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Salzmann's-like nodular degeneration following laser in situ keratomileusis

Moshirfar, Majid MD; Marx, Douglas P. MD; Barsam, Charles A. MD; Mohebali, Jahan BS; Mamalis, Nick MD

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Journal of Cataract & Refractive Surgery: October 2005 - Volume 31 - Issue 10 - p 2021-2025
doi: 10.1016/j.jcrs.2005.03.071
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Salzmann's nodular degeneration was first documented in 1925.1 This form of nodular degeneration is found most commonly in women and is typically bilateral.2 It is seen most often in patients with a history of phlyctenular keratitis, measles, vernal keratoconjunctivitis, trachoma, scarlet fever, and interstitial keratitis.3 Ocular histories of surgery, trauma, and exposure keratitis have also been reported in association with Salzmann's nodular degeneration.4 Rarely, noninflammatory conditions such as filamentary keratitis, corneal epithelial basement membrane dystrophy, hard contact lens wear, and keratoconus have been associated with Salzmann's nodular degeneration as well.3 Some cases appear to be inherited in an autosomal dominant fashion, whereas many other cases appear to be idiopathic.3

Most cases of Salzmann's nodular degeneration are asymptomatic.1 When patients do experience symptoms, the majority are related to recurrent corneal erosions.3,4 Common symptoms include decreased visual acuity (VA) and blepharospasm.3,4 Decreased VA can be caused by an irregular astigmatism or corneal scar produced in Salzmann's nodular degeneration.5 Common dry-eye symptoms such as pain, foreign-body sensation, and photophobia may also occur.3,4,6 Ocular surgeries, including corneal surgeries, have been found to increase the risk for developing Salzmann's nodular degeneration.3,4 The ophthalmic literature, however, contains no reports of the correlation between patients who have had laser in situ keratomileusis (LASIK) surgery and the later appearance of Salzmann's nodular degeneration. We report 2 patients with Salzmann's nodular degeneration following LASIK.


Case 1

A healthy 21-year-old woman presented for bilateral LASIK surgery in December 2001. Other than myopia, the patient had no significant ocular history. She was taking loratadine (Claritin), ethinyl estradial and desogestral (Ortho-Cept), and citropram (Celexa), with no ocular medications.

The LASIK procedure was performed in December 2001 at the Moran Eye Center in Salt Lake City, Utah. Preoperative corneal topography, pachymetry, and slitlamp examination at the Moran Eye Center revealed no irregularities, risk factors, or Salzmann's nodules to exclude this patient from LASIK. Preoperative manifest refractions were −2.00 diopters (D) in the right eye and −2.50 D in the left eye with a best corrected visual acuity (BCVA) of 20/20 in both eyes. Bilateral LASIK was performed using a Hansatome (Bausch & Lomb) microkeratome (180 μm) and Visx Star S3 laser (6.5 mm ablation zone). No complications were reported in either eye. The patient was instructed to administer ofloxacin (Ocuflox) as well as fluorometholone (FML) eyedrops 4 times a day for 7 days, bilaterally. Refresh Plus artificial tears were also dispensed to the patient, with instructions to apply bilaterally at least once an hour the day of surgery and then every 2 hours while awake.

One day postoperatively, the patient's manifest refractions were −0.25 + .075 × 23 in the right eye and plano +0.50 × 167 in the left eye, with an uncorrected visual acuity (UCVA) of 20/20 in both eyes. Slitlamp examination displayed no signs of flap folds, infiltrates, debris, or other irregularities in both eyes.

Approximately 1 month later, the manifest refraction was −0.50 in each eye. The patient was seen approximately 3 months later when she presented complaining of “mild dryness” in both eyes. Manifest refraction revealed plano +0.50 × 50 in the right eye and +0.25 +0.25 × 14 in the left eye with BCVA of 20/15 in both eyes. Again, corneal topography revealed no serious irregularities. Slitlamp examination, however, revealed superficial punctate keratitis (SPK). No corneal infiltrates, flap folds, or interface debris was noted on examination. To relieve her symptoms and treat the SPK, the patient was told to continue using Refresh Plus artificial tears and return in 3 months.

Three months later, the patient returned to the clinic with a chief complaint of “extremely dry eyes.” The patient's UCVA was 20/30 in both eyes. Examination revealed small Salzmann's-like nodules in the peripheral corneas bilaterally (Figures 1 and 2). The nodules were located at the 7 o'clock and 5 o'clock positions of the peripheral cornea, extending 1 clock hour in each direction. These nodules extended 2.0 to 3.0 mm inside and outside the flap margin. Despite patient report of regular use of artificial tears, SPK was still noted inferiorly. Bilateral inferior punctal plugs were inserted at this time, and the patient was instructed to continue using artificial tears.

Figure 1.
Figure 1.:
Salzmann's-like nodules in Case 1.
Figure 2.
Figure 2.:
Salzmann's-like nodules in Case 1.

One month following the punctual plug insertion, the patient's UCVA was 20/40 in the right eye and 20/30 in the left eye, with a manifest refraction of −1.00 +0.25 × 44 in the right eye and −1.50 +0.50 × 69 in the left eye. Slitlamp examination revealed inferior SPK, despite long-term use of artificial tears, and Salzmann's-like nodules. A corneal topography scan revealed a large Salzmann's-like nodule and a second smaller nodule in the right eye (Figure 3). Two small nodules were also apparent in the left eye.

Figure 3.
Figure 3.:
Postoperative topography of patient in Case 1.

Within 1 year of LASIK surgery, this patient developed a clear case of Salzmann's nodular degeneration and dry-eye symptoms bilaterally. Treatment options, including a superficial keratectomy, were refused by the patient despite continuous dry-eye symptoms.

Case 2

A 45-year-old woman was reexamined at the Moran Eye Center on October 7, 2003, after bilateral LASIK surgery approximately 5 years earlier. Before the procedure, a slitlamp examination was performed on the patient at the Moran Eye Center. This examination revealed no irregularities, risk factors, or Salzmann's nodules to exclude the patient from LASIK. Approximately 4 years following the procedure, the patient was seen by a community ophthalmologist for “corneal problems,” which were recorded as small bumps in the left eye and a decline in VA. In addition, the patient reported ocular dryness and redness, which she had treated with Refresh eyedrops for some time with no relief. The patient was referred back to the Moran Eye Center for a corneal consultation.

Examination revealed normal lids with no corneal lesions in the visual axis. The peripheral cornea, however, showed numerous small Salzmann's-like nodules bilaterally, with mild neovascularization at the bases (Figures 4 and 5). The nodules were located at the 10 o'clock and 2 o'clock positions of the peripheral cornea, extending 1 or 2 clock hours in each direction. The nodules extended 1.0 to 3.0 mm inside and outside the flap margin. The cornea did not show any haze. Mild SPK was present bilaterally, and the patient was treated with Refresh PM ointment at bedtime, doxycycline 100 mg once a day, and flaxseed oil twice a day. The patient was also treated with Refresh Endura drops every 2 to 3 hours despite the ocular irritation occasionally seen after frequent administration. Other treatment options, including possible keratectomy, were discussed with the patient at this time.

Figure 4.
Figure 4.:
Salzmann's-like nodules in the right eye in Case 2.
Figure 5.
Figure 5.:
Salzmann's-like nodules in the right eye in Case 2.

Two months later, the patient presented to the clinic with no subjective increase in VA. Examination revealed a UCVA of 20/30 in the right eye and 20/40−1 in the left eye. Manifest refractions were −0.75 +0.50 × 144 in the right eye and −1.00 +0.50 × 35 in the left eye, with BCVA of 20/20 in both eyes. Slitlamp examination revealed SPK and Salzmann's-like nodules bilaterally. The patient was offered the option of a superficial keratectomy at this time but refused the procedure.

Approximately 6 months later, manifest refraction revealed slightly increasing astigmatism in both eyes, with measurements of −0.75 +1.00 × 155 in the right eye and −1.00 +1.00 × 040 in the left eye, and declining BCVA of 20/25 in both eyes. Examination revealed no improvements in the Salzmann's-like nodules. The patient was instructed to continue using Refresh Endura, Refresh PM ointment, and flaxseed oil as tolerated. Although the simultaneous use of Endura and Restasis is not typically recommended, she was also prescribed Restasis drops twice a day because of her severe symptoms.

The patient was last seen 60 months post-LASIK. Ocular medications and manifest refractions were unchanged from her previously described visit, with UCVA of 20/50+1 in both eyes and BCVA of 20/25 in both eyes with manifest refraction of −2.00 +1.00 × 145 in the right eye and −1.75 +1.00 × 015 in the left eye. On examination, numerous nodules were noted bilaterally, with no regression of SPK bilaterally. A nodular biopsy was performed at this time. The epithelium overlying the corneal lesions appeared irregular in thickness, and Bowman's layer under the nodule was absent, with replacement by periodic acid-Schiff (PAS) positive, thickened basement membrane-like material. Underlying this basement membrane was a layer of relatively regular, hypocellular, collagen-like connective tissue that demonstrated hyalinization on trichrome staining (Figures 6 and 7). These findings are all consistent with those previously reported in Salzmann's nodular degeneration.

Figure 6.
Figure 6.:
Photomicrograph of the PAS-positive thickened basement membrane-like material replacing Bowman's layer in case 2 (original magnification ×20).
Figure 7.
Figure 7.:
Photomicrograph of subepithelial hyalinization demonstrated by trichrome staining in case 2 (original magnification ×20).

Over the course of 6 years, this patient developed a severe case of Salzmann's nodular degeneration bilaterally. Because of the patient's option to forego superficial keratectomy, the Salzmann's-like nodules and their associated astigmatism worsened over the next 8 months, leading to deterioration in visual acuity.


Salzmann's-like nodular degeneration appears as single to numerous bluish–white nodules in the peripheral and/or central cornea, characteristically elevated above the normal corneal surface.2,3,6 These nodules consist of collagen fibrils, hyalinization, and fibrocytes varying in number from none to many.1,2,5 The epithelium overlying these nodules is typically attenuated, often only composed of 1 cell layer.3,6 Bowman's membrane is often absent and replaced by scar tissue under these nodules,2 and reduplication of the basal lamina is often present as well.2,6 The histopathology in case 2 was consistent with that found in Salzmann's nodular degeneration.

Although the pathogenesis of Salzmann's nodular degeneration is not well understood, it seems to be related to chronic corneal irritiation.2 Vannas and coauthors2 concluded that the atrophic epithelium over the nodules in Salzmann's nodular degeneration is due to earlier inflammatory changes that lead to tear film changes, an uneven corneal surface, and corneal epithelial exposure. This long-term corneal irritation, which resulted in poor epithelial protection and damage, was determined to be an important factor in nodular development.5

Dry-eye symptoms are often seen in patients who have LASIK.7 Denervation of corneal sensory nerves occurs during LASIK procedures and has been proposed as a mechanism of dry-eye development following this procedure.8 The sensory innervation of the cornea, provided by the ophthalmic and maxillary branches of the trigeminal nerve,9 penetrates the limbus and forms nerve bundles in the anterior third of the stroma.10 These nerves then penetrate Bowman's layer and form the nerve plexus between the basal epithelial cells and Bowman's layer.10 Flap formation during LASIK spares the deepest stromal nerve bundles but produces a major loss of epithelial, subepithelial, and superficial stromal nerves in the cornea.11 This disruption results in a corneal anesthesia or hyposthesia that lasted up to 6 months in most studies.10,12 This denervation of corneal sensory nerves has been proposed as a major driving mechanism for the development of dry eyes following LASIK.10 It has been hypothesized that tear secretion is derived from a reflex mediated by corneal sensitivity.13,14 This decreased sensitivity could result in hyposecretion of tears.13,14 Reduced corneal sensation also reduces blink rate, which leads to dry eyes.15 Furthermore, the Dellen effect, which refers to a decrease in congruity between the posterior eyelid and anterior surface of the cornea after flattening during LASIK, may be an additional factor.16 Based on the 2 cases presented here, it seems possible that this hyposecretion of tears, decrease in blink rate, and Dellen effect could generate the corneal irritation needed to induce Salzmann's nodular degeneration by stimulating stromal keratocyte overrepair and nodule formation.2 It is possible, however, that these 2 patients had a predisposition to develop Salzmann's nodular degeneration. These nodules, therefore, could have been stimulated by the LASIK procedure rather than a resultant hyposecretion of tears.


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