patients. For the reasons described above, we chose the tests for the current study. Although visual acuity, CFF, and visual field testing are commonly performed, fixation point or visual field test in stimulation size V have rarely been considered examination for LHON. We have been detecting residual visual fields in patients with LHON by changing the size of the stimulation size for several years [10].

The association between the central visual field and quality of vision has also been reported [14, 15]. Yamazaki et al. [15] investigated the relationship between the residual central visual field and vision-related quality of life in patients with advanced glaucoma and revealed that the inferior central visual field was essential for patients to perform daily activities. Furthermore, this study examined the relationship between each activity and the inferior visual field and obtained different vision-related quality of life-associated visual fields from reading texts and walking because the gaze direction required by these activities was different. These results are well in line with the present findings, which show the close association between higher residual visual sensitivity in the central inferior nasal regions and visual acuity. Conversely, relatively good values are usually reported for CFF, and light reflex is preserved in patients with LHON, which is expected as intrinsically photosensitive retinal ganglion cells (RGCs) involved in circadian rhythm and light reflex are less likely to be impaired in LHON [16]. In the present study, there was no significant relationship between CFF and residual visual field, which is also consistent with previous reports.

Altpeter et al. [17] showed that reading speed decreases in patients with LHON and there is a negative correlation between reading speed and the size of the central scotoma. The study also revealed that approximately 60% of patients with LHON exhibited unstable fixation due to inadequate fixation points. However, our previous study showed that the visual field test using the size V stimulus identified residual visual sensitivity in the scotomatous areas measured using size III stimulus [10]. The present study further demonstrated that the fixation ellipse was located within the residual visual field. Therefore, patients with LHON may utilize their residual visual field more efficiently during their daily activities than previously acknowledged.

Based on their morphology and function, RGCs are roughly divided into three types, namely, midget, parasol, and bistratified cells, which are responsible for the parvocellular, magnocellular, and koniocellular pathways, respectively, at the lateral geniculate body [18]. Midget cells and the parvocellular pathway are involved in color and morphological perception; parasol cells and the magnocellular pathway are involved in the detection of brightness change (i.e., motion perception); and bistratified cells and the koniocellular pathway are associated with color perception.

Moreover, parasol cells are less damaged than other types of RGCs in patients with LHON with a relatively well-maintained CFF [13]. Additionally, parasol cells and the magnocellular pathway play a role in silent reading, so patients with better CFF values may be able to read better [19]. Furthermore, the lower visual field was related to high contrast sensitivity, which is mediated by the parvocellular pathway [20]. However, other studies claimed that midget and parasol cells interact with each other to transmit visual information and that all types of RGCs are active in patients with LHON [21]. Conversely, intrinsically photosensitive, melanopsin-producing RGCs were shown to be preserved in patients with LHON, who would then exhibit a less impaired light reflex [15]. Therefore, it is still controversial whether selective groups of RGCs are prone to cell death and how different types of RGCs interact during the transmission of visual information in patients with LHON.

This study has several limitations: the small sample size and its cross-sectional nature. LHON is a rare disease and patients with chronic phase usually visit the hospital less frequently. To analyze the residual visual function in LHON patients, we should continue the study and accumulate data. In addition, each visual field test was performed on one eye at a time not on both eyes. In response to your suggestion, we considered that binocular visual acuity or visual field test is necessary to evaluate the accurate visual function of patients in daily life and that is the limitation and future direction of the current study. Moreover, to investigate residual visual field in LHON, kinetic perimetry is also the important tool [22]. Kinetic and static perimetry should be used separately. While kinetic perimetry is very useful to determine the area of residual visual function, static perimetry is important to evaluate the residual sensitivity of the central visual field, which is used especially for daily activities. In this study, we focused on the residual sensitivity of the central visual field and used the static perimetry.

In conclusion, patients with LHON carrying the mtDNA 11778 mutation examined in this study tended to have residual visual sensitivity in the inferior nasal central visual field with measurement using the size V stimulus. The residual visual field in this specific area may be correlated with visual acuity and CFF, the parameter that evaluates motion perception. This correlation may be explained using an adaptive process of fixation directed toward the residual visual field area in patients with LHON.

The authors are grateful to Sae Murakami and Yumi Takagi, Clinical and Translational Research Center, Kobe University Hospital, for their valuable advice concerning the statistical analysis. Additionally, the authors would like to thank Enago (www.enago.jp) for the English language review.

This retrospective observational study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the Institutional Review Board of the Kobe University Graduate School of Medicine (B200115), which waived the acquisition of written informed consent because of the retrospective and observational nature of this study. However, patients could withdraw consent any time after reviewing information about this study by accessing the hospital homepage and selecting the opt-out option. Written informed consents were also obtained from all patients about using their examination results for publication, that do not identify individuals.

The authors have no conflicts of interest to declare.

This study was supported by Research Grant KAKEN (18K16957). Commercial relationship disclosures: none.

K.U. designed the study, analyzed the data, and wrote the manuscript; M.K. collected and analyzed the data; T.K. wrote the manuscript; and M.N. supervised the project.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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