Novel Proposed Algorithm in Congenital Hereditary Endothelial Dystrophy

ABSTRACT

Purpose

Congenital hereditary endothelial dystrophy (CHED) is a rare, autosomal recessive, monogenic corneal condition with variable expressivity. Often presents in bilateral symmetrical progressive corneal cloudiness that starts in the early infancy. It is characterized by increased corneal thickness, profound corneal edema, and thickening of the Descemet membrane due to endothelial dysfunction. The published literature lacks uniform guidelines for grading corneal cloudiness and management algorithm for CHED cases. This article focuses on applying newer investigational modalities to fine-tune surgical outcomes and more recent CHED management strategies.

Methods

This comprehensive literature review was performed based on a search on the PubMed database of relevant CHED articles focusing on those published in the last 7 years. A total of around 70 articles were reviewed, and 17 of them were included in this review. These include systemic reviews, randomized controlled clinical trials, cohort studies, case-controlled studies, and case series.

Results

Corneal cloudiness grading in CHED using subjective and objective methods using Anterior Segment Optical Coherence Tomography (AS-OCT) and densitometry using Scheimpflug imaging can help select appropriate management plan for CHED cases. DSAEK outscores penetrating keratoplasty with much fewer complications and expedites visual recovery, which helps mitigate amblyopia.

Conclusion

Managing cases of CHED has been a challenge due to the dilemma in timing and appropriate surgical method selection and lack of definitive medical or other conservative approaches. Currently, DSAEK has shown favorable results in cases of CHED. However, appropriate staging of CHED and selecting the appropriate management approach appears to play a critical role in managing such cases. Besides these, novel treatment modalities such as nonsteroidal anti-inflammatory agents (NSAIDS) that target restoring water-flux activity in subtype of CHED and gene editing using CRISPR-Cas9 are promising paradigm treatment modalities.

KEYWORDS:

• CHED
• congenital cloudy cornea
• densitometry
• DSAEK in CHED
• NSAIDS

Introduction

Autosomal recessive congenital hereditary endothelial dystrophy (CHED)¹ is a rare corneal endothelial dystrophy that is more common in seen in the Asian and Middle Eastern countries due to higher rates of parental consanguinity. Premature corneal endothelial senescence is critical in declining visual functions due to early-onset cloudy cornea in childhood endothelial dystrophies. At the same time, late-onset Fuch’s endothelial corneal dystrophy (FECD) is more prevalent worldwide with varying ethnicity and geographic distribution. CHED is characterized by bilateral, diffuse, non-inflammatory, and ground glass cloudy corneal consequences. Mutations of SLC4A11,² an abundant corneal solute transporter, have been attributed to the causation of CHED, additional post-lingual sensorineural deafness in Harboyan syndrome,³ and the early-onset variant of FECD.

The clinical spectrum in CHED can be variable even within a family. The disease is often bilaterally symmetrical but can vary in terms of age at onset of corneal clouding, the density of corneal clouding, the severity of stromal architectural changes, and presence of secondary changes like degenerative pannus, spheroidal degeneration or band-shaped keratopathy.

Several childhood corneal disorders manifest with early-onset diffuse corneal cloudiness, and few have sight-threatening (primary congenital glaucoma) or life-threatening (mucopolysaccharidosis) consequences as well. Therefore, it is imperative to unravel underlying conditions accurately, predict the natural course, and pre-empt ocular and systemic associations. Such a systematic approach would help provide timely genetic counseling, and expedite appropriate medical or surgical intervention. Current published literature lacks uniform guidelines regarding the aid of investigational modalities in grading the corneal cloudiness and a management algorithm including both surgical and medical management of a case of CHED.

This review undertakes, a comprehensive evaluation combined with investigational modalities to ascertain the effect of factors like the age of onset, the density of opacity, secondary stromal changes, and try and unravel a management algorithm for effectively managing childhood corneal clouding especially in CHED.

Method of literature search

PubMed search was performed using search terms: Congenital hereditary endothelial dystrophy, investigations, and management of CHED. All articles published in the English language and relevant to the topic published from 2015 to 2021 were reviewed and included in this review.

Investigations

Investigation modalities have been aiding in diagnosing conditions, knowing the extent of involvement, appropriate staging of the disease, and possible prognosis. Some of the modalities that help in CHED have been discussed below.

Pachymetry

CHED cases generally show a corneal thickness reading of two to three times more than age-related normal corneas. Grading of the corneal cloudiness has been very subjective, and there have not been many methods to quantify the amount of corneal opacity accurately. Some of the strategies to aid in assessing the grade of the cloudiness are as follows:

Slit-lamp Evaluation

One subjective method of grading corneal clouding is using slit-lamp biomicroscopy or slit-lamp photographs. A study by Ramappa et al.⁴ graded corneal clouding in CHED based on visibility of iris structures and presence or absence of anterior stromal scaring. as mild-minimal corneal cloudiness not obscuring the iris details (Figure 1a), moderate-obscured iris details, but visible pupillary silhouette (Figure 1b) and severe-iris and pupillary details obscured (Figure 1c). The above grading was exclusively used in CHED cases.

Figure 1. Grading of corneal haze. (a) Mild disease with minimal corneal cloudiness not obscuring the iris details. (b) Moderate corneal haze obscures the iris details, but the pupillary silhouette could be seen. (c) Severe disease wherein the iris, and pupillary details both are obscured (Ramappa et al.⁴).

Densitometry Using Scheimpflug Imaging

Corneal densitometry measures the reflectance pattern using a Scheimpflug imaging device, i.e., quantum of light being reflected from individual corneal layers. The densitometry readings are standardized from a scale of 0 to 100 grayscale units (GSU). Value of 0 denotes minimum light scatter, i.e., maximum transparency and 100 denotes maximum light scatters, i.e., minimum transparency.^5,6 Based on these readings, one can get a quantitative estimation of the amount of corneal opacification that the patient is having at individual layers (Figure 2 and 3).

Figure 2. Corneal densitometry quantifies the corneal clouding based on reflectivity pattern. Here, densitometry values are calculated after dividing the cornea into anterior (120 µm), central and posterior (60 µm) divisions, using the Pentacam.

Figure 3. Average central densitometry values. (a) Right eye of a patient with CHED – value of 68.1. (b) Left eye of the same patient post DSAEK showing reading of 20.7. Thus, showing the amount of clearing of the opacity post DSAEK.

AS-OCT (Anterior Segment Optical Coherence Tomography)

AS-OCT in CHED shows a generalized increase in corneal thickness (Figure 4b). There is thickened epithelial layer with underlying irregular Bowman’s membrane, increased stromal thickness, and abnormally thickened and hyporeflective Descemet’s membrane. Light backscattering can be studied using AS-OCT for objective estimation of corneal transparency.⁷ Long-standing CHED cases on OCT can also show the presence of secondary corneal changes like Descemet’s level scaring (Figure 4).

Figure 4. Shows the slit-lamp biomicroscopy photographs of- congenital hereditary endothelial dystrophy, with the ground-glass appearance of the cornea with the slit beam suggestive of increased corneal thickness (a). Anterior segment OCT shows CHED with a thickened epithelial layer with underlying irregular bowman’s membrane, increased stromal thickness and abnormally thickened Descemet membrane (b).

Management

Managing corneal opacification in CHED has been a challenge due to the lack of a conservative approach. Currently, the only definitive treatment modality available is various forms of corneal transplantation, which have several limitations considering the longevity of these children. The options for providing a clear optical axis in these children include conventional full-thickness penetrating keratoplasty (PK),⁸ rotational auto-keratoplasty (RAK),⁹ deep anterior lamellar keratoplasty (DALK),¹⁰ Descemet’s stripping automated endothelial keratoplasty (DSAEK),^11–13 and Descemet membrane endothelial keratoplasty (DMEK).^14–16

Penetrating keratoplasty

Penetrating keratoplasty (PK) was the standard of treatment for children with CHED. Still, the decision to proceed with PK is complex, owing to the challenges of pediatric PK and the threat of amblyopia. Paediatric PK presents unique preoperative, intraoperative, and postoperative issues that need to be addressed. Preoperatively, the timing and risk–benefit ratio of surgery must be considered. Assessment of the degree of visual impairment is challenging in the preverbal child, and some children with mild CHED may have reasonably good vision even without undergoing a surgical intervention.

The correct time for surgical intervention is still unclear. While the surgical timing lacks uniform consensus, there is a trend toward early intervention to circumvent irreversible stromal changes, particularly when it comes to endothelial grafting. Pediatric PK poses several unique challenges that are not encountered in adults. Intraoperative challenges¹⁷ in PK for CHED in younger age groups include managing the low scleral rigidity and tendency for anterior rotation of the lens-iris diaphragm that predispose to shallowing of the anterior chamber, peripheral anterior synechiae (PAS) formation, iris incarceration in the wound, endothelial trauma, glaucoma, and expulsion of intraocular contents due to an “open to sky’ procedure. Also, there is a high demand for postoperative care. Pediatric patients tend to a rapid and severe inflammatory response, predisposing them to graft rejection, PAS formation, glaucoma, and cataract. Robust wound healing may result in corneal neovascularization, uneven contraction of tissue, early loosening of sutures, irregular astigmatism, overriding of graft tissue with poor epithelialization, and ulceration. Frequent, often monthly, examinations under anesthesia and vigilant parental or caregiver observation for signs of rejection are important for early detection of graft rejection and suture-related complications. Along with these, a corneal wound that is of full-thickness is at a higher risk of traumatic rupture especially in children. Considering these, corneal surgeries have often been delayed for as long as possible, if not avoided in this age group.

A recent retrospective study comparing PK data done between 1978 and 2013 at the Royal Victoria Eye and Ear Hospital (RVEEH) reported a poor outcome in this Irish cohort with a mean graft survival rate of 36% after a follow-up of 101 months.¹⁸ However, earlier studies have shown better graft survival rates in pediatric PK cases in CHED. Despite the disadvantages mentioned above, PKP provides a pristine clear corneal grafting and can be the treatment of choice in patients with long-standing corneal edema that have developed significant stromal scarring.

Descemet-stripping automated endothelial keratoplasty (dsaek)

Descemet-stripping automated endothelial keratoplasty (DSAEK) is currently one of the treatments of choice in adults with a various corneal endothelial disease. Endothelial transplantation procedures such as DSAEK have a notable edge over conventional penetrating keratoplasty, in having a faster visual rehabilitation period, less sutures-and-suture-related complications, and a preserved structural integrity of the globe. These benefits are key in planning surgery in pediatric age group. DSAEK, being a “closed-system” technique, precludes to a great extent, sight-threatening intraoperative complications, particularly suprachoroidal hemorrhage, which not only become infrequent but also more easily manageable. The structural integrity of the globe is well maintained to its anatomical state and so, postoperative wound dehiscence is infrequent.

A recent study (Ramappa et al⁴) evaluated the long-term outcomes of DSAEK in corneal endothelial disorders in children less than 14 years of age. Out of 167 eyes that were operated, 86.2% maintained a clear graft at a median follow-up of 2.5 years. The paediatric DSAEK survival probability at 1, 3, 5, and 7 years was 92%, 87%, 78%, and 78%, superior to the results reported for pediatric Penetrating Keratoplasty (PK). In this series, CHED was the most common indication for pediatric DSAEK (116 eyes that is 69.5%), which had a long-term graft survival probability of 97%, 95%, 90%, and 90% at 1, 3, 5, and 7 years, respectively. This study also suggested that CHED with no previous interventions influenced long-term graft survival in a positive way. Visual acuity was noted to improve up to 3 years in CHED. In cases of previously failed grafts, also DSAEK gave excellent visual outcomes and could be a superior alternative to performing a repeat PK in a pediatric population. This study also highlighted that while DSAEK effectively accomplished excellent graft survival with a quick visual recovery, it was limited in attaining the pristine graft clarity in specific subset of cases like congenital hereditary endothelial dystrophy (CHED), unlike a PK due to presence of interface irregularity.^11,12,15,19

Another technical challenge in endothelial keratoplasty is the difficulty of peeling off the Descemet membrane due to impaired visibility, thickened Descemet endothelial complex, more robust stromal adhesions, and difficulty getting the right separation plane stripping Descemet membrane in a single piece. Also, in knowing orientation and attachment of lenticule intraoperatively. Therefore, EK in children merits several modifications to overcome technical difficulties not encountered in adult cases.

The double ring sign has been used to estimate the DSAEK graft orientation, intraoperative OCT also can aid in visualizing the real-time orientation of such graft as is published with “acute angled bevel sign” in these cases.^20,21 Another concern is cataracts following endothelial keratoplasty in a child possible due to a low corneoscleral rigidity resulting in anterior chamber fluctuations, and inadvertent lens injury, immature blood-aqueous-barrier resulting in extensive postoperative inflammation, air tamponade, secondary glaucoma, possible resurgeries, and long-term use of steroids in the postoperative period. Cataract development post DSAEK can be prevented by preoperative use of miotics, minimizing intraoperative manipulations, and judiciously tapering steroids.²²

During the immediate postoperative recovery period, extended sedation to ensure the child’s strict supine positioning and avoidance of eye rubbing help further minimize the complication of lenticule dislocation. Besides, recently, it has been shown that DSAEK has lower rates of IOP elevation when compared to PK. Also, some authors believe that DSAEK is associated with lower rates of acute graft rejection. This would translate into reduced postoperative visits with fewer examinations under anesthesia and a less frequent steroid dosage with an early tapering of steroids, thus avoiding the side effects of steroid use. A higher rate of infections associated with pediatric PK sutures is another disadvantage that DSAEK could overcome.²³

In conclusion, DSAEK would provide a stable, more predictable refraction with faster visual recovery that can help address the amblyopia issue in CHED patients.

The superior long-term clinical outcomes with low complication rates suggest that DSAEK is a safe and effective surgical alternative in corneal endothelial patients (Table 1).

Table 1. Comparative summary of the results of DSAEK in patients with congenital hereditary endothelial dystrophy or corneal endothelial dysfunction (studies with sample size >10 from 2011 to 2021).

Studies	No. of Eyes	Age at Surgery	Follow-up Period	Graft Survival Rate %	BCVA (LogMAR), Mean ± Standard Error
Ramappa et al^Citation4	167	Median age 7.9 years (interquartile range 5.2–11.2 years)	30 months	95% (primary CHED)	0.97 ± 0.06
Asif MI et al^Citation21	48	Mean 9.87 ± 8.2 years	17.3 months	92.3% among primary DSAEK	0.76 + 0.19
Mohebbi et al^Citation24	18	8.16 ± 4.2 years (3–16 years)	38 months (19–64 months)	88.9%	20/100 to 20/40
Yang et al^Citation25	30	4.3 ± 4.0y (6 months−13 years) 6.5 ± 3.6 years (child) 0.78 ± 0.18 years (infant)	48 ± 22.8 months (30–102 months)	-	LogMAR 0.54 ± 0.20 (child) LogMAR 0.32 ± 0.11 (infant)
Madi et al^Citation26	19	6 months–16 years	14.5 months (3–48 months)	-
Busin et al^Citation27	15 (6-nDSAEK; 9-DSAEK)	9y (6 months–30 years)	15.9 months (3–48 months)	-	6: Fix and follow 8: ≥20/40 1: 20/70

Descemet’s membrane endothelial keratoplasty (dmek)

Descemet’s membrane endothelial keratoplasty (DMEK) further refinement of posterior Lamellar approaches. The graft is prepared by manually stripping the Descemet’s membrane from the donor cornea and is transplanted into the host. The graft is extremely fragile and thin, has a propensity to roll up, and can be inserted via a smaller incision than used in DSAEK. Contrary to DSAEK, the DMEK graft has no stromal layer, which avoids the incompatibility of the host and donor stromal fibers.²⁸ However, the procedure is much more demanding and challenging to manage among infants and leads to more endothelial cell loss and dislocation than other EK techniques.

Few studies have reported DMEK to provide better results and less long-term graft rejection than DSAEK and PK.²⁹ There are very few reports of outcomes of DMEK in cases of CHED. A retrospective study compared DMEK performed in 14 eyes of CHED, showing that 13/14 eyes maintained a clear cornea at final follow-up (mean, 16.9 ± 8.1 months). Following surgery, corrected distance visual acuity improved from 0.9 ± 0.3 logMAR (Snellen 20/158) to 0.4 ± 0.2 (20/50). DMEK has been noted to offer the most rapid visual rehabilitation among all endothelial keratoplasty techniques; however, more long-term studies are required for outcomes of DMEK in CHED cases.¹⁴

Based on the outcomes from studies conducted using various surgical modalities, the cases of CHED with significant secondary corneal changes like stromal and Descemet’s level scaring, band-shaped keratopathy, etc., benefit more from undergoing a full-thickness keratoplasty than undergoing a DSAEK. DSAEK can be the treatment of choice, especially CHED cases with a relatively clearer cornea and minimal to nil secondary corneal changes. There are also those cases of CHED with a very mild haze and near-normal visual acuity that do not warrant any surgical management. All these factors can help enable us decide the modality for management of such a case (Figure 5).

Figure 5. Flowchart of proposed algorithm for congenital hereditary endothelial dystrophy.

Even though keratoplasty is the mainstay of treatment for patients with CHED, amblyopia management, and genetic counseling are crucial in the visual rehabilitation of children with CHED. Amblyopia management should be as aggressive as possible, with prompt refractive correction and patching therapy directed under the expert guidance of a pediatric ophthalmologist. Without successful treatment of amblyopia, the visual outcome is poor despite a clear medium. It is also necessary for genetic counseling of the patient and to explain that the risk of having a sibling with CHED is 25%. The risk of the patient having affected offspring is very low, provided the patient avoids consanguineous relationships.

Future Possibilities in Management

Current therapeutic interventions penetrating keratoplasty, Descemet’s stripping automated endothelial keratoplasty (DSAEK), and Descemet’s membrane endothelial keratoplasty (DMEK) face problems such as shortage of donor corneas, complex surgical procedure, the incidence of graft failure in acute and chronic phases,^30,31 and the reluctance of parents to be willing to have their child operated at such a young age. Thus, a noninvasive modality of managing such cases might tide over such issues in the future.

We know that CHED is due to a mutation in the SLC4A11 gene leading to a dysfunctional BTR1 membrane protein and unable to express this protein on the cell surface. Further, the retained protein in the endoplasmic reticulum and the effects of various drugs on its expression to the surface were taken up by studies conducted by Alka et al.³² on HEK293 cells expressing CHED and FECD mutation. They showed the efficacy of NSAIDs in moving the endoplasmic reticulum-retained missense mutant SLC4A11 in 20 out of 30 test cells, which showed a potential role of NSAIDs in these conditions.

Another potential role could be using antiglaucoma drops to reduce intraocular pressure (IOP) and thus the imbibition pressure (IP), thus reducing the amount of corneal edema in cases of CHED.

Such modalities may have a possible role in reducing the amount of corneal opacity, tiding over the time between presentation and surgery and thus may help delay surgery till the child reaches an appropriate age where the benefit outweighs the risk of surgery.

CRISPR-cas9 is another method of gene editing that can enable in-vivo reversal of the mutation in CHED cases and could have a potential role in the future of management of CHED.

Based on current evidence, the pediatric corneal surgeon can adopt an approach (Figure 5) to manage CHED cases based on critical period, presence or absence of ocular or systemic comorbidities, the density of amblyopia, and severity of corneal clouding.

Conclusion

CHED is a primarily endothelial dysfunction characterized by bilateral, progressive corneal clouding due to premature endothelial senescence. The mainstay treatment is early surgical keratoplasty to clear the visual axis during neuroplasticity. DSAEK provides superior long-term clinical outcomes with low complication rates than the conventional penetrating keratoplasty for CHED, especially in corneas with minimal secondary stromal changes. For those with significant stromal scarring, PKP can outscore EK by providing a pristine graft clarity but has the additional surgical risks involved that need to be titrated for each case. Besides these, novel, less invasive treatment modalities are being studied, including NSAIDs, IOP lowering agents, and gene editing using the CRISPR-Cas9.

Contributors

All the authors fulfill the criteria of authorship.

Ethics approval

The Institutional Review Board of LV Prasad Eye Institute, KAR campus, Hyderabad, Telangana, approved the study

Source(s) of support

Hyderabad Eye Institute and Hyderabad Eye Research Foundation, Hyderabad, India.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Hyderabad Eye Research Foundation, Hyderabad.