Salzmanns Nodular Corneal Degeneration

Etiology

The most commonly cited risk factors for Salzmann nodular degeneration (SND) are ocular surface inflammatory conditions such as dry eye, chronic blepharitis, long term contact lens (CL) wear, phlyctenular keratoconjunctivitis, pterygium, trauma, and vernal keratoconjunctivitis.[1][2][3][4][5][6]

CL-wear appears to be a risk factor for SND, accounting for 34.2% of 152 eyes in one study.[5] Mechanisms may involve a disruption of stem cell turn over, the reduced rate of exfoliation of the central corneal epithelium due to the physical barrier of the CL, and poor tear film stability over the cornea.[11][12][13]

Surgical wounds to the cornea, such as from cataract extraction, radial keratotomy, penetrating keratoplasty, or laser in situ keratomileuses (LASIK), may increase the risk for developing SND.[10][14][15][16] In a 2010 study of 180 eyes with SND, 27.2% had a history of previous ocular surgery.[5] Post-LASIK SND may occur due to post-operative dry eye disease secondary to a disruption of corneal nerves, uneven corneal tissue in the area of the flap, or the mere presence of surgical trauma.[10][14][17][18][19][20][21] Often these post-LASIK Salzmann nodules responded to conservative treatment alone; however, two published cases required superficial keratectomy.[19][21] Hopping et al. reported on a patient with Ehlers Danlos syndrome, who developed bilateral nodules following LASIK surgery.[20]

Although no specific gene abnormalities associated with SND have been identified, several cases report SND occurrence in consecutive generations,  with an autosomal dominant inheritance pattern in two cases.[22][11] A unique genetic link in SND or possibly a missense mutation in the TGF-β gene, the genetic basis for other corneal dystrophies, may play a role.[22]

Epidemiology

Salzmann nodular degeneration (SND) is a rare disorder. It most often occurs in 50 to 60 years olds; the largest study, including 180 eyes, established a mean age of 60.8 years with a range of 13 to 92 years.[5] Bimodal age distribution has also been reported, with the most affected present in the fifth or eighth decades.[8] SND is more common in women, who accounted for 78% of the patients in Salzmann’s original series, which has been reproduced in subsequent reports.[5][8][17][20][8] Studies have shown that SND occurs bilaterally more than 50% of the time, though severity may be asymmetric.[7][5][8] SND has been described in the setting of Crohn disease (CD). Aside from two reports of confirmed Salzmann nodules in patients with Crohn disease (CD), there are several descriptions of corneal nodules or masses in CD.[23][24][25][26][27]

Pathophysiology

The exact mechanism of development of Salzmann nodular degeneration (SND) is unknown; however, several important events are thought to contribute to nodule formation. These include disruption of the epithelial basement membrane and Bowman layer, changes in epithelial cells, differentiation and anterior shift of stromal fibroblasts, and deposition of the extracellular matrix material.[6]

Mechanical disruption of the barrier between the epithelium and stroma from trauma, surgery, or chronic corneal irritation from ocular surface diseases, such as meibomian gland disease (MGD) or aqueous deficient dry eye, leads to prolonged wound repair and remodeling of the epithelium thus creating the conditions for excess deposition of extracellular material.[6][7] Subsequent deposition of extracellular matrix (ECM) by fibroblasts and other cells within the nodules follows. Additionally, ground substances on collagen fibers in the nodules are stimulated by chronic exposure to sunlight or environmental irritants.[28][2][16][29]

Histopathology

Histological examination typically shows thinning of the epithelium overlying a nodule. Disruption of the Bowman layer may be seen with duplication of the epithelial basement membrane.[6] Other findings include a decreased cell density as well as deposition of matrix material within the nodule, anterior stromal scarring, and an irregular epithelial-stromal interface. There are no pathognomonic histological features of Salzmann nodular degeneration (SND), and the features that are present are also present in other pathologies such as degenerative pannus or corneal scars secondary to inflammation or trauma, requiring appropriate clinical correlation.[6]

The mechanism underlying the development of SND and subepithelial matrix deposition appears to involve the function of the corneal epithelium itself. The cells of the limbus differ from cells of the central cornea in structure as well as function. The limbal epithelium contains stem cells and transient amplifying cells (TAC), cells that are not completely differentiated but have a high potential for proliferation. Usually, the central cornea contains completely differentiated epithelium and should not contain stem cells. Immunohistochemical analysis has shown that the epithelium in SND shows similar markers as the undifferentiated TACs of the limbus.[30]

High levels of staining for CK19 and enolase, markers of the metabolically more active migrating epithelium, suggests that the epithelium that overlies SND nodules is composed of cells that are not terminally differentiated and are more comparable to limbal TACs than the surrounding corneal epithelium. Healthy central corneal cells stain strongly for CK3/12, a marker for terminally differentiated corneal epithelium. Only the superficial epithelial layers overlying Salzmann nodules stain positive for CK3/12. The cellular elements of the Salzmann nodules stain positively for matrix-metalloproteinase-2 (MMP-2), which is characteristically expressed in the central corneal epithelium only during the remodeling phase of wound repair.[10]

MMP-2 functions to break down type 4 collagen, the primary component of the corneal epithelial basement membrane. The expression of MMP-2 by the basal epithelial cells in Salzmann nodules appears to contribute to the destruction of the Bowman layer in an ongoing wound remodeling process.[29] These histopathological findings support the clinical association of chronic ocular surface disease with SND.

History and Physical

Only a minority of patients with Salzmann nodular degeneration (SND) have symptoms, which, when present, are foreign body sensation (FBS), irritation, tearing, or photophobia.[5][7][8] In one study, decreased visual acuity was the most common presenting symptom, though acuity was typically not severely reduced.[5] In another study, the visual disturbance was the most common indication for surgery, necessitating 85% of all procedures.[8]

Nodule location influences patients' primary complaint, whereby more central nodules are associated with decreased or distorted vision and more peripheral nodules with FBS. Visual distortions are caused by the involvement of visual axis by the nodules, irregular astigmatism, hyperopia, or mechanical tear film disturbances.[9][10] Peripherally located nodules can cause flattening of the central cornea.[10] This flattening induces a hyperopic change, whereby for each quadrant involved, astigmatism increases by 0.38 D.[5]

Evaluation

The diagnosis of Salzmann nodular degeneration (SND) is usually made clinically by the slit lamp exam. It may be supported by high-frequency ultrasound biomicroscopy (UBM), in-vivo confocal microscopy (IVCM), optical coherence tomography of the anterior segment (AS-OCT), or corneal topography and tomography. Slit-lamp exam reveals nodules that are typically smaller than 2mm, but as large as 4x2.5 mm.[3][31] The nodules may appear in any part of the cornea, and the location depends on the underlying risk factor. For example, nodules that develop post-LASIK are often located in the mid periphery, overlying the flap interface.[10] 

Another common pattern is the 3 and 9 o'clock location of the nodules in patients with a history of contact lens wear.[8] Nodules are bluish-white-to-gray and are usually round, but may also be conical or prismatic.[3] Peripheral SND is more common than central.[7] Opacities are most often found in the superior-nasal quadrant, followed by the superior-temporal.[10] Nodules are typically discrete from one another but may fuse if nearby one another. Several cases of ring-like peripheral confluent SND have been reported.[5][32] Other findings include decreased tear break up time, reduced tear lake, and negative fluorescein staining of the nodules.[10][33] 

In one study, each nodule was associated with an adjacent neovascular anterior stromal pannus that did not enter the nodule.[10] In a series of ten patients, a Bell or inverse Bell phenomenon was correlated with nodule location; patients with superior nodules were found to have an inverse Bell phenomenon and vice versa.[13]

Typical findings have been noted with the use of diagnostic tests. UBM of peripheral nodules in a post-LASIK patient differentiated epithelium, Bowman layer, and LASIK flap, localizing of the nodules to within the margin of the flaps and revealing the destruction of the underlying Bowman layer.[10] UBM demonstrated that the nodules were made up of an abnormally thin layer of epithelium overlying a hyperreflective substance.[10] Other findings include hyperechoic superficial corneal thickening that spares the stromal layer and a well-defined demarcation line.

Biometric values acquired through corneal topography are impacted by the presence of SND, resulting in inaccurate intraocular lens (IOL) calculations as high as 3.2 D in one study.[34] These changes may be attributable to alterations in lamellar stromal anatomy, nodular elevation above the corneal surface, and tear film disruption.[34]

AS-OCT is a non-invasive imaging modality that can be helpful in the diagnosis, management, and follow-up of SND. AS-OCT shows bright, hyperreflective, subepithelial deposits above the Bowman layer that is covered by an abnormally thin layer of epithelium. AS-OCT can perform non-invasive "optical biopsies" that have been shown to correlate with the histopathology of the disease.[32] This allows for in-vivo histological analysis of nodules in the early stages without tissue sampling.[32]

Utilizing IVCM allows morphological and quantitative analysis of the microstructure of Salzmann nodules. Normal epithelial cells imaged show a honeycomb-shaped arrangement with bright borders and dark bodies. The overlying epithelium nodules are shown by IVCM to have irregular morphology, consisting of elongated, polygonal cells of varied sizes.[35][36][37] More deeply, the keratocytes in the superficial stroma showed prominent, and hyperreflective nuclei change consistent with cells in a more activated state.[30]

Corneal stroma within the nodule appeared unstructured, with an increase in the hyperreflective extracellular background.[32] Analysis of deeper stroma revealed very prominent nerves highlighted with an unusual pattern of grouped keratocytes. The Descemet membrane and the endothelium were of normal appearance.[36][37]

Treatment / Management

Management choice is influenced by the size and location of nodules, as well as the severity of symptoms. Asymptomatic patients can be observed, mildly symptomatic cases typically respond to conservative management, but severe cases may require surgical intervention. The most common indication for surgery is a visual disturbance.[5][8][9] However, continually symptomatic nodules, despite conservative management, may also require surgical management.[5][7][8] Additionally, patients with multiple quadrants affected are more likely to require surgery.[5](B2)

Conservative Management

In most cases, patients will respond to conservative medical therapy. The use of lubricants, warm compresses, lid massage, and lid hygiene often provides symptomatic relief, especially in the context of dry eye disease. One study found that conservative therapy was effective enough to avoid surgery in 77.3% of cases.[5] Initial treatment should include preservative-free lubricant drops. Other medical options to improve ocular inflammation include topical steroids, topical nonsteroidal anti-inflammatory drugs, immunomodulators such as cyclosporine and lifitegrast, and doxycycline.[7] Post-LASIK SND has been treated with punctual plugs, in addition to loteprednol and cyclosporine, with a resolution of symptoms after six months.[10] If nodules occur in the setting of contact lens (CL) wear, cessation or reduction of lens wear may relieve symptoms. CL fit should be reviewed.(B2)

Nodulectomy/Superficial Keratectomy

The simplest method for surgical management is manual excision and superficial keratectomy.[5] The epithelium is locally removed or, in the setting of epithelial membrane dystrophy or poorly visible nodules, epithelial debridement can be performed, with or without the use of alcohol.[23] The edge of the nodule is grasped using forceps and pulled toward the periphery or limbus.[5][7][9] With an edge of the nodule peeled back, a surgical plane can be established. Manual separation or blunt dissection is typically adequate for removal at this point.[6] If a surgical plane is not present, Calibri forceps, along with a bladed instrument, can be used to create a lamellar plane at the edge of the nodule.[9](B2)

If adhesions are present between the nodule and the limbus, typically due to a fibrovascular pannus, scissors may be used to amputate the nodule close to the limbus. After removal of the nodule, the underlying stroma is usually regular and smooth.[3] This is in contrast to peripheral hypertrophic subepithelial corneal degeneration (PHSCD), a condition that involves peripheral Salzmann like opacities. Removal of a PHSCD lesion may be more challenging than its Salzmann nodular degeneration (SND) counterpart; bundles of subepithelial anchoring fibrils, as well as blood vessels, can complicate the establishment of a surgical plane.[38][39](B2)

Some SND patients are left with significant defects in the Bowman layer. These irregularities, if present, may be treated with a diamond burr or PTK.[40][41][42] Recurrences are more common in cases that have deeper defects in the Bowman layer and superficial stroma.[3] In a set of 41 cases that underwent superficial keratectomy, one report had a 22% recurrence rate.(B2)

One study utilized superficial keratectomy followed by AMT; however, the nodule recurred, the operation repeated, but the nodule recurred once again. Published data of other cases are limited.[25](B3)

Mitomycin-C (MMC) is an alkylating agent that interrupts DNA synthesis inducing apoptosis in fibroblasts.[43] MMC used intraoperatively targets the active fibrocytes and keratocytes within the stroma to halt progress on Salzmann nodules as well as prevent recurrence after excision.[44][45] In a study including 30 eyes, Bowers et al. removed nodules via manual keratectomy and twice applied an MMC soaked sponge to the area of degeneration for 10 seconds, followed by irrigation with a balanced salt solution. No recurrence was reported for 28±15 months.[45](B2)

Keratoplasty

Rarely, lamellar keratoplasty (LK) is required for sufficient resolution of SND. A comparison of automated lamellar keratoplasty (ALK) to PTK for treatment of SND found that the overall change in VA was comparable between the two groups; however, PTK had a lower rate of complications.[46] Cases of recurrent SND after keratoplasty have been reported.[7][47] Cases that necessitate PK are exceedingly rare, usually in the setting of extensive concomitant disease or intraoperative perforation during LK.(B2)

Additional Considerations

For most accurate biometric data to be obtained, SND should be removed before cataract extraction. SND induced refractive sequelae may adversely affect biometry measurements, K values, and consequently IOL power calculations.[5][34](B2)

Differential Diagnosis

Salzmann nodular degeneration (SND) resembles many conditions related to cornea. It is essential to differentiate it from these. Following differential diagnosis should be considered when making the diagnosis of SND.

• Bullous Keratopathy
  • Usually associated with Descemet membrane folds, corneal stromal edema, raised intraocular pressure. Bullae may be differentiated from Salzmann nodules at the slit lamp by the presence of water.
• Climatic Droplet Keratopathy
  • Golden-yellow or translucent droplets in the intrerpalpebral area bilaterally.
• Corneal Amyloidosis
  • Primary amyloidosis, gelatinous drops like dystrophy or primary familial amyloidosis, presents with a bilateral raised multinodular mound of amyloid in the central cornea. These deposits are typically subepithelial.[3]
  • Secondary amyloidosis present in the area of past trauma as a yellow-white to the pink waxy nodular lesion.
• Corneal Keloid
  • These are typically seen in younger age groups, with a history of inflammation, trauma, or in association with the Lowe syndrome.
• Hereditary Hypertrophic Scarring
  • Nodular scaring after minor trauma or surgery. Difficult to differentiate from SND at the slit lamp.
• Peripheral Hypertrophic Subepithelial Corneal Degeneration
  • Salzmann-like corneal opacities localized to the palpebral aperture.
  • Typically bilateral and involve nasal as well as temporal cornea.

Prognosis

Prognosis is good with the treatment of underlying factors. Though asymptomatic cases may be observed without progression, cases of spontaneous regression have not been reported. Varying rates of recurrence have been reported.[8][3][5] However, treatment of the underlying etiology may decrease the potential for further nodule formation.[8]

Complications

Salzmann nodular degeneration (SND) causes some serious complications. These include

• It may irritate the ocular surface leading to photophobia
• Tearing
• Blepharospasm
• Secondary recurrent corneal erosions [48]
• Salzmann’s nodules cause a flattening of the cornea, leading to astigmatism in many cases.[33] Removal of nodules may resolve astigmatism.