Lattice Corneal Dystrophy
Lattice Corneal Dystrophy (ICD-10 # H18.54 - Lattice Corneal Dystrophy)
Lattice Corneal Dystrophy (LCD) is a rare autosomal dominant genetic disorder that affects the cornea, the clear front part of the eye. It is characterized by the deposition of abnormal protein (amyloid) in a linear, lattice-like pattern in the stromal layer of the cornea, leading to progressive thinning and eventual loss of the Bowman layer. It usually occurs bilaterally, affecting central vision, while peripheral vision is typically spared. LCD can be further classified into different types, including LCD1, LCD2, LCD3, and LCD3A, each with specific clinical features and varying severity. The disease onset can be as early as the first decade of life and classically presents with irritation, photophobia, and a progressive loss of vision with lattice-like lines seen in the stromal layer through retro-illumination.
LCD is inherited in an autosomal dominant fashion, with mutations in the transforming human growth factor beta induced (TGFBI) gene being the most common cause. There are two types of LCD based on how they present: LCD Type 1, also known as Biber-Haab-Dimmer dystrophy, and LCD Type 2. LCD Type 1 is characterized by the onset of the disease in the first decade of life, central vision involvement, and epithelial erosions with no systemic manifestations. It is caused by mutations in the TGFBI gene on the 5q31 locus, resulting in the deposition of amyloid in the stromal layer of the cornea. The onset of the disease is usually the first decade of life and involves the central vision while the peripheral vision is spared. It is characterized by epithelial erosions with no systemic manifestations.
LCD Type 2, in contrast, results from a mutation in the Gelsolin gene on 9q3 and is known by various names, such as Finnish Familial Amyloidosis, Meretoja syndrome, Amyloidosis V, Familial amyloidotic polyneuropathy IV. It is no longer considered a Lattice Corneal Dystrophy, but instead, it is classified as a systemic disorder with ophthalmologic features. Ophthalmic symptoms typically occur during the third and fourth decades of life, but significant vision loss is not observed until the sixth decade. Unlike LCD Type 1, corneal opacities are predominantly located in the peripheral stroma layer and then spread centrally. As a result, peripheral vision is affected, while central vision is typically preserved. Furthermore, amyloid deposition in the subepithelial spaces in LCD type 2 can disrupt Bowman’s layer. Interestingly, LCD Type 2 does not exhibit epithelial erosions.
Apart from LCD Types 1 and 2, there are over eight other variants of LCD that are now regarded as offshoots of LCD type 1. They all result from various mutations in the TGFBI gene, which lead to slightly different phenotypic features. For instance, LCD Type 3 is characterized by “thick ropy lattice lines” in the stroma and is inherited in an autosomal recessive manner, unlike types 1 and 2.1 The condition typically manifests in the fourth decade of life with rare epithelial erosions. On the other hand, LCD Type 3A, similar to type 3, is inherited in an autosomal dominant pattern and features frequent epithelial erosions.
Positive family history is a crucial risk factor for LCD, given its genetic nature. Moreover, the prevalence of LCD type 1 and type 2 varies significantly. LCD 1 is the most prevalent corneal dystrophy in the Western World, whereas LCD 2 is predominantly found in Finland, where the disorder was initially identified. The Finnish ophthalmologist Jouko Meretoja first described LCD 2 in 1960.
In terms of pathology, one can observe a lattice-like deposition of amyloid between the epithelium and Bowman's layer and in the stromal layer of the cornea, with more pronounced deposition in LCD2. These amyloid deposits can be well stained with Congo Red and exhibit apple-green birefringence when viewed under polarized light.
The pathophysiology of LCD Type 1 involves the accumulation of amyloid in the corneal stromal layer. Amyloid is a misfolded protein that loses its normal function. These misfolded proteins tend to aggregate, leading to cellular stress, toxicity, and disruption of vital cell functions, ultimately resulting in disease processes.
LCD 2 is caused by the abnormal folding and precipitation of the protein gelsolin throughout the body. Gelsolin is a cytoplasmic and extracellular protein with a variety of functions, including plasma actin clearance and regulation of the intracellular actin cytoskeleton.
There are currently no known primary prevention measures for Lattice Corneal Dystrophy, which is an inherited disorder.
The diagnosis of LCD can be challenging as individuals with the same gene mutation can have varying phenotypes. According to Liu et al., the use of genetic testing is essential in diagnosing LCD, as its clinical presentation can closely resemble other corneal dystrophies. Additionally, DNA analysis can aid in both pre- and postnatal diagnoses, allowing for early management of the condition.
Patients with LCD typically present with ocular irritation and progressive visual impairment, which starts in the first decade of life with LCD Type 1. The symptoms are usually bilateral but can present asymmetrically, and corneal sensation is often diminished. Due to its genetic nature, patients may have a family history of similar signs and symptoms.
In contrast, LCD Type 2 is a systemic disease with ophthalmologic features, and visual impairment is among the first manifestations of the disease, typically occurring during the third or fourth decade of life. In addition to ocular symptoms, patients with LCD Type 2 may also experience skin and neurologic involvement, among other organ dysfunctions.
During a physical examination, a slit-lamp exam is performed to assess for the presence of subepithelial spots that start centrally and display a diffuse haziness and a ground-glass appearance. Retro-illumination reveals lattice-like lines in the stromal layer that spread from the central cornea toward the periphery. Although LCD1 has several different variants, determining the specific subtype may not be necessary to manage the disease effectively.
Patients with LCD2 typically present with a triad of symptoms that include lattice corneal dystrophy, loose skin, and progressive cranial and peripheral neuropathy. They may also present with “mask-like” facial expression, protruding lips with impaired movement, pendulous ears, and lepharochalasis. Lattice-like deposition in the corneal stroma is a hallmark feature of LCD2; however, they are less numerous, less delicate, and oriented more peripherally than those seen in LCD1. Additionally, epithelial erosions may be fewer or absent in LCD2.
Signs and Symptoms
Classically, patients with LCD1 present with ocular irritation, increased light sensitivity, and progressive vision loss, with corneal erosions possibly appearing before stromal deposits. On the other hand, those with LCD2 may exhibit droopy eyelids caused by severe skin laxity, neuropathy, and facial paralysis, in addition to ocular irritation, increased light sensitivity, and progressive vision loss. The neuropathy associated with LCD2 can cause dry eye syndrome due to reduced blink reflex and weak contraction of the orbicularis muscle, which are innervated by the trigeminal and facial nerves, respectively. Furthermore, incomplete eyelid closure can also contribute to dry eyes.
LCD can be diagnosed through various ocular exams and the patient’s family history, as it is a hereditary condition. A slit-lamp exam can reveal subepithelial spots starting centrally with diffuse haziness and a ground-glass appearance. A fluorescein dye can also be used to highlight corneal erosions during the exam. Lattice-like lines can be seen in the stromal layer through retro-illumination spreading from the central cornea toward the periphery. Additionally, the use of optical computed tomography (OCT) can reveal atrophied epithelial layers and disruptions of the Bowman's and anterior stromal layers of the cornea. Monitoring the patient’s visual acuity can also help track the disease’s progression, which is characterized by progressive loss of vision. Due to systemic involvement, a complete physical, neurological, and ocular exam is necessary for patients with LCD2.8 Clinically, the age of onset for both type 1 and type 2 differs slightly, which can be used to differentiate the two conditions.
Laboratory tests play a significant role in the diagnosis of LCD. Histopathological analysis can be done on corneal tissue samples obtained through corneal biopsy. In LCD, amyloid deposits can be observed, which stain well with Congo Red Staining and display apple-green birefringence under polarized light. Additionally, in LCD1, the linear deposits can be seen as argyrophilic when impregnated in silver preparations. Corneal amyloid deposits in LCD2 can be identified using anti-gelsolin antibodies, which do not react with the antibodies specifically produced to the amino and carboxyl end of the gelsolin protein but rather the amyloid itself. Genetic testing can also help diagnose the condition, which will show a mutation in either the TGFBI gene for type 1 or the GSN gene for type 2.
LCD can be distinguished from other corneal dystrophies by taking into account the patient’s history, clinical characteristics, ocular examination findings, and genetic analysis. The age at which significant visual acuity loss occurs varies among different corneal dystrophies and can be used as a distinguishing factor.9 LCD2 can be erroneously diagnosed as Ehlers-Danlos syndrome due to skin involvement and Sjögren syndrome because of the presence of dry eye symptoms.
Granular corneal dystrophy (GCD) is an autosomal dominant condition with a mutation in the TGFBI gene on the 5q31 locus, like LCD1. However, it is characterized by “breadcrumb”-like granular deposits of hyaline in the stromal layer of the cornea, with onset during early adulthood. GCD is also associated with epithelial erosions, photophobia, ocular irritation, and progressive loss of vision; however, there is no “lattice-like” deposition of amyloid.
Macular corneal dystrophy (MCD) is an autosomal recessive condition caused by a mutation in the CHST6 gene. It is characterized by the deposition of glycosaminoglycan in the cornea, resulting in corneal thinning and severe visual impairment. The disease typically manifests early in life, with gray-white opacities that have indistinct margins concentrated in the central stroma. Over time, these opacities spread to the periphery and involve the entire stromal layer of the cornea. MCD can be differentiated from LCD by the mode of inheritance (autosomal dominant for LCD) and the type of deposition present in the stroma (amyloid in LCD, glycosaminoglycans in MCD).
Schnyder corneal dystrophy (SCD) is an autosomal dominant condition caused by a mutation in the UBAID1 gene, also known as transitional epithelial response gene 1 (TERE1). It is characterized by the accumulation and deposition of esterified and unesterified cholesterol and phospholipids in the stromal layer of the cornea. This accumulation is believed to be due to problems with the metabolism or transport of these substances. In some cases, patients with SCD may also present with hypercholesterolemia and hyperlipidemia since the UBAID1 gene is thought to be involved in cholesterol transport and metabolism. However, systemic associations are not always present in patients with SCD. The identification of the genetic mutation is essential for the definitive diagnosis of SCD.
Congenital stromal corneal dystrophy is an autosomal dominant condition caused by a mutation in the decorin gene, which is plays a role in maintaining corneal transparency and refractive stability. The condition is characterized by bilateral corneal clouding and flake-like whitish opacities throughout the stromal layer of the cornea, which becomes evident shortly after birth.
Fleck corneal dystrophy, also known as Francois-Neetens FCD, is an autosomal dominant condition caused by a mutation in the PIP5K3 gene. This results in a slow progressive loss of visual acuity. The condition is characterized by the appearance of small white flecks scattered throughout the stromal layer of the cornea. In contrast to LCD, patients with FCD are typically asymptomatic and have normal vision, with occasional photophobia reported.
Gelatinous drop-like corneal dystrophy (GDLD) is an autosomal recessive condition caused by a mutation in the tumor-associated calcium signal transducer 2 (TACSTD2) gene located on the 1p32 locus of chromosome 1. It was first reported in Japan in 1914, where it has a higher incidence. This disease is characterized by the deposition of amyloid in multiple shapes, including yellowish-white, mulberry-line, and gelatinous, in the subepithelial and stromal layers of the cornea. These depositions result in progressive vision loss, irritation, photophobia, and lacrimation, with neovascularization of the same corneal layers occurring in the later stages of the disease. Unlike LCD, which is characterized by “lattice-like” deposition of amyloid and has an autosomal dominant inheritance, GDLD is differentiated by its characteristic amyloid deposition pattern and autosomal recessive inheritance.
To delay the need for surgery, some interventions can be implemented, such as corneal scraping, diamond burr polishing, topical antibiotic use, bandage contact lenses, and topical steroids. Antibiotics and a bandage contact lens can treat the epithelial erosion in LCD1. On the other hand, LCD2’s treatment primarily aims to manage the symptoms of dry eyes, which is its main ocular manifestation, along with droopy eyelids. Topical lenses and the insertion of a punctal plug to prevent the drainage of tears from the eye’s surface can manage dry eyes. However, as both LCD1 and LCD2 progress and visual acuity decreases significantly, surgical treatment becomes necessary.
In patients with LCD1, a corneal graft is usually not indicated until after age 40. The outcome is excellent, but the amyloid may deposit in the donor graft tissue anywhere from 2 to 14 years after the surgery. Penetrating keratoplasty (PKP) is the first-line treatment for LCD1, which may be performed when visual symptoms progress to the point where surgery is necessary. Another emerging first-line option is deep anterior lamellar keratoplasty (DALK). Retaining the bottom two layers of the cornea that are not affected – the Descemet’s membrane and the endothelium – in DALK has a lower risk for transplant rejection. It also decreases some of the intraoperative and postoperative complications associated with PKP.
Other treatments for LCD1 include phototherapeutic keratectomy (PTK), femtosecond laser-assisted lamellar keratectomy (FLK), and femtosecond laser-assisted lamellar keratoplasty (FALK). Phototherapeutic keratectomy (PTK) can be used to resolve lattice changes, epithelial erosions, and opacifications, and it can be useful to treat patients with recurrence of lattice changes after PKP or DALK because they are usually superficial.3 However, it is second line to PKP and DALK because it cannot fix deeper lesions. Some risks associated with PTK include hyperopic shift and stromal haze.
Femtosecond laser-assisted lamellar keratectomy (FLK) uses a laser to remove sections of the anterior cornea with the help of OCT mapping. It is precise with minimal intraoperative and perioperative complications and no risk for graft rejection since no foreign body is involved. PTK and FLK are both very useful in young patients and those with recurrence following PKP and DALK.
Femtosecond laser-assisted lamellar keratoplasty (FALK) is like DALK but may be even more precise in removing the diseased corneal tissue in LCD.3 It offers more depth than FLK without compromising the thickness of the cornea. There is currently a lack of data on the recurrence rates of pathology with FALK, but it may be another emerging first-line treatment for LCD. Risks of FALK include myopic shift, irregular astigmatism, and transplant rejection.
The ocular manifestations of LCD2 can be treated the same way as in LCD1. The skin changes that cause conditions like ectropion and deficient eyelid closure can be corrected through oculoplastic surgery. Patients with dry eye syndromes are treated with topical lubricants, hydrophilic contact lenses, and lacrimal duct plugs.
Because LCD is a progressive disease, patients may eventually lose their vision without proper treatment. Even with treatment, there is the risk of recurrence. Marcon et al. found the recurrence rate of LCD on graft following PKP to be 17.8% at the five years follow-up. Mohamed et al. found that the risk of recurrence increased with increasing postoperative time. For example, the recurrence rate was reported to be 5% at 1 year, 12.5% at 5 years, 26% at 8 years, and 56% at 15 years following PKP. They also noted that different studies found slightly different recurrence rates, which they stated could be due to the different types of LCDs, with one type more prone to recurrence than the other. The need for regrafting can be avoided or delayed by removing recurrent opacities following PKP with graft through Phototherapeutic keratectomy (PTK). These opacities are usually superficial and can be easily removed with PTK and extend the life of the graft. Continued monitoring is crucial for the maintenance of visual acuity. As with any surgery and procedure, intraoperative and postoperative risks are involved.
Patients respond well to surgical treatment and can live normal lives with minimal visual impairment with continued follow-up and treatment. Because LCD2 is a systemic disease, it is much more complicated to control. Even though the ocular symptoms are treated with a high degree of success, treating the rest of the systemic manifestations is difficult.
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