Clinical profile and outcomes of rejection after deep anterior lamellar keratoplasty in keratoconus
This is a retrospective study of six eyes of six patients who were diagnosed with rejection episode after DALK between 2019 and 2023. During this period, 487 eyes had undergone DALK. The demographics, clinical features, treatment, and outcomes after rejection were studied. The demographic data and clinical details such as age, history of allergic eye disease, indication of surgery, coexisting cornea vascularization (if any), donor details, surgical factors like graft size and centration, type of surgery (manual vs. big-bubble DALK), frequency of steroid usage, and status of sutures in situ at the time of rejection were analyzed. Routine postoperative care after DALK involved prednisolone acetate 1% in three-hourly frequencies for the first week or 2 weeks, followed by weekly taper to twice daily, which continued till all the sutures were removed. In the event of steroid-related raised intraocular pressure, loteprednol etabonate 1% was used instead of prednisolone acetate. The general practice pattern for management of an acute rejection episode consisted of topical prednisolone acetate 1% every hourly, which was gradually tapered over 6–8 weeks to twice daily. Resolution of rejection episode was defined by the resolution of graft haze, quiet appearance of conjunctiva, and regression of graft neovascularization.   summarizes the demographics and clinical details of the six patients. – show the slit-lamp photographs of the six eyes. Demographics The median age of the patients was 24 years (range 18–44 years), and there was an equal number of males and females. The indications for surgery were advanced keratoconus with poor contact lens tolerance and subjectively inadequate spectacle corrected distance visual acuity (CDVA) in all eyes. Of the six patients, four had concomitant allergic eye disease and one had lid margin disease. The left eye was affected in four patients. Median follow-up from the time of surgery was 2.5 (range 1–7) years. Donor and surgical details Five eyes had type 1 big-bubble DALK and one eye had manual dissection DALK. All surgeries were uneventful. Sixteen interrupted sutures were placed during surgery in all eyes. The donor graft size ranged from 8.25 to 8.75 mm. The grafts were oversized by 0.25 mm in each case. One graft was eccentric to accommodate peripheral area of thinning in the host. The donor corneas were preserved in either Cornisol or McCarey-Kaufman preservation solution for up to 1–3 days. Median age of the donors was 41 (range 35–83) years. Donor–recipient gender mismatch was noted in two patients. Clinical features of rejection Median time of rejection from the day of surgery was 12 (range 3–36) months. Median duration of symptoms was 4 (range 2–28) days. Of the six patients, five complained of mild ocular discomfort, redness, photophobia, and reduced vision. One patient (Patient 2) had excruciating pain and discomfort. The clinical signs in all eyes included congestion and haze localized to the graft. Patient 2, who complained of severe pain, had intense congestion, graft infiltration, and melt localized to the graft, which resembled microbial keratitis [ b]. Although there was no anterior chamber reaction and lid edema, a complete microbiologic work-up was performed to rule out an infective etiology. Scrapings from the site of graft were sent for smears and cultures for bacteria, fungi, parasitic infections, and virology studies. The smears did not reveal any organism, and cultures were sterile. In view of the melt, tissue adhesive was applied over the graft–host junction (1b). Two patients were using topical steroids, although inconsistently, while four had discontinued steroids. One patient (Patient 4) developed two episodes of rejection 3 months apart [ c]. This patient had stopped steroids at 1 month after the first episode of graft rejection, which could have been the possible risk factor for the second episode. Management and outcomes Five patients were treated with prednisolone acetate 1% hourly initially, with gradual tapering over weeks, until twice-a-day dosing was maintained. One patient (Patient 2) was initially treated with intensive antibiotic therapy (fortified cefazoline and ciprofloxacin) for 2 days and the steroids were instituted only after microbiologic work-up was inconclusive. Intravenous methylprednisolone therapy at a dose of 1 g given as a single dose was additionally administered in one patient (Patient 1) in view of marked drop in vision due to diffuse graft haze. All except one (Patient 2) responded favorably to the treatment regimen with restoration of graft clarity. Patient 2 was responding to topical steroids, but developed superadded fungal infection at 2-months follow-up [ c], which resolved with topical antifungal medications and developed scarring in the graft [ d]. Excluding the patient who developed scarring following secondary fungal keratitis, the median best corrected visual acuity in five patients was restored to 20/30 (range 20/30–20/50) at 3–4 months post-rejection, which was maintained till the last follow-up duration. In one patient (Patient 4), lipid deposition was seen in the mid-stroma of the graft along ghost vasculature after the second episode of rejection at 3 months [ d]. The intraocular pressure was recorded in the normal range in all eyes at all visits, and fundus examination revealed a healthy disc with a normal cup–disc ratio.   The median age of the patients was 24 years (range 18–44 years), and there was an equal number of males and females. The indications for surgery were advanced keratoconus with poor contact lens tolerance and subjectively inadequate spectacle corrected distance visual acuity (CDVA) in all eyes. Of the six patients, four had concomitant allergic eye disease and one had lid margin disease. The left eye was affected in four patients. Median follow-up from the time of surgery was 2.5 (range 1–7) years.   Five eyes had type 1 big-bubble DALK and one eye had manual dissection DALK. All surgeries were uneventful. Sixteen interrupted sutures were placed during surgery in all eyes. The donor graft size ranged from 8.25 to 8.75 mm. The grafts were oversized by 0.25 mm in each case. One graft was eccentric to accommodate peripheral area of thinning in the host. The donor corneas were preserved in either Cornisol or McCarey-Kaufman preservation solution for up to 1–3 days. Median age of the donors was 41 (range 35–83) years. Donor–recipient gender mismatch was noted in two patients.   Median time of rejection from the day of surgery was 12 (range 3–36) months. Median duration of symptoms was 4 (range 2–28) days. Of the six patients, five complained of mild ocular discomfort, redness, photophobia, and reduced vision. One patient (Patient 2) had excruciating pain and discomfort. The clinical signs in all eyes included congestion and haze localized to the graft. Patient 2, who complained of severe pain, had intense congestion, graft infiltration, and melt localized to the graft, which resembled microbial keratitis [ b]. Although there was no anterior chamber reaction and lid edema, a complete microbiologic work-up was performed to rule out an infective etiology. Scrapings from the site of graft were sent for smears and cultures for bacteria, fungi, parasitic infections, and virology studies. The smears did not reveal any organism, and cultures were sterile. In view of the melt, tissue adhesive was applied over the graft–host junction (1b). Two patients were using topical steroids, although inconsistently, while four had discontinued steroids. One patient (Patient 4) developed two episodes of rejection 3 months apart [ c]. This patient had stopped steroids at 1 month after the first episode of graft rejection, which could have been the possible risk factor for the second episode.   Five patients were treated with prednisolone acetate 1% hourly initially, with gradual tapering over weeks, until twice-a-day dosing was maintained. One patient (Patient 2) was initially treated with intensive antibiotic therapy (fortified cefazoline and ciprofloxacin) for 2 days and the steroids were instituted only after microbiologic work-up was inconclusive. Intravenous methylprednisolone therapy at a dose of 1 g given as a single dose was additionally administered in one patient (Patient 1) in view of marked drop in vision due to diffuse graft haze. All except one (Patient 2) responded favorably to the treatment regimen with restoration of graft clarity. Patient 2 was responding to topical steroids, but developed superadded fungal infection at 2-months follow-up [ c], which resolved with topical antifungal medications and developed scarring in the graft [ d]. Excluding the patient who developed scarring following secondary fungal keratitis, the median best corrected visual acuity in five patients was restored to 20/30 (range 20/30–20/50) at 3–4 months post-rejection, which was maintained till the last follow-up duration. In one patient (Patient 4), lipid deposition was seen in the mid-stroma of the graft along ghost vasculature after the second episode of rejection at 3 months [ d]. The intraocular pressure was recorded in the normal range in all eyes at all visits, and fundus examination revealed a healthy disc with a normal cup–disc ratio.   DALK has several advantages over penetrating keratoplasty (PK); however, the risk of epithelial and stromal rejection persists. Most of the rejection episodes occurring after PK begin present as graft edema with keratic precipitates, primarily due to endothelial involvement. Loss of graft clarity due to failure from endothelial rejection after PK predominantly results in edema that can be managed later with endothelial keratoplasty with good outcomes. However, the rejection after DALK can lead to a loss of transparency due to stromal haze, which may not recover completely if management is delayed. The loss of stromal clarity may also be affected severely due to development of neovascularization in the graft. It appears from various studies that the overall rate of rejection in DALK may be similar to that reported after PK. The clinical features and risk factors of rejection after DALK have been described; however, the literature on rejection after DALK is relatively sparse compared to rejection after PK. This is likely due to relatively smaller proportions of DALK when compared to PK and posterior lamellar keratoplasty. Hence, more descriptive studies on the clinical profile and management of rejection episodes in DALK will add crucial and incremental information on identifying the varied clinical presentation and outcomes of rejection after DALK in different indications. Previous studies describe that graft rejection after DALK is characterized by acute stromal haze, Descemet membrane folds, and vascularization, which can increase in extent if left untreated. Although graft recovery following treatment of rejection episodes has been documented to be favorable, risk of graft failure due to loss of graft transparency exists. Poor compliance to steroids and allergic eye diseases have been associated as the predisposing risk factors for rejection after DALK. Majority of rejections have occurred within the first year of the graft, although few reports indicate its occurrence even later at 3.5 years. In this study, all six eyes with rejection had DALK performed for keratoconus. The potential risk factors that were identified were vernal keratoconjunctivitis in four eyes (Patient 1, 2, 3, and 4), lid margin disease in one eye (Patient 5), eccentric graft in one eye (Patient 6), and poor compliance to steroid instillation in all eyes. We made the diagnosis of graft rejection based on previously elucidated features of stromal graft rejection and excluding the other differentials such as exacerbation of the comorbid clinical condition (Vernal keratoconjunctivitis (VKC) in four patients and lid margin disease in one patient). The symptoms of unilateral affliction of discomfort, photophobia, congestion, drop in vision restricted to the grafted eye, along with clinical features of vascularization at the site of sutures, cellular infiltration, and haze in the graft favored a diagnosis of stromal graft rejection. An exacerbation of allergy is typically characterized by the symptom of itching, which was not the predominant symptom complained by any of the patients. Three eyes had rejection within the first year (at 3 and 6 months), while three eyes had it later (at 16 months in two eyes and 38 months in one eye). Four eyes had all intact sutures, while two eyes had sutures out at the time of presentation. The patient who had rejection at 38 months had all sutures out, except two that remained partly embedded in the deep stroma. Similar to PK, sutures are potential trigger factors for rejection episodes in DALK. In addition, persistence of graft keratocytes for many years after DALK has also been proposed as a pathogenic mechanism for delayed rejections. This highlights the importance of compliance to steroids in DALK, when sutures are present and for some years beyond complete suture removal in proinflammatory conditions such as keratoconus associated with concomitant allergy. In our patients, the clinical features involved a variable degree of graft haze/opacification, congested conjunctiva, and vascularization at the graft–host junction and suture bed. In one patient (Patient 2), there was a marked infiltration and melt of the graft that mimicked microbial keratitis. Such fulminant clinical presentation due to a rejection episode after DALK has not been described in previous reports. The relative paucity of anterior chamber reaction, melt localized to the graft periphery, absence of lid edema, and nonconclusive microbiology can help in making an appropriate diagnosis, as was performed in this patient. The mainstay of therapy of rejection after DALK has been topical steroids, although the use of intravenous methylprednisolone at the initial presentation has been advocated by some authors. The response to intensive topical steroid therapy was satisfactory in all except patient 2, who developed fungal keratitis and scarring in the graft in the follow-up period. In one patient, intravenous methylprednisolone was instituted in view of severe graft edema, in addition to frequent topical steroids. It is uncertain if the duration of symptoms has any influence on the recovery of graft transparency. In one study, the graft recovered well even with a prolonged duration of symptoms of 13 days. In our study, the one patient who had a prolonged history of 28 days had good restoration of the graft clarity on frequent treatment with steroids. In another patient, there was a second episode of rejection on stopping steroids, which resolved with steroids, although neovascularization and lipid deposition were observed later as sequelae. This suggests that rejection episodes, if left untreated or inadequately treated, can lead to loss of clarity of the graft due to secondary changes such as vascularization and lipid deposition and can have loss of lines of vision. Based on the observations made in the present study, the suggested protocols for management of rejection are frequent usage of topical steroids initially, intravenous steroids in cases of severe rejection, and trial of steroids despite a seemingly long duration of history of clinical signs and symptoms. In addition, compliance to steroids is important even in the later years of postoperative period after DALK, as the risk of rejection exists. With prompt diagnosis and appropriate treatment, restoration of graft transparency is favorable.   Stromal rejection after DALK in keratoconus can can occur on sudden cessation of topical steroids. Prompt recognition of clinical signs and symptoms with timely management is important in quick reversal of the rejection episode. Conflicts of interest There are no conflicts of interest.   There are no conflicts of interest.   