Open access peer-reviewed chapter
Abstract
The widely accepted gold standard technique for the treatment of Macular holes is pars plana vitrectomy combined with internal limiting membrane peeling, resulting in closure rates of 80–100%. Results are influenced by the base diameter, inner opening size, and chronicity, with outcomes less favorable for larger holes and those persisting for over a year. In recent years, surgical attention has shifted toward addressing the closure of refractory or very large holes. Literature has published significant data showing satisfactory anatomical and promising visual outcomes. These techniques can be categorized based on the presumed mechanisms of closure induction. Retinal expansion, autologous retinal transplant, ILM flaps, lens capsules, or amniotic membranes within the MH, each yielding varying closure rates. Modulation of intraretinal gliosis through growth and neurotrophic factors using autologous blood-derived plugs or scaffolds to facilitate Muller cell migration and proliferation have also been documented. Plasma rich in growth factors (PRGF) exhibits anti-inflammatory, anti-fibrotic, and regenerative functions lead to high MH closure rates, garnering attention from retinal surgeons globally. The growing volume of publications suggests benefits from Plasma Rich in Growth Factors over other plasma derivatives. While there is no definitive method for treating macular holes, these newer techniques offer a promising future.
Keywords
- macular hole
- surgical management
- plasma rich in growth factors
- tissue transplantation
- scaffolds
1. Introduction
A full-thickness macular hole (FTMH) is characterized by a structural defect in the fovea where all neural retinal layers from the ILM to the retinal pigment epithelium (RPE) are interrupted [1]. This condition is diagnosed through clinical assessment and imaging modalities like optical coherence tomography (OCT), which provide additional information, characteristics, and prognostic indicators.
The central opening in the fovea can result from various mechanical factors, including tractional forces within a foveal cystoid space, breakdown and elevation of central photoreceptors, and tangential traction on the inner retinal layers. Some FTMHs might also exhibit a true retinal operculum. The hole’s edges tend to be rounded and may contain intraretinal pseudocysts. Additionally, due to the accumulation of intraretinal fluid, the edge might appear slightly elevated compared to the RPE plane. Full-thickness macular hole often exhibit an hourglass shape, which can vary based on the orientation of the OCT scan. The vitreous may or may not be attached to the edge of the MH [2].
Macular hole pose challenges for vitreoretinal surgeons. Idiopathic FTMH are relatively common, with a prevalence of about 0.3–5% in the general population over 60 years of age. This prevalence increases with age and is more common in females [3, 4]. The widely accepted gold standard treatment technique is PPV combined with ILM peeling, resulting in closure rates ranging from 80 to 100%. The outcomes are influenced by factors such as base diameter, inner opening size, and chronicity. Poorer outcomes are observed in cases of holes larger than 400 microns and those present for over a year (with a closure rate around 77%) [5, 6, 7].
In recent years, attention has shifted to surgical techniques targeting refractory, recurrent, persistent, or very large holes with limited closure potential using conventional approaches. New techniques have emerged in the literature, demonstrating satisfactory and promising anatomical and visual outcomes.
2. Pathogenesis
This passage offers an overview of the evolving comprehension of MH pathogenesis, with a specific focus on the vitreous’s role and the mechanisms that underlie hole formation and progression.
Initial theories postulated that MH might stem from a degenerative process, potentially linked to vascular insufficiency. Moreover, certain theories centered on the vitreous’s role in MH development, suggesting that tangential traction, potentially resulting from Müller cell proliferation and contraction within the vitreoretinal interface, played a substantial part [8, 9].
2.1 Involvement of the vitreous
The significance of the vitreous in MH pathogenesis is underscored. This notion is substantiated by the observation that eyes with complete posterior vitreous detachment (PVD) exhibit fewer occurrences of MH. Furthermore, MHs are less prone to enlargement when PVD is evident at the time of diagnosis [9, 10].
2.2 Gass’s theory
A pivotal aspect of Gass’s theory is that MHs arise from the centrifugal displacement of photoreceptors, rather than a mere loss of these cells. This concept elucidates the restoration of visual acuity to nearly normal levels following MH surgery [8, 9, 10, 11, 12].
2.3 Histopathological discoveries
Histopathological evaluations of operculae (tissue overlaying MHs) surgically removed have demonstrated their frequent inclusion of glial elements, albeit not necessarily implying a loss of foveal cones. However, more recent findings suggest that, in certain MH cases, substantial amounts of foveal tissue, including cones, can become torn from the foveal region (Figure 1) [5, 9].
Figure 1.
A 65-year-old male patient with a FTMH with vitreous detachment and an operculum.
2.4 Lateral displacement of photoreceptors
Some studies, including one utilizing binocular kinetic perimetry, have directly substantiated the lateral displacement of photoreceptors during MH development, explaining the typical distortion reported by MH patients [9, 12].
2.5 Revised theory with optical coherence tomography
With the arrival of OCT, Gass’s theory has undergone revision. Recent studies utilizing OCT and ultrasound have unveiled that impending macular holes often encompass perifoveal vitreous detachment with localized vitreous attachment to the foveal umbo. A division emerges between the Müller cell cone (central glial element) and foveal photoreceptors due to posterior-anterior vitreomacular traction, fostering the development of a cystic lesion [2, 5, 12].
2.6 Transition to FTMH
The progression from an impending MH to a FTMH typically commences with a disruption in the roof of the cystic lesion. Centrifugal traction, the origin of which remains enigmatic, triggers the expansion of the disruption into the photoreceptor layer, resulting in a full-thickness defect. The hole may subsequently increase in size and assume a more rounded shape over time [12].
After conducting a comprehensive review of the literature and taking clinical experience into account, we posit that MH development is a complex interplay of various factors. The interplay of posterior-anterior vitreous traction, combined with tangential traction of the inner layers, notably the ILM, contributes to this process. This perspective elucidates why solely performing PPV on small holes, or in the case of moderately sized holes, peeling the ILM, leads to lesion closure (Figure 2).
Figure 2.
A 64-year-old female patient with vitro macular traction syndrome in the right eye (upper image) and a FMTH en left eye (inferior image).
3. Natural history
The natural history of MH comprises several distinct stages. The prognosis and likelihood of spontaneous closure or progression hinge on the MH’s size and the presence of PVD [12].
3.1 Impending macular holes (stage 1)
Impending MH may lead to different outcomes. They can either resolve spontaneously, remain unchanged, or progress to FTMH. The presence of complete PVD seems to have a positive prognosis for stage 1 MH. Initial visual acuity of 20/40 or better in some cases indicates a better outcome [12].
3.2 Spontaneous resolution
In one study, about 48% of stage 1 MHs regressed, 29% remained the same, and 23% evolved into a FTMH within a year. Regressions often correlated with a posterior vitreous separation, either at baseline or during follow-up [12].
3.3 Stage 2 macular holes
Stage 2 MH also demonstrate varying outcomes. They may remain stable, close spontaneously (though full closure might not result in a normal foveal appearance), or expand over time. In a study, a significant percentage (74%) of stage 2 MH advanced to stage 3 within a year. Some spontaneously closed stage 2 MH did not regain normal foveal morphology but displayed flattened hole edges. However, reports exist of spontaneous closure with a minority of cases reverting to normal foveal contour [12].
3.4 Stage 3 and stage 4 macular holes
Spontaneous closure is rare in these advanced MH stages. Such closure, characterized by the flattening of hole edges (not necessarily returning to normal foveal morphology), was observed in a small portion of cases. Generally, stage 3 and stage 4 macular holes remain steady or enlarge with time [12].
3.5 Rhegmatogenous retinal detachment (RRD)
MH typically do not precipitate RRD. However, highly myopic eyes with a posterior staphyloma are at a rare risk of developing retinal detachment [12].
4. Classification
4.1 International Vitreomacular traction study (IVTS)
Traditionally, FTMHs were categorized using the Gass classification, which divided them into the aforementioned four stages based on clinical examination. However, advancements in OCT technology have yielded a more precise understanding of FTMH pathogenesis and progression [1, 2].
Optical Coherence Tomography-Based FTMH Classification System (Based on Size, Presence or Absence of Vitreomacular Traction, and Cause):
Hole Size: An OCT-based system permits exact anatomical measurements of FTMHs. The minimum hole width, also referred to as aperture size, holds crucial significance. Small FTMHs boast an aperture size under 250 microns, while medium FTMHs span from 250 to 400 microns. Large FTMHs exceed 400 micrometers in diameter. These size classifications are pivotal, as they influence treatment strategies [2, 13].
Vitreomacular Traction (VMT) Presence or Absence: FTMHs can be grouped based on the presence or absence of vitreous attachment. For the consideration of pharmacologic vitreolysis, only macular holes concurrently exhibiting VMT should be selected [2, 14].
Primary Versus Secondary FTMH: Full-thickness macular hole can be further categorized into primary and secondary forms. Primary FTMHs, previously termed idiopathic, stem from vitreous traction on the fovea, often linked to anomalous PVD and VMT. Secondary FTMHs result directly from underlying pathologies, devoid of pre-existing or concurrent VMT. These secondary FTMHs may arise from factors such as trauma, high myopia, macular schisis, macular telangiectasia type 2, wet macular degeneration treated with anti-vascular endothelial growth factor therapy, macroaneurysm, or surgical trauma [2, 14].
It’s important to note that FTMHs can co-occur with macular edema related to various retinal diseases, including diabetic macular edema, age-related macular degeneration, retinal vascular occlusions, and uveitis. The classification as primary or secondary FTMH hinges on VMT presence or absence. This OCT-based classification system offers a more comprehensive and precise approach to understand and manage FTMHs based on their size, underlying vitreous condition, and causative factors [1].
5. Optical coherence tomography prognosis biomarkers
Structural OCT imaging is pivotal in the diagnosis and management of FTMHs. This imaging technique has long been essential for accurately diagnosing FTMHs, distinguishing them from other vitreomacular pathologies, and predicting visual outcomes following successful surgery [15].
OCT is essential in measuring various aspects of FTMHs, including their size, base diameter, height, and the macular hole index (height/maximum basal diameter). The minimum linear dimension, representing the horizontal span between the closest retinal components, is a critical factor in assessing anatomical success post-surgery and forms the basis of an international OCT-based classification system for FTMH [16].
Smaller hole diameters tend to lead to better postoperative visual acuity. Recent investigations have explored additional OCT structural features as predictors of functional recovery after surgery [16].
Structural OCT also allows the identification of three hyper-reflective bands within the external retinal layers: the external limiting membrane (ELM), the ellipsoid zone (EZ), and the interdigitation zone (IZ). Restoration of these bands is often associated with improved visual acuity after FTMH surgery, with the preoperative length of defects serving as a strong predictor of visual acuity outcomes [16].
Furthermore, FTMHs may be associated with intraretinal cystoid cavities around their edges, which expand and separate retinal layers during hole formation. The presence of these cysts has shown mixed correlations with postoperative outcomes, varying by study [16].
Supra-RPE granular deposits have been investigated as potential biomarkers of negative prognosis. These deposits, often found in cases with lower postoperative visual acuity, may indicate photoreceptor disruption [16].
Finally, the presence of epiretinal proliferation, distinct from traditional epiretinal membranes, has been observed in some macular holes. Holes with epiretinal proliferation tend to have worse clinical and surgical outcomes compared to those without it [16].
In summary, OCT imaging is a critical tool in understanding and managing FTMHs, offering insights into their dimensions, structural features, and prognostic implications for visual outcomes after surgery.
6. Macular hole associated with other vitreoretinal interface pathologies
6.1 Macular hole and epiretinal membrane (ERM)
An ERM results from the growth of fibrous-like tissue on the inner surface of the retina. ERMs are often idiopathic but can also be linked to pre-existing conditions or caused by medical procedures. Several studies explore the connection and underlying mechanisms between ERM and FTMH [17].
6.2 Macular hole and epiretinal proliferation (EP)
EP is now considered a distinct clinical entity from conventional ERM, histological analysis supports Müller cell involvement in EP development but it is required a more specific immunohistochemical studies for other etiologies; EP has an impact on vision and surgical treatment. It is reported that almost 90% of EP cases remain stable without surgery, intervention is required for exacerbated cases or those associated with FTMH. Postoperative outcomes remain controversial but in surgery it is important to perform a gentle handling of EP to avoid further rise of FTMH [18].
The connection between ERM or EP and the success of surgical closure for FTMH has stirred controversy. Traditionally, it was believed that removing an ERM during macular hole surgery had no significant impact on postoperative results. However, recent studies, though limited in patient numbers and lacking rigorous statistical analysis, have brought this belief into question. The presence of an ERM during surgery can inadvertently introduce tangential tension on the MH, making procedures like the inverted ILM flap challenging. Additionally, ERM-induced chronic mechanical stress may trigger inflammation and neurodegeneration, hindering sufficient gliosis for closure. Regarding EP, it is mainly composed of noncontractile gliotic tissue from Müller cells, and its relationship with FTMH is still relatively unexplored due to recent improvements in OCT resolution. Although some studies suggest EP as a preoperative risk factor for adverse surgical outcomes, they involve a small patient sample and lack adjustment for baseline factors, such as age, sex, and ERM presence. Therefore, whether ERM or EP affects FTMH surgical outcomes remains controversial and necessitates further investigation [19].
We consider that vitreomacular interface pathologies can play a role in the evolution and progression of MHs. In the case of ERM, by generating additional tangential traction and thickening of the neuroepithelium, they can, in some cases, lead to FTMH and therefore require surgery for removal. Cases of EP may lead to FTMH, but in a very different and poorly understood manner. However, in the majority of published studies, removal of the EP is not recommended due to the potential iatrogenic progression to FTMH. Therefore, it has been considered that EPs contain internal components of the neuroepithelium, and removing them could lead to tissue disruption and worsen the anatomic and visual prognosis.
7. Risk factors of the fellow eye
These risk factors underscore the importance of evaluating both MH stage and posterior vitreous status in fellow eyes when contemplating treatment options for patients with newly diagnosed MHs. Vigilant monitoring and timely intervention may be imperative, especially in high-risk factor cases, to avert macular hole development in the other eye [12, 20].
Presence of Stage 1 macular hole: A stage 1 macular hole in the opposite eye bears a high risk of progressing to a FTMH within a year. This highlights the significant risk that fellow eyes with early-stage macular holes face in terms of MH development [1, 12].
Posterior vitreous status: The posterior vitreous status in the fellow eye is another pivotal factor. In cases where the posterior vitreous is detached in the fellow eye (complete posterior vitreous detachment), the risk of it evolving into a FTMH is minimal, estimated at less than 2%. Essentially, a PVD appears to safeguard against MH development in the fellow eye [10, 12].
Risk in fellow eyes with normal macula and attached posterior vitreous: In fellow eyes featuring a normal macula (no evidence of macular hole) and an attached posterior vitreous, the risk of developing a full-thickness macular hole within 5 years was approximately 15.6%, as indicated by one prospective study. A similar risk value emerged from a retrospective study. This suggests that even in fellow eyes lacking early-stage MH, a noteworthy risk of macular hole development persists [12, 21].
8. Surgical techniques
8.1 Primary FTMH
The standard approach for repairing primary FTMHs involves PPV with ILM peeling and gas tamponade. This method boasts a high success rate of 80–100%. The inverted ILM flap technique is gaining popularity, especially for large or myopic FTMHs [22].
8.2 ILM peeling
ILM peeling is associated with a lower risk of reopening and better outcomes in FTMH surgery [22].
Conventional ILM peeling: This technique entails PPV, PVD, and ILM removal. It addresses posterior-anterior tractional forces and eliminates tangential tractions on the foveal region. ILM peeling triggers mechanical trauma to the retina, stimulating Müller cells’ gliosis, migration, and potentially proliferation. This procedure also eliminates potential vitreous remnants, reducing postoperative epiretinal membrane occurrence and hole reopening. Gas tamponade is employed to seal the hole, creating retinal isolation that promotes subretinal fluid absorption and Müller cell gliosis and migration [22, 23, 24].
Inverted ILM flap: In this method, the ILM is peeled circumferentially but left attached to the hole’s borders. The central remnants are manipulated to cover the hole, adopting an “inverted” configuration where the vitreous side of the ILM faces the retinal pigment epithelium (RPE). This approach proves particularly effective for large and myopic macular holes, boasting higher closure rates and improved postoperative visual acuity compared to conventional ILM peeling. The inverted ILM flap may serve as a scaffold for Müller cell migration and proliferation, facilitating hole closure. Immunohistochemical analyses suggest the flap’s presence stimulates Müller cells’ gliosis and migration. ILM components also enhance Müller cell proliferative and migratory activities in vitro (Figure 3) [25, 26].
Figure 3.
A 65-year-old female patient with a full-thickness macular hole (FTMH) in the right eye. The left image displays the FTMH with isoreflective pseudocysts at the edges. The right image depicts the postoperative outcome with macular hole closure and evidence of an inverted internal limiting membrane (ILM) flap filling the central area.
8.3 Refractory and recurrent cases
Some FTMHs remain open after primary surgery (refractory), or they reopen after initial closure (recurrent), necessitating secondary surgery. Secondary closure proves successful in over 75% of patients, not often leading to substantial visual improvement [27].
Unsuccessful FTMH closure after primary surgery is linked to factors such as large size (> 500 μm), chronicity, high myopia, insufficient ILM peeling, Inadequate postoperative positioning, among others. Recurrent FTMHs share risk factors including cataract surgery, high axial length, and postoperative complications [13, 26].
Multiple surgical techniques are available for repairing refractory or recurrent FTMHs, but consensus on the optimal approach remains elusive due to limited literature on newer methods. These techniques can be grouped according to the presumed mechanisms driving closure [9].
8.4 Revisional vitrectomy (rePPV) with ILM peeling enlargement
This procedure involves enlarging the primary ILM peeling, if necessary, and intraocular tamponade using gases, silicone oils, or heavy silicone oils. The rationale is to weaken tangential tractions, boost retinal elasticity, activate Müller cells, and plug the hole for subretinal fluid reabsorption. The tamponade material choice depends on factors including patient posturing capabilities [9].
These techniques aim to achieve MH closure through distinct mechanisms, including Müller cell gliosis, migration, proliferation, tractional force elimination, and fostering a healing environment. The choice of technique may hinge on factors like macular hole size, type, and desired visual outcomes [5, 9].
8.5 Subretinal fluid injection
This technique causes macular detachment by injecting balanced salt solution (BSS) into the subretinal space. It’s believed to promote closure by disrupting abnormal adhesions between neuroretina and RPE, enhancing hole edge elasticity. Subretinal fluid injection may benefit refractory MHs with robust neuroretina-RPE adhesions, such as chronic, large, or traumatic holes [28].
Tissue transplantation: Autologous or heterologous tissue transplantation:
Lens capsular flap (LCF) or posterior lens capsule (PLC) transplantation: Studies indicate positive immunoreactivity of macroglia and microglia cells in transplanted PLC. This implies a potential similarity between MH closure mechanisms in the inverted ILM flap technique and PLC transplantation. Graft size and orientation are crucial, ensuring the graft is slightly larger than the MH diameter, with the smoother outer surface facing the hole. Differences exist between anterior and posterior capsules, with the anterior capsule adhering firmly with perfluorocarbon liquid (PFCL) tamponade. The posterior capsule may require silicone oil tamponade to prevent flap dislocation. The technique demonstrated partial MH closure through flap incorporation into retinal tissue, leading to visual acuity improvement [29, 30].
Autologous retinal trasplantation (ART): Proposed for refractory myopic MHs, ART involves a graft twice the MH size, using thicker retina for stability, and positioning under the hole edges. Autologous Neurosensory Retinal Flap showed visual acuity improvement and graft integration, but its value for chronic MHs with poor baseline vision is debated. Postoperative recovery of outer retinal structure, particularly the ellipsoid zone (EZ) and the external limiting membrane (ELM), is vital for improved vision. However, retinal free flap signal transmission remains unclear due to retinal circulation disruption [31, 32].
We consider it could be an alternative in cases of retinal detachment associated with MH.
Human amniotic membrane (hAM) graft: Is a layer of tissue from the innermost part of the human placenta. It is known for its rich content of growth factors and possesses various beneficial properties, including anti-inflammatory, anti-fibrotic, anti-microbial, and anti-angiogenic effects. Are used in ocular surface reconstruction, and their potential to integrate into host tissue makes them a candidate for macular hole repair. The use of hAM grafts in MH surgery is based on their potential to act as a scaffold for tissue repair and to promote healing. The hAM’s basement membrane contains components similar to those found in the internal limiting membrane (ILM), such as collagens IV, laminins, and fibronectin, which may support the adhesion and migration of retinal cells [33, 34].
The surgical procedure involves a standard PPV, similar to other MH repair techniques. After the necessary steps of PPV and confirmation of ILM peeling status, a piece of hAM is harvested from the placenta and prepared. The graft can be placed over the MH in different ways, such as epiretinally (flattened to cover the hole), intraretinally (inserted into the hole), or subretinally (inserted under the hole’s edges). The graft is usually manipulated and positioned under perfluorocarbon liquid (PFCL) to aid in its placement. Depending on the specific case and surgeon’s preference, tamponade agents like gases, silicone oil (SO), or PFCL can be used. Postoperative positioning, including face-down positioning, is determined based on the choice of tamponade agent [33, 34].
The closure rate of refractory macular holes treated with hAM grafts varies, with reported rates ranging from 66.7 to 100%. However, while successful macular hole closure can be achieved, the functional success, defined as a significant improvement in visual acuity, appears to be less common. The results suggest that while hAM grafts may effectively seal the hole, they may not always lead to substantial visual improvement. The final visual acuity can be influenced by factors such as baseline visual acuity, hole closure, and the reconstitution of the ellipsoid zone (EZ) and ELM on OCT. In summary, hAM grafts represent a potential option for the surgical repair of complex macular holes, especially those that were previously considered untreatable, such as large, recurrent, or highly myopic macular holes. While hAM grafts can effectively close macular holes, the extent of visual improvement may vary, and the graft’s integration into host tissue remains a subject of research. The choice to use hAM grafts depends on the specific characteristics of the macular hole and the surgeon’s experience and judgment [33, 34].
Autologous blood-derived plugs or scaffolds
Autologous Platelet-Rich Plasma (aPRP): The use of autologous aPRP aims to modulate intraretinal gliosis through growth and neurotrophic factors, stimulating Müller cell activation and closure. This technique involves using a portion of plasma with a higher concentration of platelets than peripheral blood. It is obtained by centrifuging the patient’s blood sample under sterile conditions to prevent contamination. The rationale for using aPRP is based on experimental evidence of the influence of platelets and their growth factors on Müller cells and RPE cells. aPRP stimulate the proliferation and migration of retinal glial cells, Müller cells, and RPE cells in vitro, aiding in macular hole closure. However, it may contain a high concentration of leukocytes that can lead to the release of free radicals and proinflammatory substances that alter or prevent tissue regeneration. Whole blood has the same disadvantage [9, 35, 36].
Plasma Rich in Growth Factors (PRGF): Is a subtype of aPRP, characterized by a moderate concentration of platelets, in the absence of leukocytes. It involves platelet activation before using it. This absence of leukocytes is based on the fact that they synthesize matrix metalloproteinases (MMPs), free radicals and proinflammatory cytokines, which do not contribute and even impair the altered tissue regeneration [37, 38, 39, 40]. Additionally, the clotted PRGF may mechanically contribute to MH closure by sealing the hole and acting as a scaffold for cell migration and proliferation.
The following procedure was standardized at Instituto de Terapias Avanzadas (ITA, Barranquilla, Colombia); the patient’s whole blood is collected in 4.5 ml vacutainer tubes containing sodium citrate as an anticoagulant. The samples were processed immediately after collection. Each tube underwent centrifugation for 5 minutes at 300 g. Three components are extracted: fraction 1 (F1), which has a similar platelet concentration as peripheral blood; fraction 2 (F2), with 2 or 3 times the platelet concentration of peripheral blood; and the lowest fraction containing erythrocytes. In this case we took fraction 1 and fraction 2 and place them into a tube. The falcon tube went under centrifugation for a second time for 18 minutes at 700 g. Two milliliters of F2 are taken to prepare the leukocyte-free PRGF. To form the three-dimensional structure, the sample is activated with C12H22CaO14 and incubated at 40°C until the membrane coagulates. This process yields three structures: fibrin, scaffold, and eye drops. The prepared material is transported to the operating room under strict aseptic and sterile conditions. The above has been carried out based on the first case report published in Latin America by the retina group of FOSCAL, Colombia [36].
In this approach, a rePPV is performed to address the MH. The previously peeled area of the internal limiting membrane is visualized, and additional peeling may be performed if necessary. After fluid-air exchange, the PRGF membrane is placed over the MH. Gas or silicone oil can be used as a tamponade, and the patient is instructed to assume a specific postoperative position, often involving a period of supine positioning followed by face-down positioning.
In the scarce published studies using this technique, a closure rate of 87.5–100% is reported for refractory macular holes, with significant improvement in visual function. We bring up a representative patient with primary macular hole in both eyes associated with epiretinal membrane and proliferation. This latter factor is a marker of poor prognosis due to the neurodegenerative association in MH formation. This type of pathology associated with MH is usually linked to a low closure rate and poor visual improvement with conventional surgery, and even manipulation of epiretinal proliferation remains a topic of debate due to atrophic changes and post-surgical visual losses. In this case, we performed conventional surgery in one eye and PRGF without EP or ILM peeling in the contralateral eye. We found anatomical closure and visual improvement in both eyes. However, the tomographic characteristics of the outer layers of the neuroepithelium showed greater approximation and regeneration in the PRFG case compared to the eye managed with conventional surgery. Nevertheless, it’s important to note that the size of the macular hole managed with ILM peeling was larger (Figures 4 and 5).
Figure 4.
The right eye of a 74-year-old female patient. OCT B-scans, demonstrates the disease progression. It starts with a lamellar hole-associated epiretinal proliferation and ERM. Then progresses into a FTMH with epiretinal proliferation (EP). The next image is from the first day postoperative after pars plana vitrectomy (PPV) without membrane or EP peeling, using the PRGF membrane. The final image depicts the evolution one month after surgery, showing partial restoration of external layers at the foveal level.
Figure 5.
Left eye of the previous 74-year-old female patient, upper image with FTMH and EP, then postoperative day 1 of PPV with ILM inverted flap, then 1 month postoperative.
8.6 Other surgical techniques
8.7 Choice of tamponade
Gases are generally preferred over silicon oil (SO) or heavy silicone oil (HSO) as tamponades, as they do not require additional removal procedures and are not associated with typical SO/HSO-related complications like intraocular emulsification, hypertension and inflammation [46].
8.8 Use of face down position after surgery
Despite the high success rate of the recent techniques, there remains ongoing debate about the best surgical approach. Also Different intraocular tamponade agents such as sulfur hexafluoride (SF6) perfluoroethane (C2F6), perfluoropropane (C3F8), silicone oil, or air have also been employed [15].
For many years, there has been a debate surrounding the ideal duration of postoperative face-down positioning following MH surgery. Although it was once deemed essential, recent optical coherence tomography (OCT) studies have hinted at the possibility of macular holes closing as early as one day after the procedure. This has prompted questions about the necessity of prolonged face-down posturing, which many patients, including older individuals, those with obesity, individuals living alone, or those with limited mobility, find challenging. Additionally, extended posturing may pose an increased risk of thromboembolism [15].
Interestingly, approximately 80% of surgeons still recommend face-down posturing, typically for a period ranging from 5 to 10 days. The rationale behind this practice is that it assists in MH closure by ensuring the buoyant force of the intraocular gas bubble, which is most potent at its apex, maintains contact with the macula. This gas bubble serves to keep the edges of the macular hole dry, prevents vitreous intrusion, and acts as a scaffold for the growth of glial cells. It is worth noting that surface tension around the bubble’s interface with the retina remains consistent. Therefore, as long as there is an adequate volume of intraocular gas (approximately two-thirds to three-quarters of the vitreous cavity) and the patient avoids a supine position, the macular hole remains covered [15].
Historical studies indicated better surgical outcomes with prolonged face-down posturing, such as a closure rate of 94.4% for patients posturing face-down for 14 days (90% of the time) followed by 14 days (50% of the time) compared to a 65.6% closure rate for patients posturing face-down for 7 days (90% of the time). However, recent research has demonstrated favorable MH closure rates even with shorter posturing periods, especially when combined with internal limiting membrane (ILM) peeling. In cases with ILM peeling, closure rates reached 92.9% compared to 79.3% without [15].
Recent findings also suggest that the rate of MH closure with face-down posturing for less than 24 hours is comparable to posturing for 5 to 10 days. Nevertheless, there’s currently insufficient evidence to definitively determine whether face-down posturing significantly influences MH closure rates after surgery. Additional research is required to establish the precise role of face-down posturing in MH surgery [15].
8.9 Less invasive vs. more invasive procedures
Less invasive revisional surgical procedures (e.g., rePPV with ILM free flap, PRGF or aPRP) appear to be at least as effective as more invasive techniques (e.g., hAM graft and autologous retinal transplantation). The choice of procedure may depend on the complexity of the FTMH, with more invasive techniques reserved for complex cases.
We believe that the choice of surgical technique to use is based on various factors, including the type of MH (primary or refractory), its size, association with vitreoretinal interface pathologies, and the retinal status (attached or detached). Taking these considerations into account, in the case of small primary macular holes, it might be appropriate to consider conventional PPV, with or without ILM peeling. For larger primary macular holes, ILM peeling with or without inverted flap technique, or even the use of PRGF, could be contemplated. For macular holes associated with retinal detachment, we could consider the use of PRGF, hAM, or ART. In the case of myopic macular holes with macular detachment, macular indentation could be complemented with PRGF, hAM, or PRP. Regarding refractory macular holes, we hold the opinion that both anatomical and visual outcomes could be improved by using blood derivatives such as PRP and PRGF. However, it’s important to highlight that these suggestions are based on our own experience and we recognize the need for further studies and publications in this field.
9. Conclusions
There is a lack of randomized controlled trials and large prospective studies comparing different surgical techniques for refractory FTMHs. The existing studies have limitations, including heterogeneity in methods, samples, and surgical approaches, as well as small sample sizes.
More research is needed to better understand the mechanisms of FTMH closure, especially when using autologous or heterologous tissue transplantation. Investigating the healing mechanisms could help optimize both anatomical and functional outcomes.
Some experimental and preliminary clinical studies have introduced potential adjuvants for treating refractory and recurrent FTMHs, such as nerve growth factor, mesenchymal stem cells, and mesenchymal stem cell-derived exosomes. These emerging therapies may hold promise for the future.
When dealing with unsuccessful closure or reopening of FTMHs, there is a trend toward surgical approaches that involve adjuvants capable of inducing and modulating intraretinal gliosis and/or membranes that can also act as a mechanical scaffold.
Acknowledgments
Thanks to Dr. Juan David Arias, Dr. Valentina Perez Vergara, Clinica Carriazo, Clinica Yepes Porto, Instituto de Terapias Avanzadas.
Conflict of interest
The authors declare no conflict of interest.
Appendices and nomenclature
macular holes | |
internal limiting membrane | |
external limiting membrane | |
plasma rich in growth factors | |
full-thickness macular hole | |
optical coherence tomography | |
posterior vitreous detachment | |
rhegmatogenous retinal detachment | |
international vitreomacular traction study | |
vitreomacular traction | |
epiretinal membrane | |
epiretinal proliferation | |
retinal pigment epithelium | |
lens capsular flap | |
posterior Lens Capsule | |
perfluorocarbon liquid | |
human amniotic membrane | |
ellipsoid zone | |
autologous platelet-rich plasma | |
matrix metalloproteinases | |
revisional vitrectomy | |
intraocular pressure | |
silicon oil | |
heavy silicone oil |
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