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Avoiding big bubble complications: outcomes of layer-by-layer deep anterior lamellar keratoplasty in children
  1. Uri Elbaz,
  2. Caitriona Kirwan,
  3. Carl Shen,
  4. Asim Ali
  1. Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Asim Ali, Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; asim.ali{at}sickkids.ca

Abstract

Background/aims To describe the visual and clinical outcomes of manual layer-by-layer deep anterior lamellar keratoplasty (DALK) in a paediatric population.

Methods The charts of all children who underwent DALK surgery between January 2007 and January 2015 were reviewed retrospectively. Data collected included preoperative and postoperative spectacle-corrected distance visual acuity (CDVA), intraoperative and postoperative complications including graft rejection and failure. Residual posterior lamellar thickness (RPLT) and endothelial cell density (ECD) were measured in eyes with follow-up longer than 6 months.

Results Fifty-one eyes of 42 patients were included in the study. The mean patient age at surgery was 11.2±5.2 years and the mean follow-up time was 36.5±23.7 months. The most common indications for surgery were mucopolysaccharidosis (29.4%) and keratoconus (23.5%). Nine eyes (17.6%) had intraoperative microperforation, none of which were converted to penetrating keratoplasty (PKP). Only one eye (2.0%) was converted to PKP. Five eyes (9.8%) had a stromal rejection episode of which one eye failed. Another four eyes (7.8%) experienced graft failure among which three eyes (75%) had infectious keratitis. Three of the five failed grafts had a successful repeat DALK. The average RPLT was 81.9±36.5μm. ECD was significantly lower in the operated eye compared with the normal eye (3096±333 cells/mm2 vs 3376±342 cells/mm2, n=11, P=0.003). The mean postoperative CDVA was 0.5±0.4 logarithm of the minimum angle of resolution (logMAR) reflecting a gain of 0.3 logMAR (P<0.001).

Conclusion Manual dissection DALK is a safe procedure in children with stromal opacities. Despite successful structural rehabilitation, functional recovery is still suboptimal mostly due to amblyopia.

  • cornea

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Introduction

Significant advancement in lamellar keratoplasty techniques has led to improvement in visual and clinical outcomes.1 Endothelial rejection rate is lower with anterior lamellar keratoplasty surgery than penetrating keratoplasty (PKP), allowing for improved graft longevity and higher survival rates.2 Presently, deep anterior lamellar keratoplasty (DALK) is the mainstay of treatment for corneal stromal diseases. In the paediatric population, indications for DALK may include mucopolysaccharidosis (MPS), keratoconus, scarring related to trauma or infection and inflammatory causes such as blepharokeratoconjunctivitis (BKC). Currently, the common practice in adults for stromal opacities is to perform DALK using the Anwar big bubble (BB) technique3 with reported conversion rates to PKP ranging from 2.3% to 46.3%.2 4–12 Given the lower reported PKP success rate in children,13 and the desired graft longevity, putting a child through a procedure that carries a high risk for PKP conversion is not desirable. Pathologies with corneal neovascularisation (CN) are another reason to prefer DALK over PKP where a higher degree of graft rejection and failure is expected in the latter.2 14–16 In addition, in some instances the BB technique cannot be applied safely due to increased stromal rigidity (eg, MPS)17 18 or very deep pathology (eg, corneal scars).8

The Melles DALK technique can be used as an alternative to the BB technique, with less chance of Descemet membrane perforation and PKP conversion.19 However, it is mostly applicable in keratoconus or in mildly scarred corneas where the optical air–endothelium interface can be seen easily. It is not feasible in opaque or scarred corneas, which comprise the majority of DALK indications in children as seen in our study.

The purpose of this study is to report the structural and visual outcomes of layer-by-layer (LBL) dissection DALK in the largest paediatric cohort reported to date.

Patients and methods

We retrospectively reviewed the charts of all consecutive children who had undergone LBL DALK between 2007 and 2015 by the same experienced surgeon (AA). All patients underwent thorough ophthalmological examination at baseline including refraction measurement where possible. Visual acuity was measured in an age-matched fashion. Our criteria for DALK donors included fresh donors with endothelial cell density (ECD)>=2200 cells/mm2 with no stromal scars, clear central zone of 8 mm or more and minimal corneal arcus. We have requested larger clear zones for cases in which we expected a large graft needed.

Surgical technique

Following general anaesthesia and prior to surgery, the boundaries of the thinned peripheral corneal areas were delineated using a marking pen and a portable slit lamp along with the guidance of AS-OCT or Pentacam images taken at the preoperative visit. A Flieringa ring was then sutured to the sclera. Once the donor and recipient sizes were defined, a partial trephination using a Hessburg-Barron trephine (Katena, New Jersey, USA) was carried out at a depth of 375 μm (6 quarters of a turn) unless the peripheral thickness was measured to be thinner. Trephination size was selected to include thinner areas inside the trephination cut so that trephination was performed safely. No paracentesis was needed during the surgery. A mini-crescent knife was used to create a superior stromal pocket from which a careful lamellar dissection was done using Melles lamellar dissectors (DORC, Zuidland, Netherlands). Intraoperative ocular coherence tomography (OCT, Bioptigen; Bioptigen, North Carolina, USA) imaging was used in selected patients to confirm residual posterior lamellar thickness (RPLT) and evenness of dissection. In the event of microperforation, the anterior chamber was formed with air to tamponade aqueous and the lamellar dissection was then continued in a different corneal plane. After removing the donor endothelium, the donor cornea was punched and sutured using 16 interrupted 10–0 nylon sutures. Astigmatic control was done using a handheld manual keratoscope. Subtenon cefazolin and dexamethasone were given and the eye was patched. In developmentally delayed patients, a temporary tarsorrhaphy was placed.

Postoperatively, patients were monitored closely at postoperative days 1, 7 and 30, and then every 2–3 months in the first year and every 6 months thereafter. Patients were administered prednisolone acetate 1% eye drops four times a day with a slow taper and moxifloxacin hydrochloride 0.5% eye drops four times a day until removal of sutures. Sutures were removed under general anaesthesia in all cases after a graft host junction fibrosis was apparent clinically at a mean time of 4.1±2.1 months (range: 1.2–10.7 months) following surgery. Systemic treatment was given where indicated (ie, oral acyclovir for herpes simplex keratitis (HSK), clarithromycin for BKC). Anterior segment OCT (AS-OCT, Visante, Carl Zeiss, Germany) images were taken after 6 months of follow-up or earlier if indicated. The latter served to assess the RPLT. Postoperative endothelial specular microscopy (Konan Medical, Hyogo, Japan) images were available in 23 operated eyes with a follow-up time of at least 12 months and were analysed manually using the centre technique. Two eyes had subsequent fine needle diathermy (FND) and intrastromal and subconjunctival bevacizumab injection to treat CN.

Data were collected on patient demographics, indications for DALK, preoperative uncorrected distance visual acuity where possible, preoperative documentation of CN, preoperative and postoperative corrected distance visual acuity (CDVA), intraoperative and postoperative complications, RPLT in eyes with a follow-up time of 6 months or longer and ECD.

For statistical analysis Vision between 20/20 to hand motions was converted to the logarithm of the minimum angle of resolution (logMAR) units.20 Eyes with less than 6 months of follow-up were excluded from visual acuity analysis. The paired Student’s t-test was used for comparison of CDVA prior to surgery and at last follow-up visit and for ECD analysis at last follow-up between DALK and contralateral non-operated eye. Kaplan Meier survival analysis was used to describe the survival rate of the first graft. A P value of less than 0.05 was considered significant.

Results

Demographics

Fifty-one eyes of 42 patients were included in the study. Demographic data and intraoperative characteristics are summarised in table 1. The most common indications for surgery included MPS (15 eyes, 29.4%) and keratoconus (12 eyes, 23.5%). The mean±SD donor and recipient sizes were 8.2±0.5 mm and 7.8±0.6 mm, respectively with a disparity of 0.25–0.5 mm.

Table 1

Demographic data and intraoperative characteristics

Complications

Intraoperative and postoperative complications are summarised in table 2. Nine eyes (17.6%) had intraoperative microperforation, though DALK surgery could be completed in all. Only one eye (2.0%) had a macroperforation, which was converted to PKP. Macroperforation and microperforation occurred only during stromal dissection.

Table 2

Intraoperative and postoperative complications

Five eyes (9.8%) had a stromal rejection episode (table 3) of which four eyes responded completely to topical treatment of prednisolone drops 1% every hour for a week with slow taper thereafter. One eye with a history of corneal anaesthesia and previous microbial keratitis failed, due to diffuse stromal haze following a rejection episode and was lost to follow-up at 38.1 months following surgery. Another four eyes experienced graft failure, of which three eyes had a repeat successful DALK. Three eyes (5.9%) had microbial keratitis of which one had suture-related infection. Two patients, aged 16.8 years and 8.6 years, had premature loosening of all sutures with no infection and no vascularisation. Sutures were removed prematurely 1.2 months following surgery with no further complications.

Table 3

Characteristics of patients with failed/rejected DALK

Preoperative corneal neovascularisation

CN was present in 13 eyes prior to surgery, involving 2.7±1.3 quadrants on average (range, 1–4 quadrants). Two of the four rejected DALKs and four of the five failed DALKs had CN prior to surgery (table 3), which was a significant risk factor for graft failure and/or rejection (P=0.002).

Structural outcomes

One eye was converted to PKP and was excluded from statistical analysis. A clear DALK at last follow-up was found in 48 eyes (96.0%; 48/50 eyes), among which 45 eyes (90.0%, 45/50 eyes) maintained clarity of their primary graft. Three other eyes of three patients needed regrafting which maintained clarity at last follow-up. Three eyes had a too deep scar for complete removal during DALK and therefore had some residual stromal scar at last follow-up, though with a clear overlying graft. Table 3 summarises patients’ characteristics with failed or rejected DALK. Kaplan Meier survival curve (figure 1) shows stabilisation of cumulative rate for graft survival of first graft at 90.8% after 7.7 months.

Figure 1

Kaplan-Meier curve for first graft survival.

The average RPLT available in 31 eyes with follow-up of 6 months and longer was 81.9±36.5 μm (range: 27–175 μm).

Good quality ECD analyses were available in 23 eyes with a mean follow-up of 46.2±20.9 months (range: 19.8–81.6 months). In patients with unilateral and partial thickness pathology ECD was significantly lower in the operated eye compared with the non-operated eye (3096±333 cells/mm2 vs 3376±342 cells/mm2, respectively) reflecting an 8.3% decrease (n=11, P=0.003). None of the eyes that were included in the ECD analysis had intraoperative microperforation.

Refractive outcomes

Postoperative sphere and cylinder refraction were available in 43 eyes. Mean spherical error was −3.8±5.5 diopters (D, range: −20.5 D to +5.0 D) and mean cylinder was 3.1±2.2 D (range: 0 D to +8.5 D) with a mean manifest refraction spherical equivalent of −2.3±5.5 D (range: −20.5 D to +5.75 D).

Visual outcomes

The mean postoperative CDVA available in 43 eyes was 0.5±0.6 logMAR reflecting a 0.3 logMAR gain in vision (P<0.002). Thirty-two eyes (74.4%) had a visual acuity of 0.6 logMAR (20/80) or better. Amblyopia was prevalent in 34 eyes (34/43; 79.1%) with a mean CDVA of 0.6±0.61 logMAR (range, 0.3–3.0 logMAR) after a mean follow-up of 35.4±24.0 months.

Patients with mucopolysaccharidosis

Fifteen eyes of nine patients (six bilateral) had MPS. This included one patient with Hurler-Scheie syndrome (MPS I-HS), one patient with Maroteaux-Lamy syndrome (MPS VI) and seven patients with Hurler syndrome (MPS I-H). The mean postoperative CDVA was 0.5±0.2 logMAR (range: 0.2–0.9 logMAR) reflecting a gain of 0.2 logMAR in vision (P=0.02). Interestingly, among the patients with a long follow-up, over 20 months, patients operated before the age of 7 exhibited statistically significant better CDVA in comparison with patients operated after the age of 7 (0.3±0.1 logMAR vs 0.5±0.2 logMAR, respectively, P=0.02). There was no statistical difference in postoperative CDVA between patients who had undergone haematopoietic stem cell transplant (HSCT) to patients who did not (P=0.15). Similarly, there was no statistical difference in the rate of intraoperative microperforation between MPS eyes and non-MPS eyes (P=0.14).

Discussion

LBL dissection DALK minimises the risk of the most serious complication of BB technique, namely Descemet membrane rupture. Despite a moderate rate of microperforation in our study (17.6%), a conversion to PKP was required in one eye only. This is significantly lower than the reported PKP conversion rates in the traditional methods (big-bubble or Melles dissection).

Manual versus BB DALK has been extensively investigated in the adult literature. Knutsson et al 11 have reported a 10% conversion rate to PKP using a modified BB technique versus 3% only in the manual dissection group.10 They also reported successful bubble formation in only 77% of BB cases. In a different study,8 comparable visual outcomes were reported between BB technique and Melles manual dissection technique, with BB showing better contrast sensitivity results only. The authors further indicated that manual dissection might be a better option for cases with deep pathology (figure 2). Pneumodissection is also not always feasible or safe in cases with increased corneal rigidity, such as in MPS.17 On the other hand, lamellar dissection using the Melles technique is challenging in scarred corneas due to the need for visualisation of the dissector image and we therefore opted for LBL dissection in all cases. In our study, the conversion rate to PKP was lower than previously reported.4–8 11 16 Nevertheless, despite the low conversion rate to PKP our study demonstrates a significantly reduced ECD following LBL DALK when compared with the other normal eye in unilateral cases. Acquisition of preoperative ECD in our study was not feasible in opaque corneas prior to surgery. This is in contrast to Baradaran-Rafii et al 8 who only examined keratoconus eyes and could therefore show a non-significant decrease in ECD following surgery. Sogutlu Sari et al 5 have reported a mean of 18.1% ECL, 30.5 months after DALK, in a mixed cohort of BB technique and LBL dissection for corneal macular dystrophy. They also reported a 14.6% conversion rate to PKP. A different study reported an overall ECL of 22.3%, 5 years following DALK16 with significantly higher ECL in the BB group compared with the LBL dissection group (27.3% vs 18.1%, P=0.01). In contrast to these studies, Salouti et al 21 have reported a significant increase in ECD starting at 3 months and up to 3 years following DALK for advanced keratoconus eyes using the Melles technique, due to a change in corneal contour. For our ECD analysis we excluded patients with deep pathology that can affect the endothelial layer and patients with bilateral involvement and assumed similar ECD between the two eyes of a given subject. Finally, our ECD analysis included only eyes with corneal scars from HSK, BKC and trauma with no keratoconus eyes analysed. We observed an 8.3% decrease in ECD between DALK eyes and normal fellow eyes after a mean follow-up of 42.7 months, which is considerably better than the ECL reported in the aforementioned adult studies. It may be that corneal endothelial cells in children are more resistant to surgical trauma than those in adults.

Figure 2

Preoperative and postoperative images of patient with a history of deep corneal scar and significant stromal thinning from BKC. Postoperative images show residual scar in posterior lamella (arrow). BKC, blepharokeratoconjunctivitis; POD, postoperative day.

CN was shown to be one of the leading factors for graft rejection by the collaborative corneal transplantation study group.22 Transplanted grafts have shown higher risk for rejection with increasing number of quadrants of stromal vessels prior to surgery. This was also found in our series, though in a significantly smaller group. In two eyes with persistent stromal vessels following surgery, an FND procedure with bevacizumab injections was pursued with complete resolution of corneal vessels. Rejection episodes following DALK surgeries are mostly stromal and were shown to come along with deep stromal and interface vessels.23 In our series, none of the patients developed interface vessels; however, our rejection group was small (n=5). All rejections were stromal with variable degree of stromal vessels and all could be reversed by topical steroid treatment.

Three previous reports on the use of DALK in children account for the majority of cases described in the literature.17 24 25 In the larger of the series, Ashar et al 24 reported on 26 eyes in a cohort without any patients with MPS. BB was attempted in seven cases but only successful in three, and manual dissection was used in the remaining eyes. At final follow-up, 69.2% of grafts remained clear, significantly lower than the 98.0% of clear graft at last follow-up observed in our study. This difference is likely related to a higher rate of infection-related scarring in their study and the use of successful repeat DALK in our cohort. This also translates to lower rate of eyes with final visual acuity of 20/80 or better (61.9% vs 74.4%, respectively). Noteworthy, their cohort included cases with less favourable outcomes to begin with. In addition, complications reported differed significantly in nature from ours. They reported two patients with detached DM, three cases of posttraumatic dehiscence and five patients with suture-related infection, all of which can affect visual and clinical outcomes.

Of particular interest in our study is the MPS group, in whom vision may be impaired by progressive corneal clouding and by the retinal accumulation of glycosaminoglycan (GAG). There have been very few published studies reporting clinical and visual outcomes in patients with MPS following DALK. Harding and colleagues17 included eight MPS eyes showing the utility of UBM in achieving a deep dissection plane. Successful UBM-guided lamellar dissection could be achieved in seven of eight eyes and viscodissection was used in the remaining eye with no microperforations reported. All eyes had improvement in visual acuity. Compared with our study, the study by Harding et al 17 reported the results of a significantly smaller group and less homogeneous in regard to the surgical technique used. In a later small case series,26 the outcomes of four eyes of two MPS I syndrome patients undergoing DALK were reported. All eyes had a successful BB DALK with an improvement in visual acuity and no occurrences of microperforation. Our study found a higher rate of microperforation; however, we feel that BB DALK still carries an increased risk for PKP conversion compared with the LBL dissection technique. This is especially true in MPS eyes where more forceful air injection is needed in order to separate the stiff anterior lamella from its thin posterior lamella counterpart. This by itself can cause DM rupture with inevitable conversion to PKP. Patients with MPS are also at significantly increased anaesthetic risk as a result of their systemic comorbidities, so minimising intraoperative complications and repeat procedures is particularly valuable. Visual recovery in our study was more significant in patients undergoing corneal transplantation at a younger age, emphasising the importance of considering surgery sooner than later in order to enhance visual rehabilitation.

Basu et al, 27 in their letter to the editor, have questioned the superiority of DALK over PKP in MPS eyes in view of the reported endothelial changes in MPS. Indeed a histological study28 of corneal specimens from patient with MPS Hurler–Scheie disease who did not undergo haematopoietic stem cells transplant has demonstrated endothelial GAG deposition. However, an animal study29 showed that high-dose, intravenous enzyme replacement therapy is effective at preventing and/or clearing corneal stromal GAG accumulation, particularly if initiated early after birth. As there is paucity of human histological data, it is not clear whether HSCT also inhibits corneal GAG deposition and, if so, DALK is a viable option in patients with MPS.

We did not routinely evaluate in our study ECD in patients with MPS, as patient cooperation was not always feasible. In addition, we focused mostly on unilateral pathologies when trying to evaluate the effect of DALK on ECD loss. Four eyes of two patients with MPS who underwent LBL DALK presented a mean ECD of 2830±716 cells/mm2 after a mean period of 34.5±14.3 months. Noteworthy, two out of these four eyes had intraoperative microperforation. Our clinical impression favours DALK, as we did not encounter any corneal decompensation or endothelial changes in any of the MPS eyes, with a clear graft over a mean period of 31.5±24.4 months.

The benefit of HSCT for altering the natural history of MPS and for prolonged survival has been demonstrated extensively. Transplantation at a very early age, usually below 1 year, was shown to be a very important predictor for neurodevelopmental function.30 It might be expected that HSCT would slow corneal GAG accumulation allowing for a relatively clear visual axis during the critical years of visual development. In our study, 10 eyes still needed DALK surgery despite HSCT at an early age. We could not find any difference in the age at DALK surgery between patients undergoing HSCT and those who did not; however, this may also be affected by other factors such as patient preference or late referral. Similarly, we could not detect visual superiority in patients undergoing HSCT, probably due to the low number of eyes making subgroup analysis difficult. Many other unknowns regarding visual development in patients with MPS remain, including the correlation between retinal and corneal deposition and the optimal timing for DALK intervention.

In conclusion, manual LBL dissection DALK shows good results in young population with a wide range of stromal diseases, including full-thickness pathology and vascularised corneas. Therefore, striving for lamellar transplantation is of great importance. Early intervention is strongly indicated in order to prevent and treat amblyopia in this young age group.

References

Footnotes

  • Contributors All authors contributed to the following: substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data; drafting the work or revising it critically for important intellectual content; final approval of the version published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Competing interests None declared.

  • Patient consent Guardian consent obtained.

  • Ethics approval The Hospital for Sick Children REB committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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