Although corneal stromal dystrophies often progress slowly, these rare inherited diseases can lead to severe visual impairment. New understandings of the underlying genetic mechanisms provide hope for future treatments.
Corneal stromal dystrophies are typically observed as bilateral, fairly symmetrical stromal deposits that slowly accumulate. The lesions are manifestations of a group of inherited diseases that are unrelated to environmental or systemic factors. The overall prevalence of stromal dystrophies is rare—less than 10 cases per million—and they comprise just a small subset of all corneal dystrophies.1
Stromal dystrophies often present in ways that do not quite match textbook examples, making their diagnosis difficult. Care is needed to determine whether systematic factors (eg, a myeloproliferative disorder) account for the deposits; and a family history is critical. Once diagnosed, progression is monitored until patients become symptomatic. Ultimately, penetrating keratoplasty may be necessary. Postponing the initial transplant as long as possible is often the best option, since post-graft recurrence is common in some stromal dystrophies.
In the following, I will discuss the way these dystrophies present, their genetic basis, and treatment.
Macular Corneal Dystrophy
Relative to other stromal dystrophies, macular dystrophy occurs earlier in life and causes the most severe vision loss. In macular corneal dystrophy clear corneas start developing stromal deposits between ages 3 and 9. In the second to third decade of life, corneal haze develops and can produce severe vision loss. Painful recurrent erosions can occur, but these are less common.
Macular dystrophy starts as diffuse gray-white stromal opacities and haze extending from limbus to limbus. This is different from other stromal dystrophies, which tend to start more centrally and spare the limbus. As the disease progresses, the deposits can appear irregularly raised, sometimes with whitish plaques (macules). Haze is observed between the affected areas, so that there is no clear cornea. The entire thickness of the cornea, including the endothelium, can be involved and the cornea can become thin. Guttae may be observed, as well as deposits within Descemets membrane. In contrast, other stromal dystrophies tend to localize in the anterior and mid stroma without affecting deep layers or overall corneal thickness.
Granular corneal dystrophy usually presents in the first decade of life, although somewhat later than macular dystrophy and with more slowly progressive vision loss. Initially, gray-white, crumb-like opacities may be seen, though they tend to be asymptomatic. These opacities can enlarge, coalesce, and lead to decreased vision. Patients can also develop recurrent corneal erosions. The deposits tend to appear first in the anterior stroma and later migrate deeper.
The pathognomonic sign of granular dystrophy is the presence of crumb-like opacities in the anterior to mid stroma with clear cornea between the deposits. In children, this dystrophy can present as a vortex-like pattern of brownish granules, superficial to Bowmans layer. Only the central cornea is involved.
Although this is not the case, granular dystrophy can appear to be associated with refractive surgery. Many people have LASIK in their twenties, a period when the granular dystrophy often develops. If deposits become visible after surgery, it may not be clear whether the deposits were preexisting or stimulated by laser treatment. A well-documented baseline and family history are important.
Lattice Corneal Dystrophy
Lattice corneal dystrophy often presents towards the end of the first decade of life, with symptoms of recurrent corneal erosion and decreased vision. Patients present with discomfort, pain, and light sensitivity. By the fourth decade of life, visual impairment usually develops.
Deposits appear as thin, linear, branching, refractile opacities usually located in the anterior stroma. The defects are restricted to the central cornea and are not seen in Descemets membrane or the endothelium. Initially, there are clear spaces between the lesions. Over time, the spaces between the lattice lines can develop a groundglass appearance.
Less Common Dystrophies
There is a large list of rare corneal dystrophies. Schnyder corneal dystrophy is one of the more obvious because of the unique appearance of crystalline lipid deposits. These deposits may not cause vision loss in early life; but later patients may have problems with glare and eventually the vision loss may require surgical intervention. These patients may also have systemic hyperlipoproteinemia; a lipid profile may be helpful in evaluation.
Congenital stromal corneal dystrophy occurs in infants. It presents with diffuse bilateral corneal clouding, and its early onset is a differentiating feature.
There are other dystrophies not listed here, but they tend to have limited impact on ocular health. (For a complete review of corneal dystrophies, see the article by Gordon K. Klintworth, which can be accessed at: http://www.ojrd.com/content/4/1/7).
The International Committee for Classification of Corneal Dystrophies (IC3D) has provided a global nomenclature for corneal dystrophy based on genetic rather than phenotypic information.2
Macular corneal dystrophy is an autosomal recessive disease (most other stromal dystrophies are autosomal dominant). Macular dystrophy is caused by a mutation on chromosome 16 of the carbohydrate sulfotransferase 6 (CHST6) gene. This abnormality leads to defective synthesis of keratin sulfate, a major corneal glycosaminoglycan, leading to an accumulation of mucopolysacharides in the endoplasmic reticulum of the keratocytes. In the stroma, accumulation can also occur extracellularly between the stromal lamellae.
In IC3D, granular stromal dystrophy is broken into three different types. Type I is the classic form discussed above. Like Type I, Type II, also called Avellino corneal dystrophy or combined lattice-granular dystrophy, is caused by a transforming growth factor beta 1 gene defect (TGFβ1 also known as BIGH3 gene defect) (Figure 1). Type III, also called Reis-Bucklers corneal dystrophy, is thought to be a superficial variant of granular dystrophy and is also a BIGH3 defect. All told, there are more than 30 known mutations of the BIGH3 gene which is located on chromosome 5q31 and normally codes for keratoepithelin, a protein secreted by the corneal epithelium.
Lattice dystrophy is classifed into five types. Type I is the classic form and related to a BIGH3 gene mutation. While type I presents early in life, the other four types present later. Type II is a systemic amyloidosis linked to a mutation in the gelsolin gene on chromosome 9 rather than a true corneal stromal dystrophy. Lattice dystrophy type III is an autosomal recessive disease and usually presents very late in life (patients are in their 60s or 70s). Lattice dystrophy type IIIa is autosomal dominant and related to a BIGH3 gene defect. Lattice dystrophy type IV is also a later onset condition that occurs in the deep stroma, also related to the BIGH3 gene.
While at the outset periodic monitoring is the only action necessary, treatment of corneal stromal dystrophies should begin with the onset of significant signs or symptoms. In the early stages, vision that has been disrupted by irregular astigmatism can be corrected with gas permeable contact lenses or phototherapeutic keratectomy (PTK). (PTK is generally ineffective in macular corneal dystrophy because the full thickness of the cornea is involved.) Recurrent erosion can be addressed with bandage contact lenses, lubricant eye drops, and PTK.
For severe vision loss, penetrating keratoplasty—with lamellar or full-thickness corneal grafts—is the treatment of choice. Unfortunately, recurrence can occur in the corneal graft, although this is less common with macular than granular or lattice dystrophies.
The treatment for the three types of graular dystrophies is different and depends on which layer of the cornea is involved. With Reis-Bucklers, a very superficial variant, patients do much better with PTK or an anterior lamellar keratectomy. In contrast, patients with other granular dystrophies typically develop deeper stromal lesions. For these patients PTK may be less beneficial and a full-thickness or deep anterior lamellar corneal transplant may be required.
For lattice dystrophies with recurrent corneal erosions, PTK treatment is commonly employed if the lesions are adequately anterior. If vision starts to deteriorate and the lesions are deeper than the anterior to mid stroma, lamellar keratoplasty or a full-thickness transplant is often needed. Unfortunately, there is a high rate of recurrence in these grafts; in one study almost half of the transplant patients with lattice corneal dystrophy had a recurrence of disease between 2 and 26 years after penetrating keratoplasty.3
Because corneal dystrophies can significantly impact both patients and their current and potential children, genetic counseling is recommended. The majority of these diseases are autosomal dominant, which means there is up to a 50% chance of developing a dystrophy if the other parent is unaffected. However, some of these dystrophies may not have complete penetrance.
In the future, we are likely to see therapies that address the genetic defects that would otherwise lead to deposit formation. Research is also investigating approaches that reduce deposition formation. One novel study evaluating the effect of lithium placed in the tissue, reduced the expression of mutant TGF beta 1.4
New, less invasive surgical techniques are also being evaluated in hopes of sparing more corneal tissue; these include lamellar keratectomy and superficial lamellar keratectomy in combination with PTK. Fibronectin eye drops are being studied to improve outcomes with lattice dystrophy. Finally, I can foresee research focused on ways to reduce or prevent recurrence of stromal dystrophies following grafts.
THE BOTTOM LINE
Corneal stromal dystrophies are rare, bilateral, inherited conditions that progress slowly. Evaluation must include a family history and elimination of systemic disease as an underlying factor. Referral to a corneal specialist may be appropriate. Since the deposits accumulate slowly, patients should be monitored until the onset of significant disease, including recurrent erosions or vision loss. Penetrating keratoplasty may be necessary for severe vision loss. New information on the genetic etiologies of corneal dystrophies is likely to lead to new treatment and prevention approaches.
Emily S. Birkholz, MD, practices with Ophthalmology Associates of Mankato, in Mankato, MN. Medical writer Jerry Stein, PhD, assisted in the preparation of this manuscript.
1. Musch, RM, Niziol, LM, Stein, LD, et al. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest Ophthalmol Vis Sci. 2011;52(9):6959-63.
2. Weiss, JS, Moller, HU, Lisch, et al. The IC3D classification of corneal dystrophies. Cornea. 2008 Dec;27(Suppl 2):S1-S83.
3. Spelsberg H, Reinhard T, Henke L, et al. Penetrating limbo-keratoplasty for granular and lattice corneal dystrophy: survival of donor limbal stem cells and intermediate-term clinical results. Ophthalmology. 2004 Aug;111(8):1528-33.
4. Choi SI, Kim BY, Dadakhujaev S, et al. Inhibition of TGFBIp expression by lithium: implications for TGFBI-linked corneal dystrophy therapy. Invest Ophthalmol Vis Sci. 2011 May 17;52(6):3293-300.