Unusual pattern of recurrence at graft–host junction and interface after non-Descemet baring deep anterior lamellar keratoplasty in granular corneal dystrophy type 1: Report on clinical, histological, and OCT correlation with a review of literature

Dear Editor,

Granular corneal dystrophy (GCD) type 1 is an autosomal dominantly inherited, epithelial-stromal transforming growth factor beta-induced (TGFBI) dystrophy, characterized by discrete white opacities in the corneal stroma.[1] Typically, the deposits are initially seen in the subepithelial region, which then gradually increase and appear in the deeper layers of the stroma. Often a significant visual disability is only noticed late in life.

The management of GCD1 is based on the predominant corneal layer involved and the depth of the deposits at the time of clinical presentation with visual complaints. Phototherapeutic keratectomy (PTK), alcohol epithelectomy, penetrating keratoplasty (PK), manual/type 1 big bubble deep anterior lamellar keratoplasty (DALK), and other treatment modalities such as femtosecond-assisted anterior lamellar keratoplasty have been used to restore vision in this dystrophy.[2] GCD1 is known to recur after any of the corneal surgical interventions at varying intervals.[3,4,5,6] The deposits have been seen to recur at the corneal epithelium, Bowman’s layer, and corneal stroma.[3,4,5,6,7,8] Interface recurrences have been reported after anterior lamellar keratoplasty.[9,10,11,12] Here, we report an unusual pattern of recurrence in one patient following non-Descemet baring DALK who had contiguous deposits at the peripheral graft–host junction and the stromal interface. The clinical pattern of recurrence was correlated with the high-resolution anterior segment optical coherence tomography (OCT) and histopathology. A literature review of various patterns of recurrences in GCD1 is also described.

A 60-year-old male, presented in 2016 with bilateral blurred vision. There was no history of previous surgery. His father underwent keratoplasty for bilateral corneal opacities. The visual acuity was 20/125 in both eyes. On slit lamp examination, there were confluent granular deposits predominantly in the anterior stroma. He underwent PK in the right eye in 2017 and after 3 months, DALK (non-Descemet baring) in the left eye elsewhere, following which his vision had improved in both eyes. In 2020, 3 years after DALK, he complained of gradually decreasing vision in the left eye and a diagnosis of recurrent GCD was made elsewhere. He returned to our clinic in 2022 with a visual acuity of 20/100. The left eye showed deposits in the stromal interface in continuity with the deposits at the peripheral graft–host junction [Fig. 1a]. On clinical examination, the donor corneal stroma appeared uninvolved. The OCT highlighted the deposits at the peripheral graft–host junction and the stromal interface, along with faint hyperreflectivity at the suture site [Fig. 1b]. The donor graft epithelium appeared regular, and the stroma appeared unremarkable on OCT. The full-thickness penetrating graft in the right eye was clear with some opacification at the suture areas at 9 o’clock [Fig. 1c and 1d]. The patient underwent PK in the left eye. Care was taken during trephination to include the peripheral graft–host junction. At 1 year of follow-up, the patient was doing well with the best-corrected visual acuity of 20/30 and no evidence of recurrence in the graft.

Figure 1.

(a–d) Slit lamp photograph (a) and OCT image (b) of the left eye of patient 5 show the recurrence after DALK. Figure (c) shows a clear PK graft, and the OCT image of the right eye shows a clear PK graft (d). Note the deposits seen on the clinical image are at the interface bed on OCT. The OCT also shows hyperreflectivity at the suture tract

Histology of the corneal button showed intact epithelium, intact Bowman’s layer, and Masson trichrome positive linear deposits localized to the stromal interface [Fig. 2a]. The peripheral graft–host junction showed Masson trichome-positive granular deposits [Fig. 2b]. The pre-Descemet’s area of the residual stromal bed also showed few discrete deposits and keratocytes [Fig. 2d, arrows]. The donor stroma, which appeared relatively clear on slit lamp and on corneal OCT, had subclinical deposits, apparent as few sparse deposits on histology [Fig. 2c, asterisk]. The deposits were negative for Congo red staining (performed to rule out GCD2/Avelino variant of GCD) and lacked birefringence on polarization. Target gene sequencing showed heterozygous mutation resulting in an amino acid change of Arg555Trp (R555W) in exon 12 of the TGFBI gene.

Figure 2.

(a–d) Histology images of the left eye corneal sample (A and B at 16× and C and D at 40 × magnification) show Masson’s trichome positive deposits at the interface (a) and the vertical graft–host junction (b), which corresponds to OCT features in seen in Fig. 1b. The deposits in the donor stroma are highlighted in (c) (asterisk, *). The interface deposits (large arrows) and deposits within the pre-descemetic stroma and keratocytes (small arrows) are seen at 40× magnification (d)

Recurrences after GCD1 have been reported at varied intervals after different types of vision-restoring corneal surgeries. Several studies report that the longest time to significant recurrence is found in PK.[3,4] Lewis DR et al.[4] reported significant recurrence of GCD at 13.7 years after PK, 1.3 years after DALK, and 1.2 years after PTK. The time of recurrence of deposits after DALK is reported to range as early as 6 months[10] to 5.4 years[13] after surgery. Table 1 illustrates the reported literature on the duration and clinical histological patterns of recurrences after DALK in GCD1. Recurrences after DALK have been reported after both manual[9,10] and type 1 big bubble DALK.[11] The source of recurrent deposits has been debated. Some reports suggest corneal epithelium as the source of deposits, while the host keratocyte activation and transformation are also hypothesized to play a contributory role.[3,9] Most of the recurrences after DALK have been seen to occur at the stromal interface or the site of suture tract canals.

Table 1.

Recurrence patterns after deep anterior lamellar keratoplasty in GCD1

Studies		No. of eyes		Type of keratoplasty		Description and pattern of recurrence		Mean duration between the first signs of recurrence and surgery
Lyons CJ et al.,[3] Ophthalmology (1994)		4		LK		Sub-epithelium, Bowman’s membrane zone		-
Park et al.,[14] Cornea (2007)		1		Not mentioned		Periphery adjacent to the graft–host junction		12 months
Salouti et al.,[9] Cornea (2009)		5		DALK (manual dissection)		Along the suture tracts and peripheral graft–host junction, later in superficial stroma		15.6±1.8 (13–16) months
Unal et al.,[15] Cornea (2013)		2		DALK (big bubble, manual dissection)		Not mentioned, ? within donor tissue		14 months
Rama P et al.,[12] (2013) Arq Bras Ofthalmol		1		DALK		Donor host interface, followed by sub-epithelium and superficial stroma later		6 months
Pantanelli et al.,[10] Cornea (2014)		1		DALK (Melles dissection)		Host stroma, anterior to DM		3 years
Scorcia et al.,[16] Cornea (2015)		1		DALK (type 1 big bubble)		Unspecified		4 years
Avardhanam et al.,[17] Ophthalmology (2016)		3		Not mentioned		Graft–host interface, along with suture tracts		5.4 years (3–8.5)
Lewis et al.,[2] Cornea (2017)		4		DALK (manual, big bubble) —3, laser assisted—1		Subepithelium and anterior stroma (3), graft–host interface (1)		1.2 years
Oke I et al.[11] (2019)		2		DALK (type 1 big bubble)		Interface		3 years, 4 years
Present study		1		Non-DM baring DALK (1 eye)		Interface, peripheral graft–host junction		3 years

LK—lamellar keratoplasty, DALK—deep anterior lamellar keratoplasty, DM—Descemet membrane

The deposits in the patient described here were noteworthy in that they were all along the peripheral graft–host junction concurrent with the stromal interface deposits. The OCT highlighted faint hyperreflectivity at the suture tracts, with intact epithelium and Bowman’s layer. Based on the presence of GCD deposits and keratocytes in the pre-Descemet’s host cornea, we believe the stromal interface deposits were derived from host keratocytes in this location. Similarly, the source of the deposits at the peripheral graft–host junction is likely from the host keratocytes at the junction. Sparse deposits were revealed within the donor stroma, which could have occurred due to migration of recipient keratocytes.

The recurrence pattern is similar to that reported by Oke I et al.[11] in two cases of interface recurrence of GCD1 after type 1 big bubble (pre-descemetic) DALK. They suggested that residual keratocytes posterior to type 1 big bubble cleavage plane continue to produce keratoepithelin. Their study did not mention any characteristic feature along the peripheral graft–host junction. Iatrogenic injury to the recipient bed during trephination could lead to activation of the host keratocytes at the peripheral graft–host junction. Perhaps, the source of host keratocytes leading to the recurrence of deposits in their cases is likely to have come from the peripheral graft–host junction rather than the stromal bed since the posterior wall of the type 1 bubble is an acellular layer that lacks stromal keratocytes. Serial OCT documentation including the peripheral graft–host junction in the follow-up period after both manual and type 1 big bubble DALK in GCD1 could help in better understanding of the onset and progression of recurrences that occur after DALK. Confocal microscopy is another diagnostic tool that may help in documenting the deposits at early stages of recurrence. Corneal imaging using confocal microscopy has an advantage as subtle deposits can also be identified; however, the operational ease is relatively better with high-resolution OCT, making it far easier to adopt in routine follow-up visits after keratoplasty.

In view of the deposits in the peripheral graft–host junction, the recurrence after DALK should be managed with recipient bed trephination larger than the previous DALK to include the graft–host junction. However, this may not be a viable alternative in large grafts, as larger diameter grafts are at a higher risk of immunological rejection.

The deposits at the stromal interface are in favor of recurrence after the surgery as these were mainly in the anterior to mid stroma before intervention. The patient had a good vision recovery in the left eye and had a gradual loss of vision over the next few years in the left eye. Furthermore, the deposits at the interface had a dense, confluent pattern with no skip areas in between, which is corroborative with the features of recurrence after lamellar keratoplasty in GCD.

The varied pattern of recurrences seen in GCD1 could be attributed to the heterogeneity in the mutation genotypes of the TGFBI gene. Most of the studies reporting recurrences after DALK in GCD1 had a heterozygous mutation in the coding sequence of the TGFBI gene leading to a change in Arg555Trp (R555W), similar to what was seen in our patient.[2,8,11] The association of the pattern and time of recurrence with the genetic mutation should be explored further, which could help in decoding the exact procedure of management in a patient, thereby developing a more customized approach to the management of TGFBI dystrophies.

To conclude, the report illustrates a notable recurrence pattern in GCD1 that reveals contiguous involvement of peripheral graft–host junction and stromal interface.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.