Salzmann Nodular Corneal Degeneration

Salzmann nodular corneal degeneration (SNCD) is a relatively rare, slowly progressive, non-inflammatory condition of the cornea that is often underrecognized and frequently misdiagnosed due to its subtle early manifestations and overlapping features with other corneal disorders. In 1925, Austrian ophthalmologist Maximilian Salzmann described a series of patients with bluish-white corneal nodules secondary to phlyctenular or trachomatous keratitis. Although initially termed as , SNCD was later redefined as an indolent, degenerative condition. SNCD is characterised by the formation of fibrocellular outgrowth anterior to the basement membrane, resulting in elevated nodules most commonly involving the mid-periphery of the cornea. The disease was initially thought to be a variant of corneal dystrophy associated with phlyctenular and trachomatous keratitis. However, as clinical and histopathological understanding evolved, the term  was refined to  to better reflect its acquired, degenerative nature.  SNCD may be either primary or secondary. Primary Salzmann, the most common form, is typically not associated with any other ocular surface disease. However, these patients typically have coexisting meibomian gland dysfunction. Infrequently, SNCD has been observed in cases with chronic ocular surface inflammation, such as vernal keratoconjunctivitis, trachoma, interstitial keratitis, and dry eyes, as well as in non-inflammatory conditions, including epithelial basement membrane dystrophy and chronic rigid contact lens use. SNCD typically occurs in the fifth to sixth decade of life, though it has been reported in individuals aged 4 to 90. Although most cases are bilateral, it may present asymmetrically. SNCD predominantly affects women and may affect the White population more often. Spontaneous remission ­is unlikely, but symptoms typically improve with lubrication and topical anti-inflammatory therapy.  Surgical options in refractory cases include manual excision, phototherapeutic keratectomy (PTK) with or without the use of topical mitomycin-C, and lamellar or penetrating keratoplasty. Though many patients are asymptomatic, SNCD may cause significant morbidity and contribute to the degradation of vision. The prognosis is generally favorable; however, prompt recognition and management of SNCD, along with its underlying etiologies, is critical, as no cases of spontaneous remission have been reported.  SNCD is characterized by the development of discrete, elevated, bluish-white, superficial nodules, typically situated in the mid-peripheral or peripheral cornea. These nodules consist of collagenous fibrocellular material deposited anterior to Bowman's layer and the epithelial basement membrane. The overlying epithelium remains intact but may show irregularity or thinning. The condition is often bilateral but asymmetrical and may be either primary (idiopathic) or secondary to chronic ocular surface inflammation or trauma. To understand the pathogenesis of SNCD, it is essential to appreciate the anatomical structure of the cornea. The cornea is composed of 5 primary layers—the epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium. The epithelial basement membrane, situated beneath the epithelium, plays a crucial role in maintaining corneal homeostasis and facilitating repair. In SNCD, pathology predominantly occurs in the anterior cornea, with fibrocellular deposits accumulating between the epithelial basement membrane and Bowman's layer, or replacing Bowman's layer altogether. Histologically, the nodules in SNCD demonstrate replacement of Bowman's layer by extracellular matrix material, including collagen types I and III, and are often accompanied by activated keratocytes and myofibroblasts. This process reflects a reparative or reactive response to chronic epithelial stress, inflammation, or trauma, rather than a genetically determined dystrophy. This distinction is important, as SNCD is not inherited and does not follow a predictable pattern of progression typical of true dystrophies. SNCD can be broadly categorized into 2 types—primary (idiopathic) and secondary. In primary SNCD, there is no identifiable preceding ocular pathology. Primary SNCD typically presents in middle-aged women and may be associated with coexisting meibomian gland dysfunction or ocular surface dryness, although not directly caused by any specific ocular condition. This form is more common and typically arises without an apparent trigger. In contrast, secondary SNCD develops in the context of chronic ocular surface disease or corneal structural abnormalities. Several ocular conditions have been implicated in its pathogenesis, including vernal keratoconjunctivitis, trachoma, interstitial keratitis, and chronic blepharitis. Patients with severe dry eye disease or limbal stem cell deficiency are also at elevated risk. Other predisposing factors include recurrent epithelial erosions, a history of ocular trauma or surgery, and long-term contact lens wear, all of which contribute to chronic irritation and corneal remodeling. Additionally, epithelial basement membrane dystrophy has been associated with SNCD, likely due to persistent epithelial irregularity and defective wound healing responses. Understanding the classification and associated conditions of SNCD is essential for targeted management and prevention of recurrence. The pathophysiology likely involves chronic low-grade inflammation and recurrent epithelial microtrauma, leading to aberrant healing and subepithelial fibrosis. The exact molecular mechanisms are not yet fully understood, but they involve dysregulated wound healing, the activation of matrix metalloproteinases (MMPs), and the stimulation of fibroblasts. SNCD typically manifests in individuals aged 40 to 70, though cases have been reported in children as young as 4 and adults older than 90. SNCD shows a clear female predominance and is more frequently reported among the Caucasian population. The condition is bilateral in over 60% of cases, but it may present with highly asymmetrical features. Due to its often indolent course, many cases remain undiagnosed unless the nodules affect the visual axis or cause ocular discomfort. Patients with SNCD may remain asymptomatic, particularly in the early stages or when the nodules are located outside the visual axis, thus sparing the central vision. However, as the disease progresses or when the nodules encroach upon the optical zone, a variety of symptoms may develop. A common complaint is a persistent foreign body sensation, often caused by elevated nodules that disrupt the smooth corneal surface. Decreased visual acuity can result from direct obstruction of the visual axis or secondary to irregular corneal astigmatism induced by the nodules. Patients may also experience fluctuating vision, particularly in association with tear film instability. Photophobia and ocular irritation are frequently reported, especially when there is concomitant ocular surface inflammation. In some cases, blurred vision may be exacerbated by surface irregularities that alter the cornea's refractive contour. These symptoms collectively impact the patient's visual function and quality of life, emphasizing the importance of timely diagnosis and tailored management. The nodules are typically 1 to 3 mm in diameter, round to oval in shape, firm, and elevated. These nodules often appear bluish-white due to underlying stromal haze and are most frequently located in the midperipheral or superior cornea. In some cases, central involvement can significantly impair visual function. Diagnosis is primarily clinical, based on slit-lamp biomicroscopy. Nodules appear elevated, smooth, and opalescent. Adjacent corneal thinning or superficial vascularization may occasionally be observed. Corneal topography may show irregular astigmatism, and anterior segment optical coherence tomography (AS-OCT) can confirm subepithelial location, epithelial thinning, and loss of Bowman's layer. IVCM may reveal increased subepithelial reflectivity, activated keratocytes, and stromal scarring. The differential diagnosis of SNCD includes several ocular surface and corneal conditions that present with similar clinical features, particularly subepithelial corneal opacities or nodules.The presence of Salzmann-like nodules observed in interstitial keratitis is an important differential diagnosis, where chronic inflammation can lead to subepithelial fibrosis and nodule formation, mimicking SNCD. Band keratopathy, characterized by calcium deposition in the superficial cornea, may also present with gray-white opacities. However, these typically follow a horizontal interpalpebral distribution and have a distinct crystalline appearance. Epithelial basement membrane dystrophy, particularly when presenting with elevated map-dot-fingerprint patterns, can be mistaken for Salzmann nodules due to the irregularities on the anterior corneal surface. Pingueculae that extend onto the cornea can cause localized elevation and opacity, leading to diagnostic confusion, especially in the nasal interpalpebral region. Lastly, peripheral hypertrophic subepithelial corneal degeneration (PHSCD), a condition with peripheral subepithelial fibrosis and opacification, should be considered, particularly when nodules are located in the peripheral cornea. Accurate clinical assessment, aided by slit-lamp biomicroscopy and anterior segment imaging, is crucial for distinguishing these entities and ensuring appropriate management. SNCD is a slowly progressive condition, but it may remain stable for many years. Spontaneous regression is rare. Some patients may experience episodic symptom exacerbation due to concurrent ocular surface disease. Without treatment, nodules may enlarge and coalesce, contributing to more pronounced vision loss. However, many patients adapt well with minimal intervention. Symptom severity does not always correlate with nodule size. Even small lesions located centrally may significantly degrade vision due to irregular astigmatism or localized tear film disruption. Management strategies for SNCD are individualized and primarily depend on the severity of symptoms, the anatomical location of the nodules, and the presence of underlying or associated ocular surface disease. In mild cases, conservative treatment is often effective, typically involving regular use of lubricating eye drops to alleviate discomfort and maintain the stability of the tear film. Anti-inflammatory therapy, such as topical corticosteroids or cyclosporine, may be employed to control subclinical or overt inflammation. Additionally, addressing contributory conditions such as meibomian gland dysfunction or chronic blepharitis is critical in halting progression and preventing recurrence. In cases where conservative management fails or vision is significantly impaired due to central nodular encroachment or irregular astigmatism, surgical intervention becomes necessary. Superficial keratectomy involves the manual excision of nodules and is the first-line surgical approach in many patients. PTK, performed with an excimer laser, enables precise ablation and smoothing of the corneal surface, often yielding excellent visual outcomes. The adjunctive use of mitomycin-C may reduce recurrence by limiting fibroblastic activity. In advanced cases with deeper stromal involvement or a history of previous surgical failure, lamellar or penetrating keratoplasty may be required to restore visual function. Regardless of the chosen approach, long-term management of the ocular surface is crucial for minimizing the risk of recurrence and optimizing surgical outcomes. Postoperative recurrence is possible, especially in cases with ongoing ocular surface inflammation. Long-term lubrication and anti-inflammatory therapy may help reduce the risk of recurrence. Unlike infectious or neoplastic conditions, SNCD does not exhibit contiguous tissue spread. However, the disease can progress centripetally, especially in the presence of unaddressed risk factors. Nodules may increase in size or number, and new lesions may form in adjacent corneal areas. The prognosis for SNCD is generally favorable. Vision can often be preserved or restored with timely and appropriate treatment—most patients who undergo superficial keratectomy or PTK experience significant symptomatic and visual improvement. However, recurrence rates vary and depend largely on the adequacy of management of coexisting ocular surface disease. SNCD is a clinically significant yet underrecognized degenerative corneal disorder. Although indolent, its impact on visual function and quality of life can be profound, particularly when lesions encroach on the visual axis or induce irregular astigmatism. Early recognition, accurate diagnosis, and a tailored approach to management are essential. Understanding the anatomical basis, natural course, and associated risk factors is key for clinicians to provide evidence-based, interprofessional care aimed at preventing vision loss and minimizing recurrence.