Salzmann's Nodular Degeneration

Salzmann’s Nodular Degeneration is a non-inflammatory, degenerative process characterised by whitish-grey or bluish-white elevated sub-epithelial nodules in the superficial corneal stroma that are usually bilateral, mid-peripheral and slowly progressive. There is usually a clear area before the limbus. It can cause blurred vision if it occurs in central part blocking the visual axis. It occurs more often in women than in men. The nodules elevate the epithelium. Peripheral lesions tend to be vascularised and may look like pseudopterygium.

Salzmann described it as a dystrophy (genetic disorders characterised by deposition of abnormal material in cornea) in 1925, but it is a degenerative change that usually occurs years after some inflammatory condition of the cornea. He described it in association with keratoconjunctivitis, but with time, several different disorders coexisting with this degeneration were detected. To date, its aetiopathogenesis remains unknown, but it is considered to be associated with ocular surface inflammation or chronic trauma. The onset of the lesions is gradual and often occurs many years after the keratitis. The antecedent eye disease usually occurs in childhood. However, several cases with no previous corneal pathology have been reported and are considered idiopathic.

There are, usually one to nine discrete para-central lesions, often in a circular array at areas of corneal scarring or at the junction of old corneal scars and clear cornea. Each nodule is separated from other nodules by clear cornea, and iron lines may outline each nodule. The underlying stroma may be vascularised but the nodules are not vascularised.




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Many patients with Salzmann’s nodular degeneration are asymptomatic.

Symptomatic patients may complain of:

  • Ocular (eye) discomfort.
  • Irritation.
  • Foreign body sensation.
  • Dryness.
  • Pain if recurrent erosions occur.
  • Photophobia.
  • Decreased visual acuity.


Though the aetiology remains uncertain in majority of the cases, it is hypothesized that Salzmann’s nodular degeneration can be triggered by multiple events that lead to a nonspecific corneal tissue reaction based on individual predisposition. It appears to be more frequent in middle-aged women, and may be bilateral in about 60% of cases.

Ocular surface disorders:

  • Meibomian gland dysfunction.
  • Phlyctenular keratitis.
  • Dry eye disease.
  • Rosacea keratitis.
  • Vernal keratoconjunctivitis.
  • Atopic keratoconjunctivitis.
  • Trachoma.
  • Interstitial keratitis.
  • Exposure keratopathy.
  • Thygeson’s superficial punctate keratitis.
  • Recurrent corneal erosions.
  • Viral diseases like measles.
  • Scarlet fever.
  • Chronic blepharitis.
  • Trichiasis.
  • Peripheral vascularisation of the cornea.

Chronic injuries:

  • Extended contact lens use.
  • Previous corneal surgery followed by actinic exposure, recurrent erosions, and chemical or thermal injuries.
  • Previous ocular trauma.

Recently, Salzmann’s nodular degeneration in patients with Crohn’s disease was reported, and a hypothesis about association with systemic diseases was contemplated.

Genetic causes have also been described.



One of the hypotheses suggests that enzymatic destruction of Bowman’s membrane results in migration and proliferation of keratocytes from the stroma, resulting in secondary deposition of extracellular matrix components in nodular areas.

Histopathological studies have shown that the corneal nodules are located in sub-epithelium, but may extend to one-third of the anterior stroma and are formed by a dense connective tissue with hyaline degeneration. The corneal epithelium has an irregular thickness, with extremely increased thinning over the corneal nodules. The Bowman’s membrane exhibits disruption, may no longer be appreciable, and frequently replaced by fibrosis. Sub-epithelial fibrosis is a frequent histopathological finding, with activated fibroblasts beneath the epithelial cells. Increased expression of matrix metalloproteinase-2 (MMP-2) was recently detected in patients affected by Salzmann’s nodular degeneration, and this may be responsible for the induction of the basement membrane and Bowman’s membrane disruption.

Immunohistochemical analysis of protein expression in the basal epithelial cells suggests a high metabolic activity. This finding implicates the involvement of the epithelial cells in the formation of the sub-epithelial collagen elements seen in nodules. This in turn correlates with the clinical association linking corneal epithelial disease with the development of nodular degeneration.

Autoimmune aetiology has also been suggested in terms of pathogenesis of nodular degeneration.

Diagnosis of Salzmann’s nodular degeneration is usually made clinically.

The patients usually present with gradual, painless loss of vision for both near and distance. The combination of corneal nodules, corneal surface irregularities, and associated refractive error may lead to visual impairment. Visual impairment is progressive and due to an astigmatic defect produced by the nodules. Severe corneal irregularities in advanced stages generate high irregular astigmatism with severe visual loss. Patients may complain of reduced vision if the nodules are located in the central cornea.

There may or may not be a history of chronic ocular surface disease. Patients may also complain of a foreign body sensation on the surface of the eye. Elevated nodules can cause discomfort and epithelial erosions.

Clinical features:

Typical clinical signs could be observed during Slit lamp (biomicroscopic) examination by an eye specialist.

  • Salzmann’s nodules: Salzmann’s nodules are solitary or multiple white-to-grey or light blue nodules, elevated on the corneal surface, and located in the mid-periphery of the cornea. Each nodule is about 0.5 to 2mm in diameter and is not vascularised. In some cases, single or few nodules are present in one or more quadrants during routine ocular examination in asymptomatic patients, and sometimes, the nodules may invade the central zone. When multiple nodules are present, they have a typical circular arrangement and might be confluent in the advanced stages. A normal clear cornea between the nodules is a characteristic clinical feature.
  • Iron pigment deposition lines: Iron pigment deposition lines in the epithelium may be seen around the base of the lesions, and there is no further extension of these degenerative changes.
  • Recurrent corneal erosions: Recurrent corneal erosions may or may not be present.


Corneal topography:

Corneal topography demonstrates the irregularities of the corneal shape produced by corneal nodules, and the induced surface alteration depends on their number and localisation.

Anterior segment- Optical coherence tomography (AS-OCT):

Anterior segment- Optical coherence tomography (AS-OCT) allows the evaluation of dimension and depth of nodules, showing stromal extension that can help decide the surgical approach.

In vivo confocal microscopy:

In vivo confocal microscopy shows normal epithelium in the central cornea with rare sub-basal nerve fibers that display increased thickness with lack of branching. Nerve fibers in corneal stroma are also abnormal in that their branches are very thick and tortuous with highly reflective segments. These stromal nerves resemble regenerating nerves as are seen after penetrating keratoplasty. Deep stroma and endothelium do not appear to be altered. The peripheral zone of the nodules displays basal epithelial cells that appear abnormally elongated. Confocal microscopy showed an increased reflectivity of the anterior stroma and marked stromal scatter corresponding to the nodules, as a result of the presence of fibrosis. Highly reflective structures representing activated keratocytes are present in both peripheral zone and in the sub-epithelial stroma of the central portion of the nodules.


  • Haematoxylin & Eosin (H&E) stain: Haematoxylin & Eosin (H&E) stain shows an absent or broken Bowman’s layer and a thinned epithelium overlying the nodules, in addition to disorganised sub-epithelial collagen fibrils.
  • Light microscopy: Light microscopy shows dense deposits of hyalinised, irregularly arranged collagen fibers anterior to fragmented, and sometimes, absent Bowman’s membrane. The tissue overlying nodules displays an attenuated epithelium. The corneal stroma contains unevenly distributed mitotically inactive keratocytes and disorganised collagen bundles.
  • Morphometric analysis: Morphometric analysis yields a thinned corneal epithelium overlying the nodules.


Salzmann’s nodular degeneration may be differentiated from similar conditions resulting in deterioration of vision such as:

  • Spheroidal degeneration.
  • Corneal scarring.
  • Corneal astigmatism.
  • Corneal abrasion.


Management should be carried out under medical supervision.

Many elderly patients who have peripheral Salzmann’s nodules are asymptomatic and do not require any treatment.

Salzmann’s nodular degeneration usually does not resolve spontaneously. Depending upon the clinical picture, medical therapy or surgical therapy is required. Surgical therapy, when indicated, usually results in rapid improvement of visual acuity.

Any potential underlying aetiology should be managed accordingly.

General measures:

  • Eyelid hygiene.
  • Warm compresses.

Medical therapy:

Medical therapy, successfully treats most patients, and may include:

  • Topical artificial tears.
  • Non-steroidal anti-inflammatory drugs.
  • Topical corticosteroids.

Surgical therapy:

Indications for surgical therapy are:

  • Persistent ocular surface discomfort due to foreign body sensation or tear film instability.
  • Reduced visual acuity due to irregular astigmatism.
  • Recurrent corneal erosions.
  • Contact lens intolerance due to peripheral nodules.

Surgical procedures are:

  • Superficial keratectomy: In superficial nodules, manual excision with a crescent knife is sufficient and leaves a uniform smooth underlying surface. In the case of deeper in-growth that involves the anterior stroma, after nodule removal, the excimer laser phototherapeutic keratectomy is usually performed for significant anterior stromal haze or to make the surface smooth. In some cases with deep in-growth, the anterior lamellar keratectomy becomes necessary.
  • Excimer laser phototherapeutic keratectomy (PTK): Excimer laser phototherapeutic keratectomy (PTK) is generally effective in establishing a uniform, smooth surface and in removing opacities causing optical degradation, while minimising induced refractive change. Nodules often have good results after PTK, but the condition may recur. PTK may be performed with or without topical mitomycin-C (chemotherapy drug used in treatment of cancers).
  • Lamellar keratoplasty: Deep anterior lamellar keratoplasty (DALK) is performed when Salzmann nodules extend to or past the mid-stroma. This procedure is rarely required. Recurrence may occur within the graft.
  • Penetrating keratoplasty: Full thickness penetrating keratoplasty is usually not required. One study showed recurrence of lesions after several years.

The recurrent lesions are often not clinically similar to the original lesions but are indistinguishable histologically.

The recurrence of Salzmann’s nodules after surgical removal can occur with varying prevalence rates and periods of time.



Prognosis is very good to excellent. Visual disturbance is relieved by lamellar keratectomy. The condition may recur after surgical excision.


Complications of Salzmann’s nodular degeneration:

  • Irritation of ocular surface: The characteristic sub-epithelial nodules may irritate the ocular surface resulting in secondary recurrent corneal erosions, photophobia, blepharospasm and watering.
  • Hypermetropic (hyperopic) visual changes:  Salzmann nodules may create a relatively steepened mid-peripheral cornea and a flatter central cornea, resulting in hypermetropic visual changes.
  • Astigmatism: Nodules may cause significant astigmatism in patients whose disease affects multiple corneal quadrants.
  • Peripheral corneal vascularisation: Peripheral cornea may become vascularised, however, this complication actually may be due to original pathology causing Salzmann’s nodular degeneration.


  • PUBLISHED DATE : Jun 03, 2016
  • PUBLISHED BY : Zahid
  • CREATED / VALIDATED BY : Dr. S. C. Gupta
  • LAST UPDATED ON : Jun 03, 2016


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