Primary Lamellar Macular Holes: To Vit or Not to Vit
There is a wide spectrum of macular conditions that are characterized by abnormalities of the foveal architecture caused by a break in the inner fovea. These conditions include full thickness macular hole (FTMH), foveal pseudocyst, lamellar macular hole (LMH) and macular pseudohole (MPH). Prior to 1991, when Kelly and Wendel [ 1 ] pioneered vitrectomy surgery for FTMH, a previously untreatable condition, differentiation between these conditions was mostly of an academic interest. Currently modern FTMH repair with PPV, posterior hyaloid detachment and ILM peeling with gas tamponade and post-operative face-down positioning results in closure of most of the FTMH ≤ 400 um in size [ 2 ]. MPH and LMH were initially defined biomicroscopically, and the purpose was to distinguish them from a FTMH [ 3 5 ]. Gass [ 3 ] described the biomicroscopic findings of an eye that developed an inner LMH hole as a result of chronic aphakic cystoid macular edema. Following the patient’s death, the eye was examined histopathologically which confirmed the biomicroscopic findings of an inner LMH. The introduction of optical coherence tomography (OCT), particularly spectral domain (SD) OCT, into routine clinical practice revolutionized our understanding of diseases of the vitreomacular interface and facilitated differentiating these conditions from a FTMH [ 6 7 ]. All of these conditions had to be reinterpreted on the basis of OCT findings. It must be borne in mind that the definition of LMH has evolved over the past two decades. Depending on when a particular manuscript was published, different and conflicting definitions, criteria and terminology were used to describe different conditions associated with an abnormal foveal contour. It is not surprising then, that natural history and treatment outcomes vary from study to study [ 8 13 ]. The purpose of the current review is to update the reader with the current understanding of LMH.
In 1975 Gass [ 3 ] reported the clinical histopathologic correlation of an eye with a well-defined macular reddish oval lesion with a preserved foveal reflex that developed a partial loss of foveal tissue secondary to long standing pseudophakic cystoid macular edema (CME). He chose to use the term LMH to describe these findings. MPH was first described by Allen and Gass [ 5 ] in 1976 as a peculiar macular lesion that simulated a macular hole. Its pathogenesis was ascribed to the spontaneous contraction of an epiretinal membrane that surrounded the foveal area. Fluorescein angiography (FA) was not a useful imaging modality to differentiate among these conditions. MPH commonly exhibit early hyperfluorescence within the area of the MPH which may be confused with a FTMH [ 14 ]. Time domain OCT is able to differentiate between a MPH and a LMH [ 8 ]. In eyes with a LMH, the OCT profile is irregular; the foveal edges are split; and the foveal center is thinner than normal. In contrast, eyes with a MPH are characterized by the presence of a deep foveal pit, verticalized edges and a thickened macula caused by the contraction of the ERM [ 8 ]. In 2013 the International Vitreoretinal Traction Study Group defined LMH and MPH based on SD-OCT B scan images [ 2 ]. However, it was soon realized that in some instances the differentiation between these conditions was not clear cut [ 15 ]. As OCT became more widely used and observations became more refined, two different phenotypes of LMH became apparent: raising the question of different pathogenic mechanisms for each phenotype. In 2016, Govetto et al. [ 16 ] proposed sub-dividing LMH into two distinct categories, namely tractional and degenerative LMH. Recently an international panel of vitreoretinal experts recognized that the prevailing definition of LMH encompassed a wide spectrum of conditions characterized by a break in the inner fovea and an irregular contour [ 17 ]. They recognized that many different clinical conditions with different pathophysiological were included together. In the hopes of facilitating future research they published an SD-OCT based consensus definition for LMH, ERM foveoschisis and MPH. Govetto et al. [ 16 ] tractional LMH became ERM foveoschisis whereas degenerative LMH became LMH [ 17 ].
Bilateral LMH appears to be a relatively uncommon occurrence [ 23 ]. A retrospective study of 35 individuals with a LMH revealed that in the fellow eye, 83% had a vitreomacular abnormality. However, only 9% of patients had an LMH. The most frequent finding was a tractional ERM seen in 74% of fellow eyes [ 23 ].
The reported prevalence of LMH in different populations has ranged anywhere from 0.1% to 3.6% [ 18 22 ]. Most people who develop a LMH are older than 50 years of age [ 18 20 ]. In the Beaver Dam Eye Study, a population-based study of people aged 63 to 102 years old, participants were assessed with SD-OCT. The prevalence of LMH was estimated to be 3.6%. It was higher in eyes with a history of prior cataract surgery. Age did not influence the prevalence of LMH. After adjusting for age and gender, ERM were associated with the presence of LMH, macular cysts and FTMH [ 18 ]. The Maastricht Study was an observational prospective population-based study of individuals aged between 40 and 75 years from the Netherlands. The prevalence of LMH was estimated to be 0.9%. Women were more prone to develop LMH [ 19 ]. The Montrachet Study, a French population-based study, reported a prevalence of 1% and 0.4% for LMH and MPH, respectively [ 20 ]. A cross sectional study of 2257 healthy Spanish individuals older than 45 years of age that underwent SD-OCT imaging revealed a LMH prevalence of 0.1% [ 21 ]. A South Korean study of 698 patients scheduled for cataract surgery with a normal biomicroscopic examination of the macula, underwent pre-operative SD-OCT or swept source OCT. They reported a 0.3% prevalence for LMH [ 22 ].
4. Multimodal Imaging
Symptoms of LMH are similar to those found in other vitreoretinal interface syndromes such as ERM, MPH and early FTMH. These conditions were all defined biomicroscopically, and the main goal was to distinguish a FTMH from the other conditions. Typically, patients have a BCVA of ≥ 20/40 [ 24 25 ]. Many patients are asymptomatic. Others complain of decreased visual acuity, metamorphopsia and a central scotoma [ 25 ]. Clinical examination of vitreomacular interface disorders is notoriously poor in differentiating these conditions. Functional tests such as visual acuity, microperimetry and the Watzke-Allen test are of little help as well [ 26 ]. MPH have the clinical appearance of a macular hole but with no loss of foveal tissue. In contrast LMH were defined by a partial tissue loss [ 2 ]. Distinguishing among these conditions proved clinically challenging. The introduction of optical coherence tomography (OCT), particularly spectral domain (SD) OCT, has been instrumental in expanding our understanding and differentiation of these conditions from a FTMH. Since prognosis and management differ among these conditions, reliable diagnostic criteria are needed. Biomicroscopic fundus examination was able to diagnose only 28% of LMH diagnosed with time domain OCT [ 8 ]. In the Beaver Dam Eye study, only 1.6% of eyes with a SD-OCT diagnosis of a LMH were detected with fundus photographs [ 18 ].
However, once OCT, particularly SD-OCT was introduced into routine clinical practice, all of these conditions had to re-interpreted on the basis of OCT findings. Since then, differing definitions and criteria for diagnosing LMH and MPH have evolved over the years. Authors have used different definitions for what they considered to be LMH at the time. In 2004 time domain OCT criteria were defined for MPH and LMH [ 8 ]. Eyes with an MPH had a steepened foveal pit whose diameter was small and the foveal edges were thickened. The central foveal thickness was within normal limits or had a slight increase. The perifoveal thickness was increased. In contrast LMH were defined by a thin irregular foveal floor, a thinner central foveal thickness, split foveal edges and near normal perifoveal thickness [ 8 ]. In 2006 findings in ultrahigh definition OCT, that included an irregular foveal contour, a break in the inner fovea, intraretinal split and an absence of a full foveal defect with intact foveal photoreceptors, were used to define a LMH [ 9 27 ]. In 2013 the International Vitreomacular Traction Study Group defined LMH and MPH according to SD-OCT B scan images. They defined a LMH as an eye with an irregular contour, a defect in the inner fovea, intraretinal splitting and maintenance of an intact photoreceptor layer. Similarly, an eye with a MPH was characterized by an invaginated or heaped foveal edges, concomitant ERM with a central opening, steep macular contour to the central fovea with near normal central foveal thickness and no loss of retinal tissue [ 2 ].
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OCT demonstrated that ERM are commonly associated with LMH ranging anywhere from 62% to 100% of eyes [ 8 29 ]. These are characterized by a highly reflective line immediately anterior to and separate from the retinal nerve fiber layer (RNFL) on SD-OCT. Ref. [ 11 ] ERM can exert unidirectional, pluridirectional and concentric tangential lines of traction on the macular surface [ 30 31 ]. Asymmetric tangential traction along different directions results in a cleavage of the foveal pit edge whereas symmetric centripetal contraction leads to straight smooth edges on the SD-OCT [ 31 ]. It was noted that in eyes with LMH the position of the foveal contour was below the outer plexiform layer whereas in normal eyes it is located at the level of the outer plexiform layer [ 28 ]. Since then, other OCT findings like epiretinal proliferation (ERP), ellipsoid zone disruption and intraretinal splitting have been described in these eyes [ 9 31 ].
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Despite these OCT based definitions, the differentiation of LMH and MPH is not always straightforward. Several investigators believe that intraretinal splitting is the key differentiator between LMH and MPH [ 8 32 ]. In contrast others do not consider the presence of intraretinal splitting as part of the diagnostic criteria of LMH [ 15 31 ]. In 2012, Michalewska and co-workers [ 28 ] reviewed their SD-OCT database of over 10,000 patients and identified 125 eyes from 116 patients with a non-full thickness macular hole. All the eyes had a co-existing ERM. Based on morphological findings on the SD-OCT, they subdivided the eyes into 4 subgroups: MPH, Para-LMH, MPH with lamellar defects and LMH. Based on the observation that 40% of eyes had different subtypes present in the same eye, they concluded that all these subtypes were different phenotypes of the same progressive condition. In addition eyes with LMH were associated with outer retinal disruptions calling into question the assumption that the photoreceptors are intact in LMH [ 28 ]. Furthermore, in several cases of MPH, progressive ERM contraction led to a LMH [ 28 33 ].
In Michalewska’s series, 60% of eyes had a declining visual acuity with a mean loss of 2.4 lines of Snellen after a mean follow-up of 14 months. Photoreceptor layer defects either appeared or enlarged in 36% of eyes. The outer diameter of the foveal defect increased in 33% of eyes [ 28 ]. These cases lend support to Gaudric et al.’s [ 31 ] observation that eyes with an intraretinal split along a foveal edge should not be classified as LMH but as a variant of MPH. In these eyes SD-OCT revealed that some eyes exhibit an incomplete lamellar cleavage between the inner and outer retina of their edges. Stretched Henle fibers still connected the inner and outer retina [ 31 ]. In contrast other authors classified these eyes as LMH [ 11 32 ].
In 2016 Govetto and collaborators [ 16 ] upon review of the SD-OCT images of their 102 consecutive eyes diagnosed with LMH, concluded that two distinct clinical entities, degenerative and tractional LMH, formed part of the spectrum of what was then defined as an LMH. According to them, tractional LMH is characterized by a schitic separation of the neurosensory retina between the outer nuclear layer and the outer plexiform layer. In contrast, degenerative LMH is characterized by intraretinal cavitations that can affect all retinal layers, non-tractional epiretinal proliferation (ERP) and a retinal bump. Underscoring the difficulty in classifying these eyes into specific categories, 11 eyes had mixed characteristics [ 16 ].
“a bulge of retinal tissue in the center of the fovea, usually surrounded by foveal cavities with undermined edges.”
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In 2020 an international panel of vitreoretinal experts recognized that the prevailing definition of LMH encompassed a wide spectrum of conditions characterized by a break in the inner fovea and an irregular contour. They felt that many different clinical conditions with different pathophysiological mechanisms were lumped together. In the hopes of facilitating future research, they published an SD-OCT based consensus definition for LMH, ERM foveoschisis and MPH [ 17 ]. Mandatory criteria for a LMH included an irregular foveal contour; a foveal cavity with undermined edges and the presence of at least one other sign of foveal tissue loss. In order for an edge to be considered undermined, the angle between the retinal surface and the edge of the hole on the B scan OCT has to be <90°. Optional criteria included the presence of epiretinal proliferation, the presence of a central foveal bump and disruption of the ellipsoid zone. A foveal bump was defined as 17 ]. ( Figure 1 ) This definition of LMH is reminiscent of Govetto et al.’s [ 16 ] definition for degenerative LMH. Mandatory criteria for an ERM foveoschisis included the presence of an ERM and the presence of foveoschisis at the level of Henle fiber layer. An ERM was defined as an irregular and hyperreflective layer over the ILM. The underlying retina may express signs of wrinkling such as the presence of hyporeflective spaces between the ILM and the ERM. Optional criteria for ERM foveoschisis included the presence of microcystoid spaces in the inner nuclear layer, an increase in retinal thickness and the presence of retinal wrinkling [ 17 ]. The description of ERM foveoschisis resembled the tractional LMH definition of Govetto et al. [ 16 ] ( Figure 2 ) Mandatory criteria for an MPH included the presence of a foveal sparing ERM; presence of a steepened foveal profile and an increased central retinal thickness. Optional criteria included microcystoid spaces in the inner nuclear layer and a normal retinal thickness [ 17 ].
Despite the capability of SD-OCT to visualize the macula in detail, it may fail to detect very small losses of foveal tissue [ 34 ]. Blue fundus autofluorescence (FAF) is more sensitive than SD-OCT in detecting these small changes. The main FAF signal is derived from the lipofuscin in the RPE. In the fovea this signal is attenuated by the presence of the luteal pigment [ 35 ]. LMH exhibit an increased signal of blue FAF [ 34 ]. Unfortunately, blue FAF cannot discriminate among LMH, ERM foveoschisis and MPH since all of these conditions exhibit an increased blue FAF signal at the fovea [ 36 ]. This hyper blue FAF is caused by either an actual loss of foveal tissue or a centrifugal displacement of foveal tissue containing macular pigment [ 37 38 ]. Italian investigators compared the blue FAF and the SD-OCT findings in eyes with LMH. They reported a strong correlation between the LMH diameter measured by blue FAF and the SD-OCT measured at the level of the outer plexiform layer [ 39 ].
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En face SD-OCT imaging and multicolor imaging, which uses a confocal scanning laser ophthalmoscope to obtain near infrared reflectance (NIR), green reflectance and blue reflectance en face images, allows visualization of the entire extent and the vectorial directions of the tractional elements acting on the macula. Contraction epicenters are easily observed under en face imaging [ 30 40 ]. Epimacular traction can be characterized as unidirectional, pluridirectional or concentric. Unidirectional traction is characterized by folds pulling towards a non-foveal center of contraction whereas pluridirectional traction consists of multiple contraction centers with multiple directions of traction. In contrast, concentric traction consists of folds pulling towards the center of the fovea [ 30 ]. ERM contraction is responsible for these morphological changes [ 40 ]. En face OCT revealed that the intraretinal splitting occurs within the outer plexiform layer [ 29 ]. NIR imaging revealed retinal folds in tractional LMH. No folds were seen in degenerative LMH in NIR imaging [ 30 ].
Several SD-OCT biomarkers have been explored as visual acuity predictors. The status of the foveal microstructure, namely the external limiting membrane (ELM) and the ellipsoid zone (EZ), correlates with the central retinal sensitivity and the BCVA [ 15 41 ]. In a prospective observational study of 54 patients with LMH, 26% of eyes had the ELM and the ellipsoid zone disrupted. In these eyes the BCVA and the central retinal sensitivity were significantly poorer [ 41 ]. They noted that 29% of the eyes with a LMH had photoreceptor layer defects. Photoreceptor layer defects, maximum retinal thickness and the outer diameter of the foveal defect correlate with visual acuity [ 28 ]. En face SD-OCT imaging allows quantification of intraretinal splitting within the outer plexiform layer. In this retrospective study of 42 eyes, the area of intraretinal splitting did not correlate with visual acuity. However, disruption of the EZ was correlated with visual loss. EZ disruption correlated with the area of splitting [ 29 ].
Tractional and degenerative LMH appear to have different macular microvascular parameters as studied by OCTA [ 42 ]. Eyes with tractional LMH exhibit a smaller foveal avascular zone (FAZ) area, a higher foveal vascular density (VD) and a lower parafoveal VD in both the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) than control eyes and eyes with degenerative LMH. Eyes with a degenerative LMH had lower parafoveal VDs in both the SCP and the DCP. Furthermore, the size of the VD was correlated with the BCVA in these eyes [ 42 ]. Catania and colleagues [ 43 ] compared OCTA parameters in eyes with LMH that progressively lost tissue to those which remained stable. Eyes with progressive tissue loss manifested decreased foveal VD in the SCP, and decreased perfusion density in both the SCP, DCP and parafoveal areas.
One of the major limitations of our current imaging techniques is that none can reliably determine the presence of actual retinal tissue loss.
