Secondary Full-thickness Macular Holes after Diabetic Vitrectomy: Clinical Manifestations and Rational Approaches to the Treatment

Purpose The aim of the study is to present the clinical characteristics and surgical treatment of secondary full-thickness macular hole (MH) after diabetic vitrectomy (DV) in patients with proliferative diabetic retinopathy (PDR). Methods In this retrospective, observational, and longitudinal study, we enrolled consecutive patients with PDR who developed MH after DV. The macular structure was evaluated using optical coherence tomography. The clinical characteristics, surgical techniques, and outcomes were also recorded. Results Three patients developed MH within 6 weeks, which was associated with foveal thinning, residual fibrovascular proliferation, or anterior proliferative vitreoretinopathy. Six patients developed MH originating from the epiretinal membrane (ERM) with lamellar MH (LMH) after a median interval of 16.5 months. Three of them were complicated with retinal detachment (RD). Various surgical procedures were performed according to the clinical scenarios, including internal limiting membrane (ILM) peeling, inverted ILM flap insertion, temporal inverted ILM flap, lens posterior capsular flap insertion, and neurosensory retinal free flap insertion. All patients achieved MH closure after surgery, and 5 patients exhibited improved visual acuity. Conclusions MH may develop after successful DV, with a high rate of associated RD. Rapid MH formation was attributed to unreleased tractional force and weakened foveal structure. The development of ERM and LMH also led to MH. Various surgical techniques could be used for MH closure.

Owing to the specific microenvironment and abnormal macular structure after DV, post-DV MH might exhibit clinical features different from those of other postoperative MHs. Additionally, the management of MH after DV may be complicated by weakened retinal structure and adherent residual fibrotic tissue.
is study investigated various clinical scenarios associated with secondary MH after DV and explored the appropriate surgical treatment to achieve MH closure.

Materials and Methods
e clinical charts of all patients with PDR who received DV between January 2010 and November 2020 at the National Taiwan University Hospital were retrospectively reviewed. All data collection and analyses were conducted in accordance with the tenets of the Declaration of Helsinki. Patients who developed secondary MH after primary DV were enrolled, while those with a history of PPV for other diseases or persistent MH from the primary DV were excluded from this study. e study was approved by the institutional review board of the National Taiwan University Hospital. e requirement for informed consent was waived owing to the retrospective nature of the study.
All patients underwent an initial vitrectomy for the treatment of PDR complications, including vitreous hemorrhage (VH), fibrovascular proliferation (FVP), or tractional retinal detachment (TRD). Patient demographic data, indications for DV, findings of dilated fundus examination, best-corrected visual acuity (BCVA) before and after each operation, the interval between the last DV and MH development, surgical procedures, and MH repair techniques were documented. e extent of FVP was classified into four grades according to the definition of a previous study [27]. FVP activity was classified as "active" (if neovascularized tissue or any degree of VH was identified) or "mainly fibrosis." [27] e macular structure was evaluated using optical coherence tomography (OCT) (Stratus OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA; Cirrus OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA; or RTVue Premier, Optovue, Inc., Fremont, CA, USA). e presence of ERM and cystoid macular edema (CME) was recorded. A manual caliper was used to measure MH size. All patients underwent follow-ups for >3 months after the final surgical procedure.

Results
is study enrolled 9 eyes from 9 patients (4 male and 5 female). e average patient age was 57.2 ± 6.1 years. e time interval between the last DV and MH formation varied significantly.
ree patients (Cases 1-3) developed MH rapidly (at 2, 3, and 5 weeks, respectively). Cases 1 and 2 showed decreased minimal foveal thickness (135 and 87 μm, respectively) after SO removal. Case 2 also had an extensive and thickened ERM at the arcades, which was exerting tractional force on the macular area. Case 3 had severe anteroposterior traction due to anterior proliferative vitreoretinopathy (PVR). Cases 2 and 3 had macular hole retinal detachment (MHRD). Five patients (Cases 4-9) developed MH > 6 months after DV (median: 16.5 months, range: 6.5-76 months). All patients developed ERM during the follow-up, and 4 patients developed lamellar MH (LMH) before the development of full-thickness MH. Only one of these patients had undergone ILM peeling during the initial DV. All patients with ERM had active and grade 2 or higher FVP. e median interval to ERM formation after DV was 7 months (range: 1-26 months). e median interval from ERM growth to MH formation was 12 months (range: 3-50 months). Case 8 had chronic RD and underwent multiple surgeries.
Regarding MH repair surgeries, Case 1 underwent lens posterior capsular flap insertion. Cases 2 and 3 had MHRD and underwent inverted ILM flap and neurosensory retinal free flap insertion, respectively. Cases 4-7 and 9 underwent ERM removal and ILM peeling, while Cases 7 and 9 underwent an additional temporal inverted ILM flap technique. Case 8 underwent ILM peeling, subfoveal band removal, and laser supplementation at the MH margin. All cases achieved MH closure. Table 1 summarizes the clinical data of all patients. e following sections briefly describe 4 representative cases.

Case 1.
A 54-year-old man with PDR and TRD underwent PPV and intravitreal SO injection at another hospital. Two years later, he visited our hospital with a BCVA of 20/100. He underwent cataract surgery, intravitreal SO removal, ICG-assisted ILM peeling, and residual FVP removal. Macular thinning was noted after the surgery. MH developed 2 weeks later, and his BCVA decreased to 20/400. Lens posterior capsular flap insertion and intravitreal  Figure 2).

Case 3.
A 68-year-old woman presented with PDR complicated with VH and TRD. At presentation, her BCVA was counting fingers at 50 cm in the right eye. erefore, she underwent PPV, FVP removal, ICG-assisted ILM peeling, and intravitreal infusion of C 3 F 8 . During surgery, peripheral temporal lower traction was noted, and iatrogenic breaks were induced. Recurrent RD and MH measuring 1063 μm developed 5 weeks later, and her BCVA had deteriorated to hand motion at 1 m. Extensive anterior PVR exerting tractional force on the macular area was noted intraoperatively. Perfluorocarbon-assisted inferior 150-degree retinectomy, neurosensory retina-free flap insertion, and intravitreal SO injection were performed. e MH was sealed, and her BCVA was 20/400 1 year later ( Figure 3).

Case 5.
A 54-year-old woman had PDR complicated by grade 3 FVP, TRD, and rhegmatogenous RD (RRD). Her initial BCVA was hand motion at 20 cm. She underwent PPV, triamcinolone and ICG-assisted ILM peeling, FVP removal, and intravitreal infusion. After surgery, the retina was reattached and her BCVA improved to 20/125. During follow-up, ERM and LMH were noted. e LMH progressed to a full-thickness MH 11 months after the initial surgery and her BCVA deteriorated to 20/200. She underwent ERM removal, ICG-assisted ILM peeling, and intravitreal C 3 F 8 infusion. e MH was sealed, and her final BCVA was 20/ 100 6 months later (Figure 4).
Images of Cases 6-8 are shown in Figure 5. As the evolutions of Cases 4 and 9 were similar to those of Cases 6-8, the figures are not presented. e possible factors related to MH formation in this series are summarized in Table 2. In brief, ERM was the most common factor. Post-DV eyes with ERM had the longest time to MH formation and the lowest association with RD. On the other hand, eyes with incomplete FVP removal and PVR showed a strong association with MHRD.

Discussion
Post-vitrectomy MH has been reported after surgery for RRD, ERM, or myopic tractional maculopathy [11,14,28], with incidence rates ranging from 0.2% to 1.9% [14]. e possible mechanisms include iatrogenic trauma or microhole formation during the induction of posterior vitreous detachment or membrane peeling, and CME tangential traction caused by vitreoschisis or ERM, and the underlying disease requiring PPV [10,11,29,30]. Secondary MH could also occur after DV for the complications of PDR. However, only a few case reports have described this non-idiopathic post-surgical condition [4,14,[30][31][32][33][34][35]. ERM and premacular fibrosis were the most common predisposing factors for secondary MH from the limited case reports. Most patients underwent ERM removal with or without ILM peeling for MH repair. In the literature, the evolutionary process and rationale for surgical management have not yet been elaborated in detail. In the present study, we focused on the secondary MHs after DV and described their clinical characteristics, possible mechanisms, and rationale for their treatment.
e major predisposing factors for secondary MHs after DV included ERM, residual FVP, anterior PVR, chronic CME, weakened foveal structure, and iatrogenic traction during surgery. e foveal structure is weakened in eyes with PDR due to longstanding CME and ischemia [2]. Surgical manipulation during DV, induction of posterior vitreous detachment, ERM removal, and ILM peeling may further damage fragile foveal structures. Previous reports on MH secondary to RD repair surgery or DV have observed rapid MH formation due to direct traction on the macula during vitrectomy [11,32,34]. Case 1 developed MH 2 weeks after SO removal. Foveal thinning implied a long-standing ischemic environment and atrophy, which may increase patient susceptibility to poor visual and anatomical outcomes. Due to simultaneous ERM and ILM peeling during the SO removal surgery and the absence of a residual premacular membrane, mechanical trauma during membrane peeling may have further contributed to MH development. Moreover, residual FVP and subsequent ERM formation or even anterior PVR could lead to tangential traction in cases complicated with RD. Case 2 developed MH and localized RD 3 weeks after SO removal. During MH repair surgery, thickened ERMs connected to the retinal vessels were observed near the superotemporal and inferotemporal arcades, which caused traction on the macula. e adhesion of membranes to the vessels suggested that the membranes might represent incompletely removed FVP from the previous surgery or proliferation from the residual FVP stumps. Strong tractional force on the fovea induced MHRD. Previous case reports also demonstrated that premacular fibrotic membranes could induce rapid secondary MH formation within 2 months [33,34]. In Case 3, recurrent RD with MH formation was observed 5 weeks after primary DV with ILM peeling. e anterior PVR in the inferior retina induced a large MH. An inferior 150-degree retinectomy was required to release traction and a neurosensory retinal flap was used to close the MH. Remote traction, if sufficiently extensive, can induce rapid MH formation. Although the strong traction from residual FVP and PVR changes induced rapid MH formation and RD, visual improvement could still be expected with prompt and proper management.
ERM was the most common predisposing factor for secondary MH after DV as reported in the literature [4,30,31,35]. e tangential traction exerted on the weakened fovea caused subsequent MH formation within 7 months to 5 years [4,30,31,35]. In the present study, Cases 4-9 (6 eyes) also showed ERM and subsequent MH formation after primary DV. LMH occurred in 4 eyes (67%) as a pre-MH condition. ERM develops in more than half of post-DV eyes and has a multifactorial pathogenesis [36]. e ischemic environment in eyes with PDR may persist or even worsen after DV, increasing the risk of cellular infiltration and epimacular membrane formation. Intraoperative bleeding or postoperative recurrent hemorrhage produces a pro-inflammatory environment and stimulates ERM formation, especially in patients with SO infusion [37,38]. Eyes with active and high-grade FVPs that were more difficult to remove were prone to significant ERM formation since residual FVP or posterior hyaloid could serve as a scaffold. Meticulous ILM peeling during primary DV ensures complete removal of the preretinal membrane and vitreoschisis, and prevents ERM recurrence in post-DV eyes [39][40][41]. Similarly, in eyes receiving PPV for RD, not using a vitreous staining agent in the primary surgery may leave residual cortical vitreous in the premacular area, leading to ERM formation and contraction from the residual vitreous [10]. In our cohort, 77.8% of eyes (Cases 2, 4-9) showed ERM formation after DV in a median of 7 months. Six of them (85.7%) did not undergo ILM peeling during primary DV. In these patients, ERM was the main factor contributing to MH formation. Due to the relatively weak traction, MH development was delayed in these cases (median: 12.0 months) compared to patients with other contributing factors. e association with MHRD was also low (29%). In the literature, the interval from the initial surgery to secondary MH    formation ranged from 1.6 to 26 months and is highly variable depending on the underlying conditions [14,30]. Generally, eyes with myopic foveoschisis show the highest incidence and shortest interval to secondary MH formation [29]. Eyes with a history of macula-off RD, pseudohole, and CME developed secondary MH after an interval of approximately 1 year [10-12, 28, 30]. Eyes that received PPV for idiopathic ERM exhibited the most extended interval to  the development of secondary MH [30]. e time to MH formation in our cohort was similar to those in eyes with macula-off RD, pseudoholes, and CME. Surprisingly, patients with ERM had limited visual improvement compared to the pre-DV status, which could be attributed to the chronicity of MH and possible delayed diagnosis.
In our cohort, one-third of the patients had MHRD. Among patients who developed MH after undergoing PPV for RD, those who underwent multiple surgeries or whose eyes were complicated with PVR exhibited a higher incidence of MHRD [10]. e complex traction and fragile structure in post-DV eyes resembled the conditions in highly myopic eyes, which also showed a higher incidence of MHRD. In our series, the predisposing factors of MH, such as incomplete FVP removal and PVR changes, had the highest associations with RD. Case 2 had foveal thinning, ERM, and subsequent LMH formation, which were worsened by residual FVP, and progressed to MHRD 3 weeks after SO removal. Case 3 had recurrent RD with concurrent MH due to severe anterior PVR 5 weeks after primary DV. Case 8 underwent multiple surgeries due to persistent chronic TRD and PVR changes. LMH developed gradually after primary DV and progressed to a full-thickness MH. When managing patients with PDR, ILM peeling during primary DV can ensure more complete removal of the premacular membrane and prevent subsequent traction. However, delicate surgical manipulation is also essential for preventing MH formation. Despite more complicated conditions, visual improvement can still be expected after successful MH repair surgery.
e standard ILM peeling technique can successfully treat most cases and achieve better anatomical and visual outcomes [3,8]. Traction release by the surgery and the pre-proliferative environment could help promote MH closure [3]. However, in more severe cases complicated by MHRD, other advanced techniques may be needed. An inverted epiretinal ILM flap may be preferred because it has the least interference with the foveal structure. If the ILM flap fails to cover the MH, inverted ILM flap insertion or free ILM flaps could be considered [9]. e management of secondary MH after DV has rarely been discussed in the literature. In previous case reports, most patients received primary DV due to nonclearing VH [4,14,[31][32][33], which was less complicated than in our cases. Most patients underwent ERM removal with or without ILM peeling as MH repair surgery. Depending on the complicated conditions in the post-DV MHs, we applied different surgical techniques for MH repair, in which meticulous ILM and ERM peeling and removal of residual FVP were pivotal for sealing MHs and preventing recurrence. In more complicated cases, the inverted ILM flap was the first choice (Cases 7 and 9). Case 2 was treated with inverted ILM insertion instead of an inverted ILM flap because the small ILM flap tended to flip back. In eyes without available ILM tissue, lens capsular flap or neurosensory retinal flaps were utilized. Neurosensory retinal flaps are useful for complicated RD because peripheral retinectomy provides retinal tissue, drains subretinal fluid, and releases traction [9]. In Case 8, only ERM removal and ILM peeling were performed because the MH was too large for adequate ILM flap coverage or insertion. As a 360-degree retinectomy had been performed in the previous surgery, we hesitated to sacrifice any viable retinal tissue for the neurosensory flap. Gap closure of the MH was achieved. In such cases, an amniotic membrane graft may be another option [24]. Although the MH closure rate was 100% in this study, the visual prognosis was guarded in these patients due to complicated PDR and concomitant MH. e final visual acuity was poor compared to that in patients with other types of secondary MHs [10,14,30]. However, all patients showed better visual acuity than at the time of MH formation. Five patients exhibited visual improvement compared to the values before DV. e final visual acuity was non-inferior to eyes with PDR complicated with MH before DV [5,19].
is study included a limited number of patients. However, the incidence of secondary MH following DV is low. To our knowledge, no previous study has focused solely on the pathogenesis and clinical features of MH secondary to DV. We observed the rapid development of MH in the presence of unreleased traction and a weakened foveal structure due to diabetic retinopathy and iatrogenic trauma. Traction from the ERM could lead to the formation of LMH, subsequently progressing to full-thickness MH. Secondary MH after DV was prone to MHRD and has a poor visual prognosis. Tailored MH repair surgery is required, considering the complicated and challenging conditions in post-DV eyes. Complete but meticulous ILM peeling is necessary to ensure the total traction release and prevent MH formation.

Data Availability
e data used to support the findings of this study are available on reasonable requests from the corresponding author.

Conflicts of Interest
e authors declare that they have no conflicts of interest.