Clinical characteristics of the lamellar macular hole according to two subtypes: a retrospective analysis

Background: The present study compared anatomical parameters and clinical characteristics of two subtypes of lamellar macular hole (LMH): tractional and degenerative. Methods: This retrospective chart-review study included patients who were monitored for more than 6 months after the initial diagnosis of LMH, from January 2011 to January 2018. Changes in the following morphological characteristics across the study period and between the two subtypes were assessed: the mean central foveal thickness, maximum outer retina diameter (MOD), and maximum inner retina diameter (MID). Differences in the following clinical parameters between the two conditions was also assessed: best corrected visual acuity (BCVA), anatomical progression rate, rate of surgery, and mean period before surgery. Results: This study included 51 eyes of 49 patients with a mean follow-up period of 18.94 months in the study: 33 tractional eyes and 18 degenerative eyes. The difference in the mean central foveal thickness between the two groups at baseline and the end of follow-up tended toward signicance. MID was not signicantly different between the two subtypes at either time point. MOD was signicantly different between two subtypes at baseline and the end-of-follow up (tractional, 1131.62 μm, 1358.18 μm; degenerative, 708.88 μm, 697.83 μm; p < 0.01 for both). The changes in the retinal diameters across the observation period were signicantly increased in degenerative eyes, and tractional eyes featured a signicant increase in MOD across the study period. BCVA was not signicantly different between the two subtypes at baseline and the last follow up. Anatomical progression rate of tractional eyes ( 81.8%) was signicantly higher than that of degenerative eyes (27.7%) (p = 0.01). The presence of ERM was signicantly different between two subtypes (tractional, 96.9%; degenerative, 22.2%; p < 0.001). Ellipsoid defect, rate of receiving surgery, and mean observation period before surgery were not signicant different between the two subtypes. Conclusion: Analyzing two LMH

groups at baseline and the end of follow-up tended toward signi cance. MID was not signi cantly different between the two subtypes at either time point. MOD was signi cantly different between two subtypes at baseline and the end-of-follow up (tractional, 1131.62 μm, 1358.18 μm; degenerative, 708.88 μm, 697.83 μm; p < 0.01 for both). The changes in the retinal diameters across the observation period were signi cantly increased in degenerative eyes, and tractional eyes featured a signi cant increase in MOD across the study period. BCVA was not signi cantly different between the two subtypes at baseline and the last follow up. Anatomical progression rate of tractional eyes ( 81.8%) was signi cantly higher than that of degenerative eyes (27.7%) (p = 0.01). The presence of ERM was signi cantly different between two subtypes (tractional, 96.9%; degenerative, 22.2%; p < 0.001). Ellipsoid defect, rate of receiving surgery, and mean observation period before surgery were not signi cant different between the two subtypes. Conclusion: Analyzing two LMH subtypes according to their clinical and morphologic features, the present study identi ed characteristics unique to each. Treatment of LMH patients will require different approaches based on the subtype exhibited by the patient.

Background
In 1975, Gass 1 described a surface macular lesion of the multilobulated cystic macular edema as a lamellar macular hole (LMH) diagnosable with conventional biomicroscopy. Because the microscopyinformed diagnosis was ambiguous, optical coherence tomography (OCT) was developed to improve examination of the internal structure of the retina and thereby to help improve diagnostic e cacy. [2][3][4] OCT allows for the distinction of LMH from other macular diseases, such as pseudohole. 5 LMH is now de ned as a partial-thickness defect of the macula with an irregular foveal outline and isolation between the outer and inner retinal layers. 7 While prior research has characterized the histology of LMH as thinning of the foveal tissue, separation of the RPE, and preservation of the photoreceptor layers with partial loss of the inner nuclear layer, the pathogenic mechanism of LMH has yet to be elucidated clearly. 6,7 The development of OCT revealed LMH to be highly heterogeneous in morphology and function.
Epiretinal proliferation occurs in approximately 30% of LMH cases and differs from formal epiretinal membranes (ERMs). Without any has no evidence of traction or retinal folds, this proliferation appears dense and yellow, further distinguishing it from formal ERMs; these ndings may indicate that the proliferation does not include myoblasts.
Previous studies have classi ed LMH into two subtypes through anatomical OCT imaging ndings: (1) tractional, which is thought to be caused by horizontal forces exerted by ERM and vitreomacular traction (VMT); (2) degenerative, which is clearly distinguished by a lack of a traction element despite the ambiguity in its underlying mechanism. Rede ning and characterizing LMH as two apparently distinct clinical entities will help to advance understanding of the pathophysiology LMH and informed more speci c, target treatments of the condition. 7 Toward this end, the present study compared anatomical parameters and clinical characteristic parameters of LMH according to the two aforementioned subtypes.

Methods
This study adhered to the Helsinki Declaration and received approval from the institutional review board of Inha University Hospital. We reviewed the medical records of patients who were monitored for more than 6 months after being diagnosed with LMH at Inha University Hospital Eye Center (Incheon, Korea) from January 2011 to January 2018.
Patients were excluded from the study if they had exhibited any of the following: history of retina surgery, diabetic retinopathy, retinal vein occlusion, age related macular degeneration, choroidal neovascularization, and uveitis.
To perform spectral domain optical coherence tomography (SD-OCT), Cirrus HD-OCT (version 6.0 software) was used in all cases.
Morphologic parameters were de ned as mean central foveal thickness, maximum inner/outer diameter (MID/MOD), presence of epiretinal membrane, and defects in the ellipsoid zone.
The clinical parameters included best corrected visual acuity, anatomical progression rate, rate of surgery, and mean period before surgery.
The mean central foveal thickness was measured as the average thickness within 500 μm from the macular center. The anatomical progression was de ned as an increase of > 50 µm in the inner or outer diameters from baseline. The MID was measured as the longest length of the ILM level using the caliper function of the Cirrus OCT, and the MOD was measured as the longest length in the intraretinal cavity.
Statistical analysis was performed using SPSS software version 18 (SPSS Inc., Chicago, IL, USA). Comparisons between the parameters of LMH subtypes were performed using the Kruskal-Wallis test.
The Wilcoxon signed rank test was performed to assess changes in parameters from baseline to the end of follow-up. Statistical signi cance was considered set to p < 0.05.

Results
Of the 80 eyes treated during the study period, 51 eyes of 49 patients (15 men; mean age, 66.37 ± 10.79; age range, 37 to 82 years; mean follow-up time; 18.94 ± 16.64 months) met the inclusion criteria and were enrolled in the study; 18 and 33 eyes were included in the degenerative and tractional groups, respectively.
The mean ages of the patients in the tractional degenerative groups were similar: 65.32 ± 11.72 years and 68.72 ± 8.18, respectively (p = 0.49). No signi cant difference was found between the mean followup periods between the tractional and degenerative groups: 16.57 ± 12.52 months and 23.27 ± 22.11, respectively (p = 0.81). Sex ratios were signi cantly different between the two groups: the tractional group featured more women than did the degenerative group (p < 0.01). The 29 eyes either met the exclusion criteria or had been subjected to a different OCT analysis. The progressions of the mean inner and outer diameters differed according to subtype. In the tractional type, while the mean inner diameter had not changed signi cantly by the last follow-up (p = 0.338), the mean outer diameter increased signi cantly across the follow-up period (p = 0.003). In the degenerative type, the mean outer diameter did not change signi cantly across the follow-up period (p = 0.231), but the mean inner diameter had signi cantly increased by the last follow-up (p = 0.045). The mean outer diameter of tractional eyes was signi cantly larger than that of degenerative eyes at baseline and the lase of follow-up (p < 0.01 for both).
The anatomical progression rate was much higher in the tractional group than in the degenerative group (tractional type, 81.8%; degenerative type, 27.7%; p = 0.01). Rate of macular surgery was not signi cantly different between the groups but was higher in the tractional group than in the degenerative group (tractional type, 30.3%; degenerative type, 22.2%; p = 0.58).

Discussion
The pathogenesis of LMH remains unclear. The development of OCT allowed for high resolution observation of morphologic features characteristic of LMH; these have been document by several studies, 8 and several rede nitions of LMH have been proposed. Time-domain OCT investigation have explained LMH morphologic features in terms of the irregular foveal contour, separation of foveal edges, and standard perifoveal thickness. 9 Spectral-domain OCT studies have described the morphologic features of LMH in four ways: irregular foveal contour, break in the inner fovea, intraretinal split situated between the outer plexiform and nuclear layers, and intact foveal photoreceptors. 12 However, these LMH concepts have not uni ed the various morphologic and clinical observations. It is particularly di cult to ascribe intraretinal cyst caused by tractional force to the concept of LMH: though several concepts have been proposed to explain these cases, none could explain the LMH to unify and prognosis of the data of these de nitions were observed differently. The controversy among current de nitions of LMH indicates the need for its rede nition.
Thus, Govetto et al classi ed LMH into two subtypes: tractional and degenerative. The former is de ned by the presence of traction, such as ERM and VMT, while the latter is exhibits traction-free epiretinal proliferation. 7 In tractional LMH, horizontal ERM-and VMT-induced tractional forces affect the outer diameter rather than the inner diameter. Indeed, the present study revealed that tractional eyes exhibited larger maximum outer diameters than did the degenerative eyes across the study period.
Thus, the rate of increase in the ratio between the inner and outer diameters is larger among tractional than degenerative eyes. In the case of the former, since the horizontal force is constant, the outer diameter increases by the end-of-follow-up compared to the baseline; hence, tractional eyes featured a relatively heightened anatomical progression rate. Our study also showed that the outer diameter increased during the follow-up period among tractional eyes. Previous studies demonstrated that observation alone achieved better clinical outcomes than did surgery, despite anatomic progression.
The conditions of degenerative eyes progresses gradually and chronically; many cases are only discovered accidentally during regular checkup, while others are based on the subject interpretation of symptoms. Tractional eyes often exhibit subjective symptoms such as deformity. For this reason, the best corrected visual acuity was superior in degenerative eyes, although the difference was not statistically signi cant.
In the case of patients tractional rapid hole size progression, the surgical procedure was performed to remove traction. The rate of surgery was therefore higher in the tractional group than in the degenerative group; however, this difference was statistically nonsigni cant.
This study is subject to the limitation of diminished statistical validity due to a small sample size. Because visual function is preserved in cases of LMH, there is a bias against completion of long-term follow-up observation. Moreover, could be easily classi ed as either tractional or degenerative; some cases presented features of both. 7 Only best corrected visual acuity was used to assessed visual acuity. In future studies, it may be necessary to evaluate the quality of visual acuity in multiple aspects such as comparing metamorphosis between two subgroups. In addition, such additional metrics may help to indicate surgery.
In conclusion, this study analyzed morphologic and clinical features of two LMH subtypes and con rmed

Consent for publication
Not applicable.

Availability of data and material
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.   Figure 1 The measurement of the retinal diameter through the caliper of optical ocherence tomography software is described.