Lattice Corneal Dystrophy

Etiology

LCD type I is caused by mutations in the transforming human growth factor beta-induced (TGFBI) gene, located on chromosome 5 at locus 5q31.[5][6] This gene is also called BIGH3.[1][8] Multiple different nucleotide substitutions in this gene can cause type I LCD. The phenotypic variation seen in LCD may correlate with specific nucleotide substitutions. Mutations also cause the LCD variants in this same gene locus.[6]

Mutations cause type II LCD in the 9q34 locus of the GSN gene.[6] As in type I, several different nucleotide substitutions have been identified at this location.[9]

Epidemiology

Lattice corneal dystrophy affects males and females equally, with age of onset varying as described in history and physical.[4]

Type I LCD is among the most common corneal dystrophies. It is found worldwide, most commonly in the western world.[3] The LCD variants are most common in Japan and Italy.[6]

Type II LCD is most common in Finland, although a few cases have been found in America, Denmark, the Netherlands, the Czech Republic, and elsewhere.[3][9]

Pathophysiology

Type I LCD is caused by the accumulation of a mutant form of the transforming growth factor beta-induced protein, also called kerato-epithelin. It is the product of the TGFBI gene. While this protein is found throughout the body, its effects are limited to the cornea. These effects are most likely mediated by abnormal protein folding and precipitation as amyloid.[1][5][10] The LCD variants are less common forms of the same disease, also caused by kerato-epithelin-derived amyloid deposits.[5]

Type II LCD is caused by the accumulation of a mutant form of the protein gelsolin, resulting in amyloid deposits throughout the body. It is caused by the substitution of uncharged amino acids for asparagine at residue 187, resulting in a change in conformation. It is suggested that this conformational change causes the protein to form the previously described amyloid deposits.[9]

Histopathology

LCD type I is characterized histopathologically by multiple eosinophilic amyloid inclusions between the epithelium and the Bowman layer, as well as within the corneal stroma. The deposits stain well with Congo red, exhibiting birefringence and dichroism under polarized light. They also show metachromasia when stained with crystal violet, and fluorescence when stained with thioflavin T.[6][8] Epithelial atrophy is seen with degeneration of basal epithelial cells and loss of or damage to the Bowman layer.[4]

Confocal microscopy shows linear, branching structures in the corneal stroma with indistinct margins.[6]

Optical computed tomography shows atrophic epithelium, disruption of the Bowman layer, and inclusions extending from the Bowman layer into the anterior stroma.[4]

Electron microscopy shows deposits of extracellular, electron-dense fibrils that are 8-10 nm diameter, consistent with amyloid protein. Corneal fibroblasts are reduced in the number surrounding these deposits.[6][8]

Type II LCD is characterized by thin lattice lines concentrated in the anterior and middle stroma. These are initially seen peripherally and spread centrally. There are fewer lines as compared to type I LCD, and epithelial erosions are not seen. Similar to type I, there is a disruption of Bowman’s layer by amyloid invading the subepithelial space.[3][6][11][12]

In Avellino dystrophy, histology shows hyaline and amyloid deposits spanning from the basal epithelium to the deep stroma.[4][6]

The location of these inclusions and their relative size varies between the different types and is described below.[6]

History and Physical

Type I LCD patients often present with visual impairment and ocular irritation. These symptoms are progressive, starting as early as the first decade of life and causing visual impairment between the fourth and sixth decade.[5][6] Type I shows an autosomal dominant inheritance pattern, and patients usually have a strong family history of similar symptoms. It is a bilateral process but may affect the eyes asymmetrically.[5] The LCD variants often present later than type I LCD but with similar symptoms. Most are autosomal dominant, with the possible exception of type III.[5][6]

Type II LCD symptoms may begin after the age of 20, with mean diagnosis at 39 years of age.[13] Mild lattice corneal dystrophy is often among the first symptoms to manifest.[7] Vison is often minimally affected until later in life, as late as the seventh decade. Symptom onset varies by the specific mutation, with homozygous patients developing visual symptoms at an earlier age. It also shows an autosomal dominant inheritance pattern.[6][7][14]

Evaluation

Type I diagnosis is made clinically. On slit-lamp examination, subepithelial spots or flecks are seen, starting centrally, sometimes with diffuse haziness and a ground-glass appearance. Retroillumination reveals branching or lattice-like lines in the superficial stroma spreading from the central cornea toward the periphery. (See figures 1 and 2) The deposits result in recurrent erosions. The deep stroma, Descemet’s membrane, and endothelial layers are spared. LCD1 is almost always a bilateral process, but may not be symmetric and has been seen unilaterally. Genetic analysis will also reveal the TGFBI mutation.[6]

LCD variants, now considered offshoots of LCD1, vary from type I only slightly, and subtype diagnosis may not be necessary for appropriate treatment.[6] A brief description of each is below. See table 1 for details.

• Type IA has lattice lines similar to type I, with the addition of “mulberry shaped” gelatinous deposits in the affected corneas. Erosions appear in adolescence. Also called gelatino-lattice corneal dystrophy.[15]
• Type III has thicker lattice lines, radially oriented, which occur after the seventh decade of life.[5][10][16]
• Type IIIA is the most well-defined of the variants and shows thicker, ropy lattice lines extending from limbus to limbus. It also occurs later in life.[5][10]
• Type IIIB is poorly elucidated, has asymmetric corneas, and occurs in middle age as opposed to type I and III, which occur in young and older ages, respectively.[5][10]
• Type IV has deeper deposits than the earlier types and therefore exhibits erosions less often than other types. It has large, nodular lattice lines that progress from posterior to anterior, unlike the other varieties which progress from anterior to posterior. It has a late onset and shows substantial phenotypic variation.[5][17]
• Type V is poorly elucidated and has deposits that are indistinguishable from type I. It is also called French type IIIA and type III-like LCD.[5][18]
• Type VI, also called type I/IIIA, has thinner lattice lines than type III but thicker than type I, and presents in the second to third decade of life.[5][19]
• Type VII is also poorly elucidated, onsets late in life, and is characterized by patients with bilateral symptoms but a greater degree of asymmetry than is seen in other LCDs. It is indistinguishable from type 1 on histology or electron microscopy. Also known as Asymmetric LCD.[5][18]
• Polymorphic corneal amyloidosis has mostly polygonal inclusions in the deep, central stroma with few or no lattice lines. No erosions are seen.[6][20][21][22]

Type II diagnosis is also made clinically by the triad of lattice corneal dystrophy, cutis laxia (loose skin), and progressive cranial and peripheral neuropathy.[13] Symptoms arise from the accumulation of amyloid in nerve sheaths, basal membranes, vascular walls, and elsewhere. This alters the flow of nutrients and waste in the body and distorts the structural makeup of most tissues. Ocular symptoms include irritation, open-angle glaucoma, increased sensitivity to light, and eventual loss of visual acuity. Chronic open-angle glaucoma, peripheral neuropathy, meibomian gland dysfunction, and early cataract development have been described as well. Dermatological symptoms include laxity of skin, drooping of eyelids, skin fragility, easy bruising, and dry skin throughout the body. Neurological symptoms, derived from amyloid invasion of brain and nerves, include cognitive impairment, numbness, tingling, paresthesias, dysarthria, bilateral carpal tunnel syndrome, and loss of balance. Cardiac arrhythmias, hair loss, renal failure, and poor oral health have been associated with the disease as well.[3][5][6][7][13][23] In comparison with type I LCD, fewer and more delicate lattice lines are seen, oriented more peripherally, and sometimes entirely sparing the visual axis. Deposits are also less numerous with no epithelial erosions. Genetic analysis reveals the 9q34 locus of the GSN gene is affected.[3]

Avellino dystrophy, included here for the sake of facilitating differential diagnosis, shows superficial spots in the stroma with small “thorns,” linear inclusions, and superficial circular patches.[4] OCT shows large, dense, hyperreflective deposits in the epithelium and anterior stroma with irregular disruption of the Bowman layer. These deposits may also have a slightly lattice-like appearance; however, they rarely cross one another and therefore are less likely to form a true lattice.[4][6] GCD type II can be distinguished from LCD in two ways.[6]

1. The linear deposits are whiter and more dash-like, while the lattice lines in LCD are more refractile.
2. The linear deposits rarely cross or form the characteristic “lattice” for which LCD was named.

It is important to note that the size and appearance of lattice lines in any of these pathologies change with the patient’s age and progression of the disease.[6]

Treatment / Management

Penetrating keratoplasty is the treatment of choice for LCD once visual symptoms progress to the point that surgical intervention is warranted. Transplant is not usually necessary before the fourth decade, although it may be required as early as the second decade of life. The prognosis after PK is excellent; however, recurrence is quite common with amyloid deposits forming in the grafted cornea anywhere from 2to 14 years after transplant.[3][5] There are reports of delayed corneal epithelial wound healing in LCD after PK, and any patient undergoing PK is at risk of graft rejection and development of irregular astigmatism.[24][25][26](B2)

Deep anterior lamellar keratoplasty (DALK) has similar outcomes to PK. With recent advances in operative techniques and equipment, some studies now show that DALK may have better visual outcomes and lower risks of graft rejection. Because of these advantages, DALK is now considered first-line therapy for LCD in addition to PK.[24][27][28] Retaining the Descemet’s membrane and the endothelium reduces the risk of graft failure or rejection. It also maintains the structural stability of the eye and reduces some of the intraoperative and postoperative risks associated with PK.[26][28][29] One study found clinically significant recurrence at five years on average.[29] DALK includes the risk of intraoperative micro-perforation, irregular resection, hyperopic shift, and irregular astigmatism.[26][28][29](B2)

Phototherapeutic keratectomy (PTK) may also be used to improve vision.[30][31] It resolves lattice changes, erosions, and opacifications – these being the three defects common to LCD that tend to inhibit visual acuity. It is considered a second line intervention to keratoplasty, as it is unable to resolve the deeper lesions which are often present. It is also associated with hyperopic shift and stromal haze.[26] Improvement in vision is seen by three months.[30] PTK can be particularly useful in several settings:(B2)

1. PTK can be used to delay the necessity of corneal grafting.[31][32]
2. PTK can be used to treat the recurrence of lattice changes after corneal grafting. Recurrent opacities after grafting are often more superficial and within reach of PTK. Removing these opacities can delay or prevent the need for regrafting.[31]
3. PTK is especially useful for epithelial erosions, which have a significant impact on visual acuity. Both the erosions and any associated opacifications are easily removed, being superficial and, therefore, easily within reach of PTK.[31]
4. Childhood corneal dystrophy, particularly concerning due to the risk of amblyopia, is another indication for PTK. Corneal grafting is less successful in the very young, and PTK is well adapted to treating the early opacifications seen in this age. PTK also provides rapid visual improvement, particularly important in the avoidance of amblyopia.[31]
(B2)

Recurrence is frequent, with the average recurrence occurring 9-10 years after the procedure.[30][33] These recurrences tend to be superficial, and the deposits are easily removed by additional rounds of PTK.[30] It is worth noting that these recurrence rates include patients undergoing PTK after previous PK, and thus the recurrence rate of PTK in isolation cannot be well ascertained.(B2)

Femtosecond laser-assisted lamellar keratectomy (FLK) removes a section of the anterior cornea, as does PTK. However, FLK can proceed to a greater depth than PTK (20% to 30% of corneal thickness). Because of this, FLK may be another second-line therapy in LCD when treating the anterior to middle depth of the cornea. OCT can accurately map the corneal deposits, and with the precision afforded by FLK, the deposits can be carefully resected with minimal damage to healthy structures. This results in fewer intraoperative and perioperative complications and is free of the risks of graft rejection, as seen in first-line therapies. While it is capable of removing opacifications deeper than PTK can reach, it remains limited to anterior disease and is often used as a temporizing measure. Eyes treated with FLK will most likely need eventual treatment with PK or DALK. Like PTK, FLK is particularly useful in young patients and recurrent LCD after a corneal graft. FLK is not as useful in patients with deep pathology or with notable corneal thinning in the area of the pathology. In one study, mild recurrence was seen at around two years of follow up.[26] Another study used PTK after FLK to smooth the cut surface and suppress keratocyte proliferation. They saw no recurrence in their LCD patients at two years of follow up and attribute this to the PTK.[34] Risks of FLK include irregular astigmatism, weakening of the cornea, and recurrence of pathology.[26](B2)

Femtosecond laser-assisted lamellar keratoplasty (FALK) is another modality that may be used to treat LCD. This method precisely removes diseased tissue via femtosecond laser, followed by the replacement of removed tissue with grafted corneal explant. The cornea is carefully mapped prior to the procedure via OCT, allowing for extreme precision. This process allows for increased depth (up to 500 um, as compared to less than 200 um in FLK) without dangerously thinning the cornea. It is similar to DALK, but with the femtosecond laser, there are the advantages of additional precision.[26][35] Because of these advantages, FALK may be another emerging first-line treatment for LCD. No data is currently available on recurrence rates for FALK. Myopic shift, irregular astigmatism, and graft rejection are risks in this procedure.[35](B2)

A note on the recurrence rate: Data is currently inadequate on the relative rates of recurrence in the various treatment modalities due to varying definitions of recurrence and often insufficient follow-up. In comparing the different treatment modalities, it can be assumed that recurrence is likely with any treatment due to the reaccumulation of amyloid after 5 to 10 years.

Other temporizing measures may be employed to delay the necessity of long-term treatments. These include corneal scraping, diamond burr polishing, topical antibiotic use, bandage contact lenses, and topical steroids. While none of these are curative, they may temporarily give some improvement in vision and allow for the delay of more invasive surgical treatments. 

Treatment of type II LCD is broader due to the systemic nature of the disease. The corneal dystrophy itself is also treated with penetrating keratoplasty or PTK as above with excellent results. The dry eye symptoms are treated with topical lubricants, hydrophilic contact lenses, and lacrimal duct plugs. Symptoms related to increased skin laxity, including ectropion and deficient eyelid closure, can be treated with oculoplastic surgery to minimize symptoms.[7][14] Some locations, including Boston University, Cleveland Clinic, Stanford, University of Pennsylvania, University of Utah, Vanderbilt, and others, have amyloid centers or programs with multidisciplinary programs to treat the multi-system effects of systemic amyloidosis. Patients with type II LCD may benefit from treatment at one of these centers.(B3)

Gene therapies are also under development and may soon be the mainstay of treatment for corneal dystrophies. Significant progress has been made in identifying specific mutations associated with LCD. Because of this progress, therapies targeted at these specific mutations are becoming more feasible. Chaperone nanobodies, siRNA, CRISPER, and antisense oligonucleotides have all been suggested as possible treatments for LCD. So far, siRNA and nanobodies show promise for type I and type II LCD, respectively. Antisense oligonucleotides and CRISPR show promise in investigations for treatment of other corneal disorders, but have not yet been investigated for use in LCD.[36][37][38][39][40][41][42][43][44](B3)

Differential Diagnosis

Lattice corneal dystrophy is distinguished from other corneal dystrophies by comparing distinctive clinical features or through genetic analysis.

Type II LCD, being systemic amyloidosis, has a broader differential diagnosis. It is occasionally confused for Ehlers-Danlos syndrome due to the skin laxity found in both diseases. Dry eye symptoms are also common and can be confused for Sjögren syndrome.[7] It must also be differentiated from other systemic amyloidoses.

Prognosis

LCD is a progressive disease, resulting in the eventual loss of vision without treatment. For the subtypes limited to the cornea, patients tend to respond exceptionally well to surgical intervention, as described above. In these patients, symptoms may recur due to continued amyloid invasion of the grafted tissue, requiring further or repeated treatment.[3][31] With treatment, however, patients can live normal lives with minimal visual impairment.

In type II LCD, there is a broader range of symptoms that may have an impact on a patient’s life. While the ocular symptoms may be treated with a high degree of success, the neuropathy and facial paralysis are harder to treat and likely to cause long-term symptoms.[7]

Complications

Complications of LCD are primarily related to the lack of treatment, intraoperative and postoperative risks, and recurrence after treatment as described above.