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Contact Lens & Anterior Eye 34 (2011) 173–178

Contents lists available at ScienceDirect

Contact Lens & Anterior Eye

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alzmann’s nodular corneal degeneration (SNCD): Clinical findings,isk factors, prognosis and the role of previous contact lens wear

amer Hamada ∗, Kanupriya Darrad, Peter J. McDonnellirmingham and Midland Eye Centre, City Hospital, Dudley Road, Birmingham B187QH, UK

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eywords:alzmann’sodularegenerationoft contact lensrognosisisk factors

a b s t r a c t

Purpose: To revisit the clinical presentations of Salzmann’s nodular corneal degeneration (SNCD) and toidentify risk factors, occurrence and prognosis, and in particular to assess the role of previous contactlens wear as an aetiological factor.Methods: Retrospective case note review of all cases of Salzmann’s nodular degeneration over the lasttwenty years. We analysed epidemiological features, characteristics of lesions, risk factors and finaloutcomes.Results: Thirty eyes (19 patients) were identified with SCND. Eleven patients had bilateral disease. Ourcohort included 14 female (73.7%) and 5 males (26.3%). Average age at presentation was 58.9 (range30–75) years. Follow up range was 0–13 years. The most common presenting symptom was foreignbody sensation (68.4%). Ocular pathologies were: dry eyes (56%), chronic blepharitis (32%), trichiasis(8%), trachoma (32%), previous ocular trauma (8%), and previous ocular surgery (21.4%). Sixteen percentof cases were soft monthly disposable contact lens wearers. None of our patients with rigid contactlens wear developed Salzmann’s nodules. Surgical excision was needed in 4 cases (13.3%). Two of themdeveloped recurrent disease.

Conclusion: Salzmann’s nodular corneal degeneration is a disorder affecting middle-aged white womenpredominantly, and seems to be associated with concomitant chronic MGD, dry ocular surface, softcontact lens wear and previous ocular surgery. The prognosis is very good, and most patients are “suc-cessfully” treated with medical management alone, and therefore correct diagnosis of the disease isparamount. If indicated, various surgical options are available and give good outcomes. However, Salz-mann’s nodules can recur after penetrating keratoplasty.

Britis

© 2011

. Introduction

Salzmann’s nodular corneal degeneration (SNCD) is a worldwideccurring, relatively rare, non-inflammatory, slowly progressiveisease originally described by Maximilian Salzmann in 1925 [1].owever, Ernst Fuchs may have made the initial case observation

n 1901 [2].SNCD is classically described as bluish-greyish nodular corneal

pacities of various sizes (mostly 1–3 mm) occurring in isolationr in multiple numbers anywhere on the cornea (Fig. 1(a–b)).alzmann’s nodules can occasionally take up fluorescein stainingFig. 2). Histopathological findings involve thinning or denudationf the epithelium, destruction of Bowman’s layer, duplication of

he epithelial basement membrane and disorganisation of colla-en lamellae in the superficial anterior stroma. These histologicalndings are entirely non-specific and can be seen in scarring

∗ Corresponding author. Tel.: +44 (0) 7808174099.E-mail address: samerhamada@yahoo.com (S. Hamada).

367-0484/$ – see front matter © 2011 British Contact Lens Association. Published by Elsoi:10.1016/j.clae.2011.02.004

h Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

from any cause. The cause of the degeneration is uncertain andstill debated upon [3], but associations with chronic ocular irri-tation and inflammation have been made. It may be idiopathic;however it is often associated with pre-existing corneal disease.SNCD has been associated with trachoma, interstitial keratitis, ver-nal keratoconjunctivitis, phlyctenular keratoconjunctivitis, oculartrauma, corneal exposure, measles, scarlet fever, and previous ocu-lar surgery. The purpose of this study is to revisit the clinicalpresentations of SNCD and to identify risk factors, occurrence andprognosis. In particular, the role of previous contact lens wear inthe development of SNCD will be investigated.

2. Patients and methods

Retrospective case note review of all cases of Salzmann’s nodular

degeneration that we have identified in our centre (Birming-ham and Midland Eye Centre) over the last twenty years (March1990–April 2010). We analysed epidemiological features, charac-teristics of lesions, risk factors and final outcomes.

evier Ltd. All rights reserved.

174 S. Hamada et al. / Contact Lens & An

Fig. 1. (a–b) Salzmann’s nodules appear as bluish-white nodules raised above thesurface of the cornea. It can be single, multiple (separated or confluent).

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As the majority of the patients in our study were middle aged

Fig. 2. Cobalt blue light shows fluorescence staining of Salzmann’s nodules.

. Results

Thirty eyes (19 patients) were identified with the clinical diag-osis of Salzmann’s nodular degeneration. Our cohort included 14

terior Eye 34 (2011) 173–178

females (73.7%) and 5 males (26.3%). Average age at presentationwas 58.9 (range 30–75) years. Follow up period varied accordingto initial presentation, severity, and progression of the disease;and ranged from 0 to13 years. More than half of patients werewhite Caucasian (11/19). The remaining were Asian (7/19) andAfro-Caribbean (1/19). Demographical data are summarised andcompared with other studies in Table 1.

Eleven patients had bilateral disease. Salzmann’s nodule dis-tribution varied among patients. All eyes had peripheral cornealnodules. 10% of all eyes had lesions in the central cornea involvingvisual axis. We looked at the distribution of corneal lesions, whichwere as follows: super-nasal quadrant 28.2%, super-temporalquadrant 23%, infra-nasal quadrant 20.5%, infra-temporal quadrant17.9%, and central cornea 10.3%. All of which were not statisticallysignificant (Table 1). Central corneal nodules were seen in the eyesof Asian females who also showed signs of ocular surface trachoma.These females had both eyes affected with SCND but only one eyemanifested Salzmann nodules in the central cornea.

Peripheral corneal vascularisation (360◦) was seen in onepatient (two eyes) who had bilateral disease and a history of bilat-eral penetrating keratoplasties. Penetrating keratoplasties wereperformed to treat severe corneal scarring from herpes simplexkeratitis.

The majority of patients (68.4%) complained of foreign body sen-sation. Other symptoms included “white spots on cornea” (5.3%)and reduced vision (5.3%). However, 15.8% were asymptomatic andreferred by their optometrist to exclude the presence of treatablecorneal disease (Table 1).

We looked at other ocular pathologies that were documentedat the time of first presentation and these included: dry eyes (56%),chronic blepharitis (32%), trichiasis (8%), trachoma (32%), previousocular trauma (8%), previous ocular surgery (21.4%) of which 8%were post pterygium surgery (Table 1). We identified that 16% ofcases were soft monthly disposable contact lens wearers but theyhad no other ocular pathology. None of our patients with rigidcontact lens wear developed Salzmann’s nodules.

Management of SNCD involved: ocular lubrication (66%), topicalanti-inflammatory (33%) mainly Prednisolone 0.5% eye drops, andsurgical excision in 4 cases (13.3%). Two underwent penetratingkeratoplasties, one had simple surgical excision, and one had ante-rior lamellar keratoplasty. The disease has recurred in two patients(2 eyes), both had penetrating keratoplasty. Finally, we reportedfinal visual outcomes i.e. visual acuities measured at last hospitalvisit: 21 eyes ≥ 6/9, 1 eye = 6/12, and 4 eyes ≤ 6/36 (all trachomacases). No visual acuities data at last visit for 4 eyes.

4. Discussion

Originally Salzmann described 23 patients with bluish-whitecorneal lesions, 18 of whom were females [1]. Later studies by Farjoet al. and Graue-Hernandez et al. [2,3] supported Salzmann obser-vations that SNCD affect mainly middle aged females. Our cohortreflected the same trend; 73.7% of our patients were females andthe average age was 58.9 years (30–75).

Furthermore, our study showed a preponderance of SNCD toaffect the white population (57.9%). Graue-Hernandez reported themajority of his cases were white (76.1%) in a group where the totalwhite population was only 47.8% [3]. However he suggested thataccess to medical care may have been more readily available tocertain populations, which can introduce bias in the study sample.Therefore, more studies are needed to support these findings.

females and older males, and the commonest associations withSNCD were dry ocular surface (56%), chronic meibomian gland dys-function (MGD) 32%, it can be postulated that there may be an

S. Hamada et al. / Contact Lens & Anterior Eye 34 (2011) 173–178 175

Table 1Comparision of our results with those by Graue-Hernandez et al. [3] and Farjo et al. [2].

Variables Our study Graue-Hernandez et al. [3] Farjo et al. [2]

Gender Male: 26.3% Male: 27.8% Male: 11.8%Female: 73.7% Female: 72.2% Female: 89.2%

Bilateral disease (%) 57.9 66.7 63.4Mean age (years) 58.9 60.8 54.3Range of age (years) 30–75 13–92Follow up time range (months) 0–156 0–357 Not statedRace (%) White Caucasuian: 57.9 White Caucasian: 76.1

Asian (Indian): 36.8Afro-Caribbean: 5.2

Commonest symptoms at presentation Foreign body sensation: 68.4% Reduction in visual acuity: 30% Reduction in visual acuityAsymptomatic: 15.8%Reduction in visual acuity: 5.3%

Commonest ocular co-morbidities Dry eyes – 56% MGD – 41.7% MGD – 54.8%MGD – 32% Contact lens wear – 33.3%Trachoma – 32% Pterygium excision – 16%Contact lens wear – 16%Previous ocular surgery – 21.4%

Location of lesions Peripheral (90%) Visual axis involvement – 30%Peripheral and central (10%)(one eye in bilateral disease)

Peripheral corneal vascularization 6.6% (360◦ vascularisation) Not stated 31.2%Surgical treatment (PK or lamellar

keratoplasty)4/30 eyes 41/ 180 eyes 49/152 eyes

Indicators for surgery Reduction in vision and oculardiscomfort in all cases

Reduction in vision(commonest)

Reduction in vision (85.7%)Ocular discomfort (8.2%)Contact lens intolerance (6.1%)

Successful surgical outcome(improvement in visual acuity)

100% of patients withimprovement in visual acuity

90.2% of patients 79.2% of patients withimprovement in visual acuity

Recurrence of disease in 21.9%of patients

100% of patients with reducedocular discomfort

Visual acuities at last visit 4 < 6/36 (trachoma cases)1 = 6/1221 ≥ 6/94 Unknown

Lesions distribution Super-nasal quadrant 28.2%Super-temporal quadrant 23%

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Infra-nasal quadrant 20.5%Infra-temporal quadrant 17.9%Central cornea 10.3%

nfluence of changing levels of female and male sex hormones.ndrogen deficiency can lead to MGD and subsequent evaporativery eye and reduced tear production. This leads to poor epithelialrotection which as mentioned earlier is thought to be a promotingactor for SNCD [4,5].

.1. Clinical features

SNCD was bilateral in 57.9% of cases, with similar figuresescribed by Farjo et al. [2], and Graue- Hernandez [3]. All ourases had peripheral corneal nodules, of which three involvedhe visual axis (peripheral nodules (90%), peripheral and centralodules (10%)). This may explain why the commonest presentingomplaint in this study was of foreign body sensation (68.4%) aspposed to a decrease in visual acuity (5.3%), which was noted toe the commonest presentation in some other studies.

The association of peripheral corneal vascularisation and SNCDas explored in this study, however only 2 eyes (one patient) out

f 30 eyes with SNCD had peripheral vascularisation. This patientad chronic viral keratitis and a history of bilateral penetratingeratoplasties; therefore the original pathology could be respon-ible for the development of corneal vascularisation. Farjo [2] hademonstrated that 33.6% of eyes with SNCD had peripheral cornealascularisation but there is no mention of whether this associationas statistically significant. Recurrent corneal erosion is reported

o be a possible consequence of SNCD, however this has not beenbserved this in any of our patients [2].

The three most common ocular pathologies associated withNCD were dry eyes (56%), chronic blepharitis (32%), and trachoma

(32%). Blepharitis was the main ocular co-morbidity in studies byFarjo et al. and Graue-Hernandez et al. (54.8% and 41.7% respec-tively) [2,3].

Trachoma was the most common ocular co-morbidity in ournon-Caucasian group. The trachoma sub-group which comprisedpatients belonging to the South Asian race only, did show a ten-dency to have bilateral, central corneal, and recurrent disease. Allcases that needed surgery were among this group, and had poorfinal visual outcomes.

4.2. Formation of salzmann’s nodules

There is no uniform theory to explain how Salzmann’s nodulesare formed. Abbott and Forster [6] have postulated that hyalinedegeneration might be a precursor of the disease. Yoon and Park [7]have further described hyaline plaques between corneal epitheliumand Bowman’s layer. They suggest that histological findings are notdifferent from a degenerative pannus or an old corneal scar fol-lowing trauma or inflammation. However another possible theorysuggested by Yoon and Park which requires further investigationis one of an active immune process playing a role in the pathogen-esis of SNCD after detection of B and T Lymphocytes and MajorHistocompatibility Complex class II antigen in histopathalogicalexamination of corneal specimens [7]. Furthermore, an impor-tant promoting factor for SNCD is thought to be external irritation

because of poor epithelial protection. This provides the stimulus forthe overgrowth of fibroblasts, eventually leading to the formationof nodules. Chronic exposure to sunlight and environmental irri-tants can cause hyaline changes in the nodules by precipitation of

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round substance onto the collagen fibres [7–9]. Stone et al. haveescribed an increase in matrix metalloproteinase-2, sub epithe-

ial fibrosis, and disrupted Bowman’s membrane suggesting thathe nodules may result from longstanding epithelial remodellingnd wound repair [10]. This may support the findings in our studyhere the commonest associations with SNCD were blepharoker-

toconjunctivitis, dry ocular surface, and a history of contact lensear.

.3. Contact lenses wear and SNCD

We identified that 16% of cases were monthly disposable softontact lens wearers but had no other ocular pathology. None ofur patients with rigid contact lens wear developed Salzmann’sodules. Farjo et al. [2] reported that 33.3% of SNCD cases wereontact lens wearer. It is possible that the increase use of contactenses in population has highlighted contact lens wear as a risk fac-or for the development of SNCD, presumably as a result of constantL-related cornea irritation.

Contact lens wear has been associated with significant cornealpithelium thinning, lower levels of oxygen uptake, as well asncrease in corneal epithelial micro cysts, thinner stroma and anncrease in significant levels of daytime corneal oedema [11,12].

As suggested by Yoon and Park that poor corneal epithelial pro-ection can be a stimulus for the development of Salzmann nodules,t is important to highlight the effects of contact lens on the cornealpithelium which leads to poor epithelial protection. These factorsre:

1) Stem cell turnover: contact lens wear slows down stem cellturnover and thus reducing corneal epithelial renewal [13].

2) Corneal homeostasis: extended wear with all types of soft orrigid gas permeable lenses results in significant reduction inthe rate of exfoliation of central corneal epithelium. Combinedwith the suppression of epithelial cell proliferation, migra-tion, and a reduction of epithelial cell exfoliation, the cornealepithelial cell turnover is significantly slowed down in contactlens wear. These processes may be mediated by lens-inducedhypoxia. Another theory is suppression of apoptosis-driven celldeath seen in corneal epithelium after contact lens wear by theconstant expression of Bcl-2 at the corneal surface (an anti-apoptotic protein) [14].

3) Physical presence of contact lenses which lift the lid away fromthe cornea leading to poor tear film stability with subsequentdrying of the cornea. This is often exacerbated by incompleteblinking. A small amount of staining (at the 3- and 9-o’clockpositions) is benign, but persistent epithelial erosions can leadto dellen formation, neovascularisation, Salzmann-type ele-vated lesions, and pseudo-pterygium formation. In fact, SNCDseen in contact lens wearer were noted in the interpalpebralfissure. This type of punctate staining is alleviated by usinga larger lens, reducing edge lift with a thinner-edged lens orsteeper fit, or by refitting a lens that rests under the upperlid.

4) It has been postulated that Salzmann’s nodules appear in dryeye patients who wear contact lenses. Those patients often haveareas of localised drying that lead to Salzmann’s scarring [15].

Reduced corneal thickness and increased cornea surface irreg-larity occur after both soft and RGP contact lenses [16]. To ournowledge, SNCD has not been reported in rigid gas permeableRGP), or scleral contact lens wearers. We propose that RGP lenses

nduce less ocular surface inflammation and irritation.

Corneal punctate staining is seen more in soft lenses comparedith rigid lenses. Soft contact lens wearer with symptoms of mild

rritation or slightly decreased vision usually benefit from refitting

terior Eye 34 (2011) 173–178

with a higher water content or RGP lenses. Moreover, epithelialsplitting is a common finding in asymptomatic soft contact lenswearers. This finding often is overlooked on a routine examina-tion because it usually does not cause severe symptoms and maybe covered by the upper lid. The splits usually heal after the lenshas been removed for 24 h, and refitting with RGP lenses preventsrecurrence. Furthermore, contact lens induced superior limbal ker-atitis may be caused by excessive lens movement or sensitivity tothimerosal. The treatment consists of discontinuing contact lenswear until the epithelium returns to normal and the symptomsresolve. Refitting with better fitting lenses, using preservative-free solutions with a hydrogen peroxide disinfecting system, orswitching to rigid gas-permeable (RGP) contact lenses may per-mit a resumption of contact lens wear. Ichijima at al. found outthat epithelial barrier functions are more affected in soft contactlens wear compared to rigid gas permeable contact lenses wear[17].

Finally, the prevalence of neovascularisation is low with RGP orPMMA contact lenses, more common with daily wear soft contactlenses, higher with extended-wear soft contact lenses, and veryhigh with aphakic extended-wear lenses. Extended wear of RGPlenses usually induces less central oedema than extended wear ofsoft hydrogel contact lenses.

Confocal microscopy has helped to identify a novel type of stro-mal change which is chronic in nature, displaying highly reflectivepanstromal microdot deposits in the corneal stroma. This deposi-tion is more common with long-term wear of contact lenses andmore common with soft lenses than with RGP lenses [18].

4.4. Management

Recognition of this disorder is very important as it has a goodprognosis with conservative and surgical management. Manage-ment of underlying condition is an essential part of disease control,and this was part of our protocol plan in managing patients withSCND.

Symptoms related to SCND and progression of the conditionmay be helped by reducing or stopping contact lens wear, reviewingthe fit of the contact lenses, and by providing plentiful preservativefree ocular lubrication. As the condition stabilises and symptomsimprove, it may be possible to cautiously resume contact lens wearbut the patient should be carefully monitored for further prob-lems or progression. In some patients superficial keratectomy canbe helpful to remove very prominent and symptomatic lesions asdiscussed further below. The majority of our patients had non-symptomatic inflammation accompanying scarring that show afavourable response to medical management alone. Conservativemanagement consisted of eye lubrication, warm compresses, lidhygiene, topical steroids, and/or oral doxycycline. All patients wereinitially treated with ocular lubricants (preservative free). Topicalsteroids were needed occasionally to treat ocular surface inflam-mation when present.

Where nodules were raised, located on the central visual axis,or particularly symptomatic, conservative treatment failed to con-trol symptoms and therefore surgery was the next option (less than10% of cases). The simplest method is to peel off a nodule, whichis referred to as Salzmann nodulectomy (Graue-Hernández et al.).This is normally done in theatre under the microscope. Cornealepithelium is removed locally over the nodule and the nodule isthen easily peeled off with forceps. Alternatively, Superficial ker-atectomy, lamellar or penetrating keratoplasty can be performeddepending on the extent and depth of stromal involvement of the

corneal nodules [19]. Excimer laser (photo therapeutic keratectomyPTK) has been used to smoothen out the surface after removal ofSalzmann’s nodules [20–22]. As one would expect, PTK inducedmyopic shift [23,24]. In our series, four eyes needed surgical

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anagement. Indication for surgery was reduction in visual acu-ty and ocular discomfort despite being on medical treatment.ne eye had simple excision of lesions, another eye underwentnterior lamellar keraroplasty, and two eyes (trachoma cases)nderwent penetrating keratoplasties because of associated deeptromal opacity. Both cases had improvement in vision and relief ofcular discomfort post surgery. However, recurrence of SNCD hap-ened in two cases that had penetrating keratoplasties. These were

ater treated conservatively.Previous studies have shown that the most common reason to

rogress towards surgical management was disturbance in vision3,21,25]. As SNCD does not seem to consist of one clinical entity,n some cases elevated and pannus-like tissue can be manuallyeparated from the corneal surface leaving Bowman’s layer almostntouched. In these cases subsequent photo therapeutic keratec-omy (PTK) may not be necessary to smooth the surface [19]. Inther cases, deep defects are left in the Bowman’s layer and in theuperficial stroma after difficult mechanical removal of the nodules,hich then require multiple laser ablation procedures to acquire aomogenous surface. Cauterisation of the nodules is not advisables it may lead to corneal opacification.

Penetrating or lamellar Keratoplasty may be effective in caseshere the lesion extend to the mid-stroma. As patient normally hashealthy uninvolved endothelium, penetrating keratoplasty (PK) is

ig. 3. (a–b) Recurrent Salzmann’s nodules on corneal graft. This patient underwentenetrating keratoplasty for SNCD. She developed recurrent nodules soon after theurgery. Initially recurrent nodules were noted at graft–host interface; however,hese have later increased in number and size over time.

terior Eye 34 (2011) 173–178 177

generally not recommended, unless other concurrent pathologiesinvolve the deeper stroma and endothelium. The majority of Salz-mann’s nodules involve the superficial cornea; hence the preferredoption is Superficial Keratectomy, especially for sub epitheliallesions within visual axis or for mid peripheral lesions inducingastigmatism [19,21,25].

4.5. Recurrent SNCD

Recurrences have been reported several years after lamellar orpenetrating keratoplasty [26,27]. In our study, there were two casesof recurrent SNCD post PK where the nodules appeared on the junc-tion of the host and donor cornea (Fig. 3(a–b)). In one case recurrentcorneal nodules appeared as early as two months after the surgery.In addition to the original causes of Salzmann’s nodule formation,immune reaction in the graft can contribute to the recurrence ofSalzmann’s nodules [26]. Multifactorial processes lead to cornealsurface alterations, dryness, and development of epithelial defects,which may lead to scarring in Bowman’s membrane resulting ina flat opacity, eventually giving rise to characteristic nodules ofSalzmann’s degeneration afterwards.

Recurrence of SNCD may manifest long time after the initialsurgery because the underlying aetiology may still be presentdespite removal of nodules and elimination of ocular surface irri-tation or inflammation. Long term follow up results are needed toquantify the risk of disease recurrence. Controlling post-operativeocular inflammation is a key factor to reduce the risk of recurrentdisease. Yoon and Park described a case of SNCD where super-ficial keratectomy was performed in conjunction with amnioticmembrane graft in order to prevent inflammation, scarring, andvascularisation [2]. Whereas, Bowers et al. performed superficialkeratectomy with mitomycin-C (MMC 0.4 mg/ml) application andreported no recurrence of the disease in the follow up period28 ± 15 months [21]. Therefore, superficial keratectomy seems togive a stable, successful, predictable results as well as being aneconomical method of preventing and treating recurrence [19].Additional procedures can enhance results and reduce risk of dis-ease recurrence [7,21].

5. Conclusion

Salzmann’s nodular corneal degeneration is a disorder affect-ing middle-aged white women predominantly, and seems to beassociated with concomitant chronic MGD, dry ocular surface, softcontact lens wear and previous ocular surgery. The prognosis is verygood, and most patients are “successfully” treated with medicalmanagement alone, and therefore correct diagnosis of the disease isparamount. Surgical treatment results in good outcomes (improvedvisual acuity and relief of ocular irritation), however recurrence ispossible especially after penetrating keratoplasty. Further studieswith longer follow up times are required to determine the fre-quency of recurrence of the disease.

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