Salzmann Nodular Corneal Degeneration

Etiology

The most commonly cited risk factors for SNCD in ocular surface inflammatory conditions include dry eye, chronic blepharitis, meibomian gland dysfunction, phlyctenular keratoconjunctivitis, pterygium, trauma, and vernal keratoconjunctivitis.[1][2][4][5][6][5][7] Additionally, contact lens wear also appears to be a risk factor, accounting for 34.2% of 152 eyes in one study.[5] Mechanisms may involve a disruption of stem cell turnover, 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.[18][19][20]

Surgical wounds to the cornea, such as from cataract extraction, radial keratotomy, penetrating keratoplasty, or laser in situ keratomileusis (LASIK), may increase the risk of developing SNCD.[10][21][22][23] In a 2010 study involving 180 eyes with SNCD, 27.2% had a history of previous ocular surgery.[5] Post-LASIK SNCD may occur due to postoperative 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][21][24][25][26][27][28] Often, these post-LASIK Salzmann nodules responded to conservative treatment alone; however, 2 published cases required superficial keratectomy.[26][28] SNCD in posterior keratoconus after a penetrating corneal injury has also been reported.[29]

SNCD has been reported in association with several systemic diseases, although a definitive causal relationship remains unproven. Notably, SNCD has been observed in patients with Crohn disease, dermatopathia pigmentosa reticularis, Kabuki syndrome, Kartagener syndrome, Ehlers-Danlos syndrome, thyroid eye disease, and Dandy-Walker syndrome.[13][30][31] Although no specific gene abnormalities have been identified in association with SNCD, several cases have been reported in which SNCD occurs in consecutive generations, with an autosomal dominant inheritance pattern in 2 cases.[18][32] A unique genetic link in SNCD, or possibly a missense mutation in the TGF-β gene, which is the genetic basis for other corneal dystrophies, may play a role.[32]

Table 1. Etiological Classification of Superficial Nodular Corneal Disease

Epidemiology

SNCD typically occurs in the fifth to sixth decade of life, though it has been reported in individuals aged 4 to 90.[2][4] The largest study, which included 180 eyes, established a mean age of 60.8 years, with a range of 13 to 92 years.[5] A bimodal age distribution has also been reported, with the most affected individuals present in the fifth or eighth decades.[3] SNCD is more common in women, who accounted for 78% of the patients in Salzmann's original series, which has been reproduced in subsequent reports.[3][5][24][27] The female preponderance in SNCD has been linked to hormonal influences, as most affected women are middle-aged, whereas men tend to be older.[8][33] Studies have shown that SNCD occurs bilaterally more than 50% of the time, though severity may be asymmetric.[3][5][8][3]

SNCD is an uncommon, slowly progressive, non-inflammatory degenerative corneal condition. The true prevalence of SNCD is difficult to ascertain due to its indolent nature and frequently asymptomatic presentation, especially when the nodules are located away from the visual axis. Although comprehensive population-based data are limited, SNCD is increasingly recognized in routine clinical ophthalmic practice, particularly among patients with chronic ocular surface disorders and those undergoing refractive evaluation.[34]

SNCD is most commonly diagnosed in the fifth to sixth decades of life, although the reported age range spans from childhood (as young as 4) to older patients (up to 90). The degenerative changes are generally insidious and may take years to become clinically apparent. Pediatric cases are rare and typically associated with secondary forms due to predisposing inflammatory or traumatic causes. A consistent observation across multiple studies is the predominance of SNCD among females, with some literature suggesting a female-to-male ratio of approximately 2:1. The underlying reason for this sex disparity is not fully understood but may be related to hormonal influences, differences in meibomian gland function, and a higher prevalence of dry eye disease and autoimmune disorders among women.[35]

SNCD tends to be bilateral in most cases but is often asymmetrical in presentation. In unilateral cases, an identifiable predisposing factor such as trauma, surgery, or localized ocular surface disease is typically present. Nodules typically occur in the mid-peripheral or peripheral cornea, though they may extend centrally in advanced cases.[36] There is limited literature examining ethnic or racial predisposition to SNCD. However, some studies and case series suggest that White or Caucasian individuals may be disproportionately affected. Whether this is due to genetic predisposition, environmental exposures, or referral bias remains unclear and warrants further epidemiological investigation.[13]

Several ocular and systemic risk factors have been associated with an increased likelihood of developing SNCD:

• Ocular surface inflammation: Chronic conditions such as vernal keratoconjunctivitis, trachoma, and blepharitis are frequently reported in patients with secondary SNCD.
• Dry eye disease: A significant proportion of patients with SNCD exhibit signs of aqueous-deficient or evaporative dry eye, including meibomian gland dysfunction.
• Contact lens wear: Particularly long-term rigid gas-permeable contact lens users have shown an increased incidence, possibly due to mechanical microtrauma and reduced oxygen transmission.
• Previous ocular surgery or trauma: Individuals with a history of penetrating keratoplasty, radial keratotomy, or LASIK may develop secondary SNCD, often at sites of surgical incisions.
• Corneal dystrophies: Epithelial basement membrane dystrophy has been observed to coexist with SNCD in a subset of patients.[37]

With the increased use of high-resolution anterior segment imaging (eg, AS-OCT and confocal microscopy), ophthalmologists are now more adept at detecting subtle nodular changes even in early or atypical presentations. Additionally, the growth of corneal refractive surgery has contributed to heightened detection of SNCD during preoperative evaluations, as nodules may influence corneal curvature and refractive outcomes. SNCD is generally nonprogressive or slowly progressive. Many patients remain stable for years without significant visual disturbance. However, in the presence of ongoing ocular surface inflammation, nodules may enlarge, migrate toward the visual axis, and lead to visual impairment, necessitating surgical intervention. Although SNCD remains a relatively rare corneal degeneration, Increased awareness among clinicians and advancements in diagnostic modalities have led to more frequent diagnoses. The condition shows a female predominance, typically affects individuals in middle to late adulthood, and is often bilateral but asymmetric. Identification of underlying inflammatory or structural ocular pathologies is crucial in understanding the epidemiological profile of this disorder.[38]

Pathophysiology

The exact mechanism of SNCD development is unknown; however, multiple theories have been proposed. Histological studies have revealed hyaline plaques between the epithelium and Bowman's layer, resembling changes observed in degenerative pannus or old corneal scars, suggesting a potential role for chronic inflammation or immune processes. External irritation, trauma, or chronic exposure to sunlight and environmental irritants are thought to stimulate fibroblast overgrowth and hyaline degeneration. Additionally, prolonged epithelial remodeling and wound healing responses, marked by subepithelial fibrosis, MMP-2 activity, and disruption of Bowman's layer, are believed to contribute to nodule formation. 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 or aqueous-deficient dry eye, leads to prolonged wound repair and remodeling of the epithelium, thus creating the conditions for epithelial cell differentiation and anterior shift of stromal fibroblasts, along with excess deposition of extracellular material.[7][8] Subsequent deposition of extracellular matrix by fibroblasts and other cells within the nodules follows. Moreover, ground substances on collagen fibers in the nodules are stimulated by chronic exposure to sunlight or environmental irritants.[2][23][39][23][40] Decreased PAX6 and DSG1 protein expression has also been found in the corneal epithelium of patients with SNCD.[41]

Wilson and Dupps reviewed atypical cases of SNCD that developed years after keratorefractive surgeries.[42] Their findings support a pathophysiological model in which damage to the epithelial basement membrane allows pro-fibrotic cytokines, such as transforming growth factor-beta, to penetrate the subepithelial space, stimulating the transformation of fibrocytes or corneal fibroblasts into myofibroblasts. These cells generate disorganized extracellular matrix, forming the characteristic subepithelial opacities of SNCD. When the injury involves deeper structures, such as Bowman's layer, as often occurs in LASIK, the fibrotic changes can extend into the anterior stroma, making treatment more complex and less amenable to conventional superficial keratectomy. The authors propose Salzmann's subepithelial fibrosis as a more accurate term for such presentations. SNCD is a non-inflammatory, degenerative corneal disorder characterized by the formation of bluish-white or grayish nodules anterior to the Bowman's layer. These nodules result from chronic degenerative changes in the corneal epithelium and subepithelial layers. The exact mechanisms underlying the formation of these nodules remain incompletely understood, but recent histopathological, immunohistochemical, and imaging studies have provided insight into the pathophysiological processes involved.[43]

Anatomical Basis

The cornea comprises 5 primary layers—epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium. In SNCD, the pathology is confined primarily to the anterior corneal stroma and subepithelial zone, often with disruption or complete absence of the Bowman's layer beneath the nodular lesions. The nodules are situated between the basal epithelial cells and the anterior stroma, and are composed of fibrocellular tissue with extracellular matrix deposition.[44]

Role of Chronic Irritation and Inflammation

The pathogenesis is closely linked to chronic ocular surface inflammation or mechanical irritation.

• In secondary SNCD, conditions such as vernal keratoconjunctivitis, chronic blepharitis, dry eye disease, and trachoma lead to a sustained low-grade inflammatory state. Such inflammation promotes the release of proinflammatory cytokines (eg, interleukin-1 and tumor necrosis factor-alpha) and MMPs that degrade the standard extracellular matrix and stimulate aberrant wound healing responses.
• In primary (idiopathic) SNCD, even in the absence of overt ocular inflammation, subtle chronic epithelial microtrauma from meibomian gland dysfunction or subclinical dry eye may activate similar pathways.[45]

Epithelial-Stromal Interaction and Fibrosis

In SNCD, repetitive epithelial injury or stress leads to dysregulated wound healing, characterized by the following:

• Loss of Bowman's layer integrity.
• Migration of basal epithelial cells into the subepithelial space.
• Activation of keratocytes in the anterior stroma, which transdifferentiate into myofibroblasts.
• The secretion of abnormal extracellular matrix proteins, including collagen types I, III, and V, as well as fibronectin, contributes to the formation of nodules.[46]
• Lack of normal basement membrane regeneration further perpetuates fibrosis.

This sequence results in fibrocellular nodules that gradually accumulate over time, often without significant vascularization or immune cell infiltration, reflecting the non-inflammatory but degenerative nature of the disease.

Histopathological Findings

Microscopic evaluation of excised nodules reveals the following features:

• Epithelial hyperplasia or thinning overlying the nodules.
• Subepithelial fibrous tissue containing disorganized collagen bundles.
• Absence or disruption of the Bowman's membrane.
• Presence of fibroblasts and myofibroblasts within the nodules.
• Occasional deposition of hyaline-like material, often Periodic acid-Schiff–positive but Congo red-negative (excluding amyloid), has been observed. These findings are consistent with a chronic reparative process rather than an acute inflammatory or dystrophic mechanism.[47]

Contributions of Contact Lens Wear and Surgery

• Long-term use of rigid gas-permeable contact lenses can cause microtrauma to the corneal surface, leading to subepithelial fibrosis and the formation of nodules.
• Surgical trauma, particularly from penetrating keratoplasty, radial keratotomy, or refractive procedures (eg, LASIK and PRK), may induce abnormal healing responses and contribute to the formation of secondary SNCD at the wound sites.[48]

Biomechanical Changes

The formation of elevated nodules distorts the regular corneal surface, particularly when nodules encroach upon the visual axis. This distortion can:

• Alter the tear film stability, contributing to symptoms of ocular surface irritation.
• Induce irregular astigmatism, degrading visual quality.
• Compromise corneal transparency, especially in advanced cases with stromal involvement.[49]

Natural Course and Progression

The nodules tend to be indolent and slowly progressive. However, in the absence of intervention, especially in cases with active ocular surface disease, the nodules may:

• Increase in number and size.
• Become more elevated.
• Migrate centrally and interfere with the optical zone.

There is no evidence of spontaneous regression; however, stabilization is common with appropriate treatment of the underlying causes.

SNCD is a fibrodegenerative corneal process initiated by chronic epithelial microtrauma and perpetuated by impaired epithelial-stromal interaction and abnormal wound healing. The histological hallmark includes subepithelial fibrocellular nodules with variable epithelial changes and disruption of Bowman's layer. Whether arising idiopathically or in association with ocular surface disease, the pathophysiology of SNCD reflects the cornea's maladaptive repair mechanism, making early recognition and management of the inciting factors crucial in preventing visual morbidity.[50]

Histopathology

Histological examination typically shows thinning of the epithelium overlying a nodule. Disruption of the Bowman's layer may be observed with duplication of the epithelial basement membrane.[7] Other findings include a decreased cell density and deposition of matrix material within the nodule, anterior stromal scarring, and an irregular epithelial-stromal interface. There are no pathognomonic histological features of SNCD, 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.[7]

The mechanism underlying the development of SNCD and subepithelial matrix deposition appears to involve the function of the corneal epithelium itself. The cells of the limbus differ from the cells of the central cornea in structure and function. The limbal epithelium contains stem cells and transient amplifying cells, which are not completely differentiated but have a high potential for proliferation. Typically, the central cornea contains completely differentiated epithelium and should not contain stem cells. Immunohistochemical analysis has shown that the epithelium in SNCD shows similar markers to those of the undifferentiated transient amplifying cells in the limbus.[51]

High levels of staining for CK19 and enolase, markers of the metabolically more active migrating epithelium, suggest that the epithelium that overlies SNCD nodules is composed of cells that are not terminally differentiated and are more comparable to limbal transient amplifying cells 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's layer in an ongoing wound remodeling process.[40] These histopathological findings support the clinical association of chronic ocular surface disease with SNCD.

Toxicokinetics

Toxicokinetics typically refers to the ADME (absorption, distribution, metabolism, and excretion) of toxic substances in the body. Although SNCD is fundamentally a degenerative and nontoxic condition, there are some relevant connections to consider when examining ocular surface exposure to topical or environmental agents that may contribute to or exacerbate the disease, particularly in secondary SNCD. In this context, the toxicokinetic framework applies primarily to exogenous agents, as outlined below.

Absorption

Topical ophthalmic agents, environmental toxins, and preservatives (eg, benzalkonium chloride in eye drops) can be absorbed across the corneal epithelium and into the stroma. This absorption may lead to several issues, including:

• Trigger epithelial injury.
• Disrupts tear film and corneal surface homeostasis.
• Promote chronic low-grade inflammation leading to fibrocellular proliferation.[52]

Distribution

Once absorbed, these agents may:

• Accumulate in the superficial corneal tissues.
• Alter corneal stromal cell behavior by modifying extracellular matrix production.
• Enhance local cytokine production or oxidative stress—factors implicated in SNCD pathogenesis.[53]

Metabolism

The cornea possesses limited enzymatic activity. Metabolism of exogenous substances occurs minimally within corneal and conjunctival cells. Persistent presence of unprocessed agents (eg, preservatives, contact lens solutions, and pollutants) may lead to several issues, including:

• Chronic irritation.
• Delayed epithelial repair.
• Promotion of abnormal healing cascades, as observed in SNCD.[54]

Excretion and Clearance

Tears and conjunctival vasculature play a role in clearing topical or environmental exposures. However, in dry eye disease or ocular surface dysfunction (often comorbid with SNCD), clearance may be impaired. Prolonged retention of irritants exacerbates epithelial-stromal interactions, fueling nodule development.

Although SNCD is not classically viewed through a toxicokinetic lens, chronic exposure to topical drugs, preservatives, environmental pollutants, or prolonged contact lens use may result in toxic effects on the ocular surface. These agents, through impaired clearance or cumulative damage, can disturb the epithelial and stromal integrity, setting the stage for the degenerative remodeling observed in SNCD. Understanding these pathways may aid in preventing disease progression, particularly in cases of secondary SNCD.[55]

History and Physical

Most patients with SNCD are asymptomatic. As the disease progresses, patients typically present with symptoms such as foreign body sensation, irritation, tearing, or photophobia.[3][5][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.[3]

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

Obtaining a detailed history and performing a thorough physical examination are essential in diagnosing SNCD and identifying contributing factors and complications. As SNCD is a slowly progressive degenerative disorder of the cornea, patients often remain asymptomatic for years until nodules encroach upon the visual axis or induce irregular astigmatism. Therefore, eliciting subtle signs and symptoms, as well as associated ocular conditions, becomes crucial during evaluation.[8]

Patient History

Symptom onset and progression: Patients may report gradual worsening of vision or ocular discomfort. In primary SNCD, the onset is insidious and often bilateral, with a slow course over years. Secondary SNCD may follow chronic inflammatory eye diseases or ocular trauma.[56]

Visual complaints: Symptoms vary depending on the size and location of nodules. Common complaints include the following:

• Blurred vision
• Fluctuating visual acuity
• Glare or halos, especially at night
• Ghost images (monocular diplopia)
• Photophobia [57]

Ocular surface symptoms: Patients commonly report the following complaints:

• Foreign body sensation
• Dryness and burning
• Redness
• Irritation [58]

Past ocular history: The following details should be elicited during history-taking:

• History of vernal or atopic keratoconjunctivitis
• Previous ocular surgery or trauma
• Chronic blepharitis or meibomian gland dysfunction
• Contact lens use (exceptionally rigid lenses)
• Recurrent corneal erosions or epithelial basement membrane dystrophy [59]

Systemic history: Although SNCD is primarily ocular, associations with autoimmune diseases or systemic inflammation (eg, Stevens-Johnson syndrome and ocular cicatricial pemphigoid) should be ruled out in atypical presentations.

Physical Examination

The ophthalmic examination typically reveals the following features:

• Elevated, whitish-blue nodules in the corneal mid-periphery
• Nodules located between Bowman's layer and the epithelium
• Clear intervening corneal stroma
• Flattening or indentation of the surrounding cornea
• Absence of inflammation [60]

Slit-lamp findings include the following: 

• Nodules appear gray-white, translucent, or chalky
• Surface may be smooth or irregular
• Nodules may coalesce in advanced cases
• Fluorescein staining is typically absent unless epithelial breakdown occurs

Corneal topography shows localized irregular astigmatism with decreased corneal regularity index. This technique is particularly helpful in assessing visual axis involvement.

AS-OCT reveals elevated subepithelial masses with normal underlying stroma, aiding in the differentiation from other causes of corneal opacities.[61]

Table 2. Clinical Features of Salzmann Nodular Corneal Degeneration

Abbreviation: AS-OCT, anterior segment optical coherence tomography.

Evaluation

The diagnosis of SNCD is typically made clinically through a slit-lamp examination. Slit-lamp examination reveals nodules that are typically smaller than 2 mm but may also be as large as 4 × 2.5 mm.[6][62] The nodules may appear in any part of the cornea, and their 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] See Image. Slit-Lamp Photograph of a Patient Suffering From Primary SNCD.

Another common pattern is the 3 and 9 o'clock location of the nodules in patients with a history of contact lens wear.[3] Nodules are bluish-white to gray and are typically round but may also be conical or prismatic.[6] Peripheral SNCD is more common than central.[8] 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 they are adjacent to each other. Several cases of ring-like peripheral confluent SNCD have been reported.[5][63] Other findings include decreased tear breakup time, reduced tear lake, and negative fluorescein staining of the nodules.[10][64] 

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 10 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.[20]

Although most cases are accurately diagnosed through clinical examination, the diagnosis may be supported by ancillary investigations, such as high-frequency UBM, in vivo confocal microscopy (IVCM), AS-OCT, or corneal topography and tomography. UBM of peripheral nodules in a post-LASIK patient showed differentiated epithelium, Bowman's layer, and LASIK flap, localizing the nodules to within the margin of the flaps and revealing the destruction of the underlying Bowman's 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, as well as a well-defined demarcation line.

Biometric values obtained through corneal topography are influenced by the presence of SNCD, leading to inaccurate intraocular lens calculations, with errors as high as 3.2 D reported in a study.[65] These changes may be attributable to alterations in lamellar stromal anatomy, nodular elevation above the corneal surface, and tear film disruption.[65] 

AS-OCT is a noninvasive imaging modality that can be helpful in the diagnosis, management, and follow-up of SNCD. AS-OCT shows bright, hyperreflective, subepithelial deposits above the Bowman's layer that are covered by an abnormally thin layer of epithelium. AS-OCT can perform noninvasive optical biopsies that have been shown to correlate with the histopathology of the disease.[63] This technique enables in vivo histological analysis of nodules in the early stages without requiring tissue sampling.[63]

Using 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, as shown by IVCM, have an irregular morphology, consisting of elongated, polygonal cells of varying sizes.[66][67][68] More deeply, the keratocytes in the superficial stroma showed prominent, hyperreflective nuclei consistent with cells in a more activated state.[51]

The corneal stroma within the nodule appeared disorganized, with an increase in the hyperreflective extracellular background.[63] Analysis of the deeper stroma revealed very prominent nerves, highlighted by an unusual pattern of grouped keratocytes. The Descemet membrane and the endothelium were of normal appearance.[67][68]

A careful, stepwise evaluation is essential for confirming SNCD, gauging its functional impact, and distinguishing it from look-alike corneal pathologies. The assessment combines targeted history-taking, meticulous slit-lamp examination, and selective anterior-segment imaging.

Comprehensive Clinical Examination

• Visual acuity and refraction: Measure best-corrected distance and near acuity. Perform manifest and cycloplegic refractions to reveal irregular astigmatism or monocular diplopia caused by nodules encroaching on the visual axis.
• Slit-lamp biomicroscopy: Identify elevated, bluish-white or gray nodules lying anterior to Bowman's layer. Note their size (1-3 mm), location (typically mid-peripheral superior cornea), surface smoothness, and any overlying epithelial defects or punctate staining.
• Fluorescein staining and tear-film evaluation: Although the epithelium is generally intact, tear breakup time often decreases over nodular elevations, explaining fluctuating vision.
• Eyelid and meibomian gland assessment: Look for blepharitis, meibomian gland dysfunction, or Demodex infestation that can sustain ocular-surface inflammation and drive secondary SNCD.[69]

Anterior-Segment Imaging

Table 3. Diagnostic Modalities and Key Findings in Salzmann Nodular Corneal Degeneration

Abbreviations: AS-OCT, anterior segment optical coherence tomography; SNCD, Salzmann nodular corneal degeneration; PTK, phototherapeutic keratectomy.

 Ancillary Tests

• Keratometry/keratograph: Reveals skewed mires and irregular cylinders >1 D, corroborating visual complaints.
• Tear osmolarity and inflammatory markers (eg, MMP-9): Abnormal in concomitant dry eye disease; treating tear-film instability may halt progression.
• Routine microbiology/serology: Not required unless atypical inflammation or associated infection (eg, interstitial keratitis) is suspected.[70]

Diagnostic Pitfalls and Differentials

Given that SNCD presents with superficial opacities similar to other conditions, maintaining a high index of suspicion is essential in the following scenarios:

• Nodules contain chalky calcium (band keratopathy)—AS-OCT shows a hyperreflective line in Bowman's layer rather than discrete plaques.
• Central corneal guttata or stromal edema are present—consider Fuchs endothelial dystrophy.
• Nodules are peripheral, crescentic, and vascularized—rule out Terrien marginal degeneration.[71][72]

Functional Assessment and Grading

Table 4. Grading of Salzmann Nodular Corneal Degeneration Severity Across Centers

Reference for the table.[44]

Abbreviation: PTK, phototherapeutic keratectomy.

Key Take-Home Points

• Patient history, slit-lamp examination, AS-OCT, and topography should be combined to confirm diagnosis and quantify visual impact.
• Concomitant ocular-surface disease should be continually evaluated and managed; treating the underlying condition reduces the recurrence.
• Imaging not only differentiates SNCD from mimickers but also guides surgical depth and optical zone planning for PTK or keratoplasty.

This thorough evaluation framework equips clinicians and interprofessional eye-care teams to detect SNCD early, stratify severity, and choose evidence-based interventions that preserve visual function and patient quality of life.[73]

Treatment / Management

Management choices are influenced by the size and location of nodules, as well as the severity of symptoms. Asymptomatic patients may be treated with observation alone, whereas mildly symptomatic patients typically respond to conservative management. In contrast, severe cases may require surgical intervention. Visual disturbance is the most common indication for surgery.[5][3][9] However, continually symptomatic nodules, despite conservative management, may also require surgical management.[3][5][8] Additionally, patients with multiple quadrants affected are more likely to require surgery.[5](B2)

Conservative Management

In most cases, patients 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. A study found that conservative therapy was effective enough to avoid surgery in 77.3% of cases.[5] Initial treatment should include the use of 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.[8] Post-LASIK SNCD  has been treated with punctal plugs, in addition to loteprednol and cyclosporine, with a resolution of symptoms after 6 months.[10] If nodules occur in the setting of contact lens wear, cessation or reduction of lens wear may relieve symptoms. Contact lens fit should be reviewed.(B2)

Nodulectomy/Superficial Keratectomy

Manual excision and superficial keratectomy are the most straightforward surgical approaches for managing SNCD.[5][74] 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.[75] The edge of the nodule is grasped using forceps and pulled toward the periphery or limbus.[5][8][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.[7] 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 typically regular and smooth.[6] This presentation contrasts PHSCD, a condition that involves peripheral Salzmann-like opacities. Removal of a PHSCD lesion may be more challenging than its SNCD counterpart; bundles of subepithelial anchoring fibrils, as well as blood vessels, can complicate the establishment of a surgical plane.[76][77] Borgia and associates described intraoperative optical coherence tomography–assisted superficial keratectomy to enhance precision in Salzmann nodule removal by providing real-time visualization and enabling accurate dissection while preserving healthy corneal tissue.[43](B2)

Some patients with SNCD are left with significant defects in the Bowman's layer. These irregularities, if present, may be treated with a diamond burr or PTK.[78][79][80] Recurrences are more common in cases with deeper defects in the Bowman's layer and superficial stroma.[6] In a set of 41 cases that underwent superficial keratectomy, one report indicated a 22% recurrence rate. A study utilized superficial keratectomy followed by amniotic membrane transplantation; however, the nodule recurred. Although the procedure was repeated, recurrence occurred again. Published data on similar cases remain limited.[81](B2)

Mitomycin-C is an alkylating agent that interrupts DNA synthesis, inducing apoptosis in fibroblasts.[82] Mitomycin-C, used intraoperatively, targets the active fibrocytes and keratocytes within the stroma to halt the progression of Salzmann nodules and prevent recurrence after excision.[83][84] In a study involving 30 eyes, Bowers et al removed nodules via manual keratectomy and applied a mitomycin-C-soaked sponge to the area of degeneration twice, each time for 10 seconds, followed by irrigation with a balanced salt solution. No recurrence was reported for 28±15 months.[84] (B2)

Phototherapeutic Keratectomy

PTK is a viable management option for the treatment of SNCD. In a study, Trufanov and Riks found that both PTK and anterior automated lamellar keratoplasty (ALK) effectively improve vision in patients with central corneal opacities due to Salzmann's nodular degeneration.[44] PTK is preferred for superficial lesions due to faster healing and re-epithelisation, whereas ALK with a 200 μm head provides more consistent astigmatism outcomes for deeper stromal involvement. Unlike the typical hyperopic effect observed with PTK in other conditions, PTK in Salzmann's nodular degeneration usually results in a myopic shift, likely due to the midperipheral location of the nodules and asymmetric tear film pooling before surgery.[85]

Keratoplasty

In rare cases, lamellar keratoplasty (LK) is required for sufficient resolution of SNCD. A comparison of ALK to PTK for the treatment of SNCD found that the overall change in visual acuity was comparable between the 2 groups; however, PTK had a lower rate of complications.[86] Cases of recurrent SNCD after keratoplasty have been reported.[8][87] Cases that necessitate PK are exceedingly rare, typically in the setting of extensive concomitant disease or intraoperative perforation during LK.(B2)

Newer Advances

Newer antifibrotic agents are being studied for their potential role in the management of SNCD. Subbot and colleagues found that pirfenidone and cyclosporine A significantly reduce myofibroblast proliferation, metabolic activity, and alpha-smooth muscle actin expression in corneal cell cultures derived from patients with Salzmann's nodular degeneration.[45] These findings suggest their potential as antifibrotic agents in developing targeted, pathogenetically driven treatments for SNCD and related corneal fibrotic disorders.

Additional Considerations

For the most accurate biometric data to be obtained, SNCD should be removed before cataract extraction. SNCD-induced refractive sequelae may adversely affect biometry measurements, K values, and consequently intraocular lens power calculations.[5][65](B2)

Postoperative Care and Recurrence Prevention

Postoperative care plays a pivotal role in minimizing recurrence after superficial keratectomy or PTK. The ocular surface should be optimized with the following:

• Preservative-free lubricants to support epithelial healing
• Prophylactic topical antibiotics for 5-7 days
• Topical corticosteroids tapered over 4-6 weeks to control fibroblastic proliferation
• Temporary use of bandage contact lenses in cases of large epithelial defects
• Close follow-up during the first postoperative month to monitor re-epithelialization and rule out infectious keratitis

Recurrence is often associated with incomplete excision of nodular tissue or untreated underlying ocular surface disease. Long-term suppression of inflammation using topical cyclosporine, lifitegrast, or low-dose steroids may help prevent recurrence, particularly in patients with chronic meibomian gland disease, dry eye, or blepharitis.[88]

International Guidelines and Best Practices

Although no universal guideline exists solely for SNCD, consensus-based approaches and recommendations from corneal subspecialty societies such as the American Academy of Ophthalmology and European Society of Cataract and Refractive Surgeons emphasize the following principles:

• Conservative therapy is the first-line treatment for asymptomatic or mild cases
• Preference for PTK over lamellar keratoplasty when the lesion is superficial
• Use of mitomycin-C intraoperatively for recurrent or aggressive cases to reduce fibroblast proliferation
• Preoperative imaging (eg, AS-OCT and topography) to guide treatment planning and laser ablation depth
• Patient education and involvement in long-term ocular surface care [89]
(A1)

Role of Interprofessional Collaboration

Effective management of SNCD requires a coordinated interprofessional approach.

• Ophthalmologists (corneal specialists) lead surgical and diagnostic decision-making.
• Optometrists assist with refraction, contact lens adjustments after surgery, and the early recognition of recurrence.
• Primary care physicians or rheumatologists may be involved if autoimmune associations are suspected.
• Nurses and ocular surface technicians play a role in perioperative care, postoperative counseling, and procedural assistance.
• Pharmacists ensure appropriate formulation of topical agents (eg, preservative-free steroids and compounded cyclosporine)
• Patient educators support adherence to long-term lid hygiene and artificial tear regimens [90]

Differential Diagnosis

SNCD may resemble several other corneal disorders, making accurate differentiation essential. The following differential diagnosis should be considered when making the diagnosis of SNCD.

• Bullous keratopathy
  • Typically associated with Descemet membrane folds, corneal stromal edema, and raised intraocular pressure (IOP). 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 interpalpebral area bilaterally.

• Corneal amyloidosis
  • Primary amyloidosis, characterized by gelatinous drops such as dystrophy or primary familial amyloidosis, presents with a bilateral raised multinodular mound of amyloid in the central cornea. These deposits are typically subepithelial.[6]
  • Secondary amyloidosis presents in the area of past trauma as a yellow-white to pink, waxy nodular lesion.

• Corneal keloid
  • These lesions are typically observed in younger age groups, with a history of inflammation, trauma, or in association with Lowe syndrome.

• Salzmann's subepithelial fibrosis [42]
  • A clinically distinct form of SNCD characterized by dense subepithelial corneal opacities that often extend into Bowman's layer and anterior stroma. This form typically arises following surgical or traumatic epithelial basement membrane injury and may require more extensive surgical management than classic SNCD.

• Hereditary hypertrophic scarring
  • Nodular scarring after minor trauma or surgery. Difficult to differentiate from SNCD at the slit lamp.

• Peripheral hypertrophic subepithelial corneal degeneration [91]
  • Salzmann-like corneal opacities localized to the palpebral aperture.
  • Typically bilateral and involve the nasal and the temporal cornea

Table 5. Differential Diagnosis for Salzmann Nodular Corneal Degeneration

Abbreviation: SNCD, Salzmann nodular corneal degeneration.

Pertinent Studies and Ongoing Trials

SNCD has been the subject of several retrospective and prospective studies that have shaped the current management protocols. Although randomized controlled trials are limited due to the rarity and indolent nature of the disease, observational studies and interventional case series have provided robust clinical insights.

Bowers et al (2009) conducted a prospective interventional study on 30 eyes with SNCD undergoing superficial keratectomy with intraoperative application of mitomycin-C. The study demonstrated excellent outcomes, with no recurrence observed over a mean follow-up period of 28 months. This study supports the use of mitomycin-C in reducing recurrence rates after excision.[84]

Sharma et al (2012) compared PTK with ALK. Both interventions improved visual acuity in patients with centrally located SNCD nodules. PTK demonstrated a faster healing time and a favorable safety profile, whereas ALK was preferred for deeper lesions to achieve better refractive control.[86]

Borgia et al (2021) introduced intraoperative AS-OCT–guided superficial keratectomy, enabling precise dissection and real-time assessment of nodule depth. This approach reduced the risk of residual fibrosis and recurrence.[43]

Subbot et al (2022) investigated the antifibrotic effects of pirfenidone and cyclosporine A on cultured SNCD keratocytes. Their findings demonstrated downregulation of α-SMA expression and myofibroblast transformation, suggesting a potential role in modulating pharmacological disease.[45]

Ongoing trials registered on ClinicalTrials.gov are evaluating the long-term efficacy of topical immunomodulators such as lifitegrast and low-dose topical corticosteroids for subclinical inflammation in early SNCD. Although results are pending, these therapies have the potential to redefine first-line treatment strategies for early disease.

These studies collectively contribute to the evolution of evidence-based recommendations for both conservative and surgical approaches in managing SNCD. They emphasize the importance of individualized therapy tailored to lesion location, depth, and associated ocular surface inflammation.

Treatment Planning

Effective treatment planning for SNCD requires a comprehensive, individualized approach tailored to the patient's clinical evaluation, symptom severity, nodule characteristics, and visual demands. The overarching goal is to preserve or restore visual function while minimizing recurrence and procedural morbidity.

Step 1: Clinical Assessment

• Visual acuity testing, slit-lamp examination, and documentation of nodule location, size, and depth using AS-OCT or ultrasound biomicroscopy (UBM) are essential.
• Assess for associated ocular surface conditions, such as meibomian gland dysfunction, dry eye disease, contact lens intolerance, and prior ocular surgery (eg, LASIK and PRK).
• Identify the patient's functional complaints, such as glare, photophobia, and fluctuating vision, especially if nodules involve or distort the visual axis.[3]

Step 2: Determine Management Pathway

• Asymptomatic or peripheral nodules: Observation and conservative treatment.
• Mild-to-moderate symptoms: Initiate medical management.
• Central, symptomatic, or visually significant nodules: Plan for surgical intervention.[92]

Step 3: Medical Management (First-line Therapy)

• Preservative-free lubricants to improve tear film and ocular surface comfort.
• Topical corticosteroids (eg, loteprednol) or immunomodulators (eg, cyclosporine A and lifitegrast) for inflammatory control.
• Address underlying contributors:
• Blepharitis: Practice lid hygiene and use warm compresses.
• Meibomian gland dysfunction: Lipid-based lubricants, oral doxycycline if needed.
• Contact lens overuse: Temporary cessation or lens refitting.[93]

Step 4: Surgical Planning (When Medical Management Fails)

• Superficial keratectomy: Indicated for elevated, visually significant nodules. The procedure can be performed under topical anesthesia. Intraoperative AS-OCT guidance should be considered for precision.
• Adjunctive mitomycin-C: Applied intraoperatively to reduce recurrence, especially in younger patients or cases with recurrent nodules.
• PTK: Best for central or irregular stromal surface nodules causing higher-order aberrations.
• Lamellar keratoplasty: Reserved for deep stromal involvement or failed superficial keratectomy/PTK.
• Amniotic membrane transplantation: Considered when epithelial healing is delayed or the ocular surface is severely compromised.[94]

Step 5: Postoperative Care

• Topical corticosteroids, antibiotics, and frequent lubricants in the early postoperative period.
• Tapering of steroids should be based on resolution of inflammation and epithelial healing.
• Follow-up schedule:
• Day 1: Assess for epithelial defect, inflammation.
• 1 Week: Monitor healing, comfort.
• Monthly (up to 6 months): Evaluate for recurrence, visual rehabilitation.

Step 6: Long-Term Surveillance and Counseling

• Educate patients on the chronic nature of the condition.
• Emphasize the importance of long-term lid hygiene, avoidance of ocular trauma, and regular follow-up, especially for patients with a history of prior ocular surgeries or contact lens wear.
• Counsel regarding the potential for recurrence, particularly in high-risk cases (eg, limbal involvement and recurrent epithelial erosions).[95]

Toxicity and Adverse Effect Management

Management of SNCD often involves both pharmacological and surgical interventions, each of which carries the potential for adverse effects. Proactive identification and management of these toxicities is crucial to optimizing patient outcomes and avoiding iatrogenic complications.

Pharmacologic Toxicities

Topical corticosteroids:

• Potential toxicities:
  • Elevated IOP → steroid-induced glaucoma
  • Cataract formation (posterior subcapsular)
  • Delayed corneal epithelial healing

•  Management:
  • Limit duration and frequency
  • Use low-potency agents (eg, loteprednol)
  • Regular IOP monitoring in long-term users
  • Taper gradually under supervision[96]

Topical cyclosporine A and Lifitegrast:

• Potential toxicities:
  • Local irritation, burning, redness, and stinging on instillation
  • Transient blurred vision

•  Management:
  • Administer artificial tears to reduce discomfort
  • Educate patients about the delayed onset of effect (6-8 weeks)
  • Monitor compliance and reinforce proper technique [97]

Oral doxycycline:

• Potential toxicities:
  • Gastrointestinal upset
  • Photosensitivity
  • Esophageal irritation

•  Management:
  • Prescribe with food (but not dairy)
  • Advise sun protection
  • Recommend taking with a full glass of water and an upright posture[98]

Mitomycin-C:

• Potential toxicities:
  • Corneal endothelial cell toxicity
  • Delayed epithelial healing
  • Scleral thinning (rare)

•  Management:
  • Apply intraoperatively in a controlled, timed manner (eg, 0.02% for 10-30 seconds)
  • Rinse thoroughly with balanced salt solution
  • Avoid in thin corneas or limbal stem cell deficiency
  • Use judiciously with an ophthalmic surgeon's expertise [99]

Surgical Complications and Toxicities

Superficial keratectomy:

• Risks:
  • Corneal haze or scarring
  • Recurrence of nodules
  • Delayed epithelial healing

•  Management:
  • Ensure proper dissection plane
  • Postoperative use of topical steroids and lubricants
  • Diamond burr polishing or PTK for residual surface irregularity [100]

Phototherapeutic keratectomy:

• Risks:
  • Hyperopic shift or unexpected refractive changes
  • Stromal haze
  • Delayed epithelialization

•  Management:
  • Predict refractive shifts (typically myopic in SNCD)
  • Use lower ablation depths
  • Apply topical steroids and lubricants postoperatively
  • Consider bandage contact lenses for comfort [101]

Lamellar or penetrating keratoplasty:

• Risks:
  • Graft rejection
  • Infection
  • Astigmatism

•  Management:
  • Routine follow-up and graft monitoring
  • Use of topical immunosuppressants and antibiotics
  • Spectacle or contact lens correction for postoperative refractive errors [102]

Contact Lens–Related Adverse Effects

In patients with long-term contact lens wear contributing to or complicating SNCD:

• Risks:
  • Hypoxia-induced corneal changes
  • Infection (eg, microbial keratitis)
  • Mechanical trauma

•  Management:
  • Temporary discontinuation
  • Refitting with high Dk lenses
  • Daily disposable lenses to reduce protein buildup [103]

Delayed or Missed Diagnosis

• Adverse outcome:
  • Unnecessary visual impairment
  • Misdiagnosis as dystrophies, keratitis, or degenerations (eg, band keratopathy)

•  Management:
  • High index of suspicion in patients with chronic ocular surface inflammation and subepithelial opacities
  • AS-OCT for accurate diagnosis
  • Histopathological examination in atypical cases

Although SNCD is typically a benign and indolent disease, both medical and surgical interventions carry a risk of toxicity and adverse effects. A tailored, cautious, and evidence-based approach—along with patient education and regular monitoring—can mitigate complications and improve long-term outcomes. The integration of imaging tools, such as AS-OCT, and surgical aids, such as intraoperative optical coherence tomography, can further reduce procedural risks.[72]

Staging

Although there is no universally accepted formal staging system for SNCD, clinicians have informally stratified the disease into stages based on clinical severity, nodule characteristics, and visual impact, which aids in treatment decisions and prognostication. A proposed practical staging framework includes:

Table 6. Proposed Clinical Staging of Salzmann Nodular Corneal Degeneration

Abbreviation: PTK, phototherapeutic keratectomy.

• Imaging tools: AS-OCT is valuable for assessing depth, morphology, and surgical planning.
• Histopathology may be considered in atypical presentations.
• Recurrent SNCD may demonstrate deeper stromal involvement and may require more aggressive surgical planning.
• Staging helps in determining candidacy for surgical intervention versus continued medical management.[104]

Prognosis

Prognosis is good with the treatment of underlying factors. Although asymptomatic cases may be observed without progression, cases of spontaneous regression have not been reported. Varying rates of recurrence have been reported.[3][6][5] However, treatment of the underlying etiology may decrease the potential for further nodule formation.[3]

The prognosis of SNCD is generally favorable, particularly with the timely identification and management of underlying ocular surface disorders. Most patients respond well to both conservative and surgical interventions, mainly when inflammation and ocular surface disease are addressed concurrently.

Asymptomatic cases—especially those with peripheral nodules that do not involve the visual axis—can often be monitored without intervention, without evidence of progression. However, spontaneous regression of nodules has not been reported in the literature, and untreated cases may ultimately lead to visual impairment due to progressive irregular astigmatism, tear film instability, or scarring.[13]

Recurrence rates vary significantly depending on the type of treatment and the presence of persistent underlying risk factors. Reported recurrence rates range from 0% to 22% following superficial keratectomy, with recurrence being more common in cases involving deeper stromal involvement or inadequate management of the predisposing etiology.

Importantly, addressing the primary cause—such as blepharitis, dry eye disease, or contact lens misuse—has been shown to reduce the risk of recurrence and prevent the formation of new nodules. The use of adjunctive therapies, such as intraoperative mitomycin-C or anti-fibrotic agents, may further reduce the risk of recurrence in surgical cases.[16]

Visual prognosis is excellent in most cases after treatment, with many patients achieving significant improvement in both uncorrected and best-corrected visual acuity. Refractive stability is typically restored following resolution of nodules, although some patients may require spectacle or contact lens correction for residual astigmatism. Overall, SNCD is a benign but potentially vision-impairing condition with good outcomes when managed appropriately.[105]

Complications

Complications secondary to SNCD include the following:

• Irritation of the ocular surface leading to photophobia, tearing, and blepharospasm
• Secondary recurrent corneal erosions [106]
• Salzmann's nodules cause a flattening of the cornea and induce tremendous local irregularities, leading to hyperopia and astigmatism in many cases.[64] Due to their elevated nature, the nodules accentuate the flattening that typically occurs from the center to the periphery. Moreover, when located paracentrally, they produce central pooling of tears, which flattens measured corneal curvature.[107] Surgical removal of these nodules can often reverse the hyperopia or further cause a myopic shift.
• Superficial corneal scarring

SNCD is generally a slowly progressive and benign condition. However, if left untreated or in cases of recurrence, several ocular complications may arise. These complications can result from the disease process itself or as sequelae of surgical interventions. The location, size, and number of nodules influence both symptom severity and the risk of complications.[46]

Table 7. Complications of Salzmann Nodular Corneal Degeneration

Abbreviation: PTK, phototherapeutic keratectomy.