Dendritiform Keratopathy Associated withExposure to Polyquarternium-1, a CommonOphthalmic Preservative

Alice Y. Matoba, MD,1 Jeff R. Peterson, MD,2 Kirk R. Wilhelmus, MD, PhD1

Purpose: To describe dendritiform keratopathy associated with exposure to polyquaternium-1, a commonpreservative found in contact lens solutions and tear replacement products.

Design: Case series.Participants: Sixteen patients who demonstrated dendritiform keratopathy during topical ophthalmic

exposure to polyquaternium-1.Methods: Records were reviewed of all patients diagnosed with dendritiform keratopathy between 1999

and 2014 who had documented exposure to contact lens care disinfecting solutions or artificial tear solutionscontaining polyquaternium-1. Patients were excluded who had coexisting potential causes for dendritiformkeratopathy, such as prior herpes simplex keratitis, varicella-zoster viral keratitis, the linear form of Thygeson’ssuperficial keratitis, epithelial regeneration line, Acanthamoeba keratitis, mucus plaque keratopathy,medication-related keratopathy, or limbal stem cell deficiency characterized by conjunctivalization of thecorneal epithelium.

Main Outcome Measures: Effect of discontinuation of exposure to polyquaternium-1 on the dendritiformkeratopathy.

Results: Sixteen patients demonstrated dendritiform keratopathy after exposure to the preservativepolyquaternium-1. Thirteen patients had a history of recent exposure to contact lens disinfecting solutions(Opti-Free, Equate) containing polyquaternium-1. Three patients used a tear replacement product (Systane)containing a polyquaternium-1 preservative. Four patients were treated with antiviral medications for pre-sumed herpes simplex keratitis; 4 patients underwent diagnostic testing for Acanthamoeba keratitis. Twoadditional patients were diagnosed sequentially with herpes simplex keratitis, then Acanthamoeba keratitisbefore referral. All dendritiform lesions resolved within 2 to 6 weeks after elimination of exposure to poly-quaternium-1.

Conclusions: Ophthalmic products containing polyquaternium-1 may cause dendritiform keratopathy thatmay be confused with infections of the superficial cornea, such as herpes simplex virus keratitis or Acanthamoebakeratitis. Ophthalmology 2016;123:451-456 ª 2016 by the American Academy of Ophthalmology.

Polyquaternium-1 (Polyquad) is a polycationic preserva-tive that was introduced in the United States first in 1985 asa disinfecting agent for soft contact lenses.1 Polyquad wasmarketed first in Opti-Soft and subsequently reformulatedinto Opti-Free (Opti-Free Express and Opti-Free Pure-moist) contact lens care products at a concentration of0.001%. The same concentration of polyquaternium-1 alsois used in the artificial tear product Systane (Systane andSystane Balance). In the past, it was also found in Equate,the Walmart contact lens care solution; however, the cur-rent formulation for Equate no longer containspolyquaternium-1. During a 15-year observation period,we identified 16 patients in whom dendritiform keratop-athy developed in association with the use of Opti-Free orEquate contact lens care products or Systane tear replace-ment products. To our knowledge, this is the first report ofthe association of dendritiform keratopathy with the pre-servative polyquaternium-1.

� 2016 by the American Academy of OphthalmologyPublished by Elsevier Inc.

Methods

Records were reviewed of all patients diagnosed with dendritiformkeratopathy between 1999 and 2014 who had documented exposureto contact lens care disinfecting solutions or artificial tear solutionscontaining polyquaternium-1. Patients were excluded who hadcoexisting potential causes for dendritiform keratopathy, such as priorherpes simplex keratitis, varicella zoster viral keratitis, the linear formof Thygeson’s superficial keratitis, epithelial regeneration line,Acanthamoeba keratitis, mucus plaque keratopathy, or medication-related keratopathy. For contact lens-related polyquaternium-1 ker-atopathy, patients with clinical limbal stem cell deficiency (LSCD),characterized by conjunctivalization of the cornea, were excluded.Institutional review board or ethics committee approval was obtained.

Results

During a 15-year period, 16 patients were identified with den-dritiform keratopathy in association with the use of Opti-Free or

451http://dx.doi.org/10.1016/j.ophtha.2015.10.063ISSN 0161-6420/15

Table 1. Patient Characteristics

PatientNo.

Age(yrs) Gender

Unilateral orBilateralDisease Solution

Daily or ExtendedWearing Schedule

Duration ofExposure

Misdiagnosis of HerpesSimplex Virus or

Acanthamoeba Keratitis

Time toResolution

(wks)

1 60 F Bilateral Opti-Free, Systane Daily 6 mos 22 17 F Bilateral Opti-Free Daily Unknown Acanthamoeba keratitis 33 20 F Bilateral Opti-Free Daily 4 mos 64 35 F Bilateral Opti-Free Daily 4 mos Both 65 76 M Unilateral Systane e 3 mos 26 27 F Unilateral Opti-Free Daily 2 mos 37 28 F Bilateral Opti-Free Daily Unknown 38 16 F Bilateral Opti-Free Extended Unknown Acanthamoeba keratitis 39 37 F Bilateral Opti-Free Daily Unknown 510 22 F Bilateral Opti-Free Daily 3 yrs Herpes simplex virus 311 48 F Unilateral Equate Daily Unknown Herpes simplex virus 412 24 F Bilateral Opti-Free Daily 6 mos Acanthamoeba keratitis 213 57 F Bilateral Opti-Free Daily Unknown Both 414 61 F Unilateral Opti-Free, Systane Extended 2 yrs Herpes simplex virus 215 85 F Unilateral Systane e Unknown 416 65 M Unilateral Systane e Unknown 4

F ¼ female; M ¼ male.

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Equate contact lens care products or with Systane tear replacementproducts (Table 1). Six cases were unilateral and 10 were bilateral.Eight patients with contact lens-related keratopathy had begunusing lens care products containing polyquaternium-1 from 2 to 36months before the onset of symptoms. In 8 patients, the exposureduration was unknown. All 3 with Systane-associated keratopathyhad pre-existing ocular surface disease: 2 patients had tear defi-ciency, and 1 patient had completed topical mitomycin therapy forcorneal intraepithelial neoplasia 1 month before the diagnosis ofdendritiform keratopathy. One of the patients also used topicalbetaxolol 0.25% (preserved with benzalkonium chloride 0.001%).Rarely, the use of a topical b-blocker has been associated withdendritiform keratopathy.2 However in this case, the keratopathyresolved after discontinuation of only the Systane product whilecontinuing betaxolol. The dendritiform keratopathy had 3 mainforms: (1) branching, coarse epitheliopathy with tiny nodularcomponents scattered along the linear formation (Figs 1, 2, and8); (2) a primarily linear keratopathy with minor branching

Figure 1. Slit-lamp photograph showing bilateral dendritiform keratopathyin patient 2 associated with daily wear soft contact lens wear and Opti-Freecontact lens solution.

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(Figs 3, 4, and 9); and (3) whorl-like keratopathy (Figs 5, 7,and 10).

Case Reports

Patient 1. A 60-year-old woman was referred with a 1-monthhistory of irritation of the right eye. She had been wearing dailywear soft contact lenses (DWSCLs) and used an Opti-Free brandcontact lens solution for 6 months. The patient had been treatedwith prednisolone acetate 1% and Systane 4 times daily for 1week without improvement. Contact lens wear had been dis-continued for 2 weeks, but she continued to use Systane 4 timesdaily. Despite increase in the prednisolone regimen to 1 dropevery hour for 1 week, she had persistent irritation. On exami-nation, the conjunctiva was noninflamed. The superior cornea hada dendritiform lesion composed of thickened, gray epitheliumlocated just superior to the visual axis. The limbus was normal.The stroma had minimal haze. The lesion persisted despite

Figure 2. Slit-lamp photograph showing bilateral dendritiform keratopathyin patient 2 associated with daily wear soft contact lens wear and Opti-Freecontact lens solution.

Figure 3. Slit-lamp photograph showing bilateral linear keratopathy withminor branching in patient 3 associated with Opti-Free contact lenssolution.

Figure 5. Slit-lamp photograph showing dendritiform lesion associatedwith use of Opti-Free contact solution (patient 4).

Matoba et al � Dendritiform Keratopathy Associated with PQ-1

treatment with topical prednisolone; however, she continued touse Systane, which also contains polyquaternium-1. Afterdiscontinuation of Systane, the lesion resolved within 10 days.Contact lens wear was resumed using a different sterilizationproduct. With no recurrence of the keratopathy at the 1-monthvisit, she returned to the care of her referring physician with nofurther reports of problems.

Patient 2. A 17-year-old girl was referred with a 1-monthhistory of mild irritation of both eyes and blurring of the righteye. She wore DWSCLs and used Opti-Free contact lens solution.The patient had discontinued contact lens wear for 1 week andapplied Genteal artificial tears 3 times daily without improvement.On examination, the conjunctiva was noninflamed. The rightcornea had linear branching epithelial keratopathy with scatteredsmall subepithelial infiltrates (Fig 1). There were bead-like mucoidopacities scattered along the linear lesion. The left cornea had a lesspronounced epithelial keratopathy (Fig 2). Confocal microscopydid not reveal micro-organisms. Corneal scraping was not per-formed. The patient was treated 4 times daily with topical pred-nisolone acetate 1%, with marked improvement after 1 week andresolution after 3 weeks. There was no recurrence reported by herprimary ophthalmologist after resumption of contact lens wearusing a different sterilizing system.

Figure 4. Slit-lamp photograph showing bilateral linear keratopathy withminor branching in patient 3 associated with Opti-Free contact lenssolution.

Patient 3. A 20-year-old woman had worn DWSCLs for 4years. Four months before her visit, she switched from a ReNucontact lens solution to an Opti-Free solution. One month beforeher visit, scars in both corneas were first noted. She discontinuedregular contact lens wear and used prednisolone acetate 1% twicedaily, but continued to wear contact lenses on occasion. She re-ported persistent mild blurring of vision. Best-corrected visualacuity was 20/30 in the right eye and 20/20 in the left eye. Bothcorneas showed linear, slightly branching, grayish, thickenedepithelium and scattered tiny subepithelial infiltrates (Figs 3 and 4).The superior limbus showed bilateral mild neovascularization. Thepatient was advised to avoid contact lens wear completely. Twoweeks later, the dendritiform lesions had resolved, but both eyeshad a few scattered subepithelial infiltrates. The patient resumedcontact lens wear with Complete contact lens solution with nofurther problems during 1 year of follow-up.

Patient 4. A 35-year-old woman was referred with a diagnosisof possible Acanthamoeba keratitis. She had worn DWSCLs for 20years. She had switched from ReNu to Opti-Free contact lens so-lution 4 months before her visit. Two months before her visit,bilateral corneal lesions were noted that were diagnosed as herpessimplex keratitis and were treated with topical ganciclovir in botheyes. Contact lens wear was discontinued temporarily. The lesions

Figure 6. Slit-lamp photograph showing resolution of dendritiform lesionwith change in contact lens solution, but continued contact lens wear(patient 4).

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Figure 7. Slit-lamp photograph showing dendritiform keratopathy associ-ated with use of Systane tear replacement (patient 5).

Figure 9. Slit-lamp photograph showing linear keratopathy with minorbranching similar to patient 9 in Table 1 and similar to patient 3.

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resolved in the left eye, but persisted in the right eye. She reportedwearing her contact lenses on occasion during this period. Visualacuity was 20/25 in the right eye and 20/40 in the left eye. Theright eye showed a central dendritiform epithelial lesion (Fig 5)with mild subepithelial haze. The left eye showed scatteredepithelial granular changes. A diagnosis of dendritiformkeratopathy associated with polyquaternium-1 was made. The pa-tient was asked to avoid contact lens wear completely, but shedeclined. She had high myopia and stated that her spectacles didnot provide adequate vision. She continued contact lens wear, butchanged her contact lenses and lens solution. She continued contactlens wear, using ReNu solution. One month later, the dendritiformlesion had resolved (Fig 6). There was no recurrence at the9-month follow-up.

Patient 5. A 76-year-old man with a history of dry eyesymptoms had used topical tear replacement products 4 to 6 timesdaily for several years without incident. Three months afterswitching to Systane Balance 6 times daily in both eyes, he notedbilateral irritation. On examination, the right cornea had scatteredpunctate epitheliopathy. The left cornea had dendritiform kerat-opathy (Fig 7). The patient was instructed to discontinue Systaneand to use nonpreserved artificial tears. Two weeks later, theepitheliopathy had improved in the right eye and the dendrite

Figure 8. Slit-lamp photograph showing coarse linear dendritiform kerat-opathy with a nodular component (Table 1, patient 7) similar to patient 2(Figs 1 and 2).

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had resolved in the left eye. During 9 months of follow-up, norecurrence took place.

Discussion

Dendritiform corneal lesions rarely are associated withpreservative exposure. In the 1980s, the mercuric preser-vative thimerosal was implicated in the development ofocular surface inflammation.3,4 Associated findings includedfollicular conjunctivitis, small corneal infiltrates, superiorlimbic keratoconjunctivitis, and rarely, dendritiform corneallesions.3,4 An immunologically mediated mechanism waspostulated because in some cases, sensitization wasdemonstrated by ocular challenge or patch testing.4

Thimerosal was removed from most ocular products toavoid delayed hypersensitivity reactions.5

The pathogenesis of the corneal epithelial lesions associatedwith polyquaternium-1 exposure is not known.Polyquaternium-1 is a polymeric quaternary ammonium anti-microbial agent that was developed as an alternative to ben-zalkonium chloride (BAK), the monoquaternary ammonium

Figure 10. Slit-lamp photograph showing dendritiform keratopathy withwhorl-like appearance in Table 1, similar to patients 4 and 5.

Matoba et al � Dendritiform Keratopathy Associated with PQ-1

compound that is the most commonly used preservative intopical ophthalmic medications.6 Polyquaternium-1 has beenshown to be less toxic to human corneal epithelial cells7,8 andbetter tolerated clinically9,10 than BAK. A review of the liter-ature did not reveal an association of polyquaternium-1 withocular hypersensitivity reactions, although polyquaternium-7and quaternium-15 are reported to cause contact dermatitisrarely.11,12 Although generally less cytotoxic than BAK,polyquaternium-1 may produce more inflammation than BAKvia activation of nuclear factor k B under some conditions.13

Components of lens care products other thanpolyquaternium-1, such as myristamidopropyl dimethyl-amine in Opti-Free, could have contributed to the epitheli-opathy. No sensitivity testing or provocative testing withpolyquaternium-1 was performed. However, the keratop-athy was documented with several different products con-taining polyquaternium-1, including Opti-Free, Equate, andSystane products. For each patient, resolution occurred onlyafter discontinuation of topical ocular products for which thecommon component was polyquaternium-1. In patient 1, thekeratopathy developed while the patient was using Opti-Free and Systane and persisted after discontinuation ofcontact lens wear and institution of topical corticosteroidtherapy. The keratitis resolved only after Systane also wasdiscontinued. Patient 3 demonstrated dendritiform keratop-athy after switching from ReNu to an Opti-Free contact lenssolution. As soon as contact with Opti-Free was dis-continued completely, the lesion resolved. It did not recurafter resumption of contact lens wear using a differentcontact lens solution during 1 year of follow-up. Patient 4demonstrated keratopathy 2 months after switching to anOpti-Free solution. The lesion resolved 1 month after Opti-Free was discontinued, although she continued to wear hercontact lenses. This case suggests that the inciting factor inthe development of the dendritiform keratopathy was theexposure to polyquaternium-1, rather than the contact lenswear.

The differential diagnosis of dendritiform corneal surfacelesions includes herpes simplex viral keratitis, varicellazoster viral keratitis, Thygeson’s superficial punctuatekeratitis, epithelial healing line, Acanthamoeba keratitis,mucus plaque keratopathy, medication-related keratopathy,thimerosal exposure, and LSCD. In the setting of contactlens wear, LSCD is an important consideration. Recent re-views of contact lens-associated LSCD14e16 all describeLSCD as being characterized by conjunctivalization of thecorneal epithelium. Thus, conjunctival epithelium that isthickened, grayish or opaque, often accompanied by neo-vascularization, emanated from the limbus onto the cornea.Although neovascularization of the superior limbus wasdocumented in some of our contact lens patients, none hadconjunctivalization of the corneal epithelium. Kim et al,14

Chan and Holland,15 and Jeng et al16 mention “whorl-like” epitheliopathy; however, the term refers toepithelium located at or near the advancing edge of theconjunctivalization phenomenon, rather than isolateddendritiform lesions in the mid cornea.

It is likely that, in patients wearing contact lenses, limbalstem cell stress exists in a continuum with prolonged orsevere stress leading to clinically overt LSCD and mild or

short-term stress leading to more self-limited clinical find-ings. It is possible that limbal stem cell stress is a contrib-uting factor in contact lens-related dendritiform keratopathy.However, clinically, the keratopathy associated with contactlens wear and polyquaternium-1 exposure can manifestwithout overt LSCD.

The coarse, gray, elevated nature of the lesion, withsurrounding coarse epitheliopathy and lack of epithelialerosion, should help to differentiate the keratopathy asso-ciated with polyquaternium-1 from infectious entities.However, 4 patients initially were treated for herpes simplexviral keratitis and 4 patients underwent either cornealscraping or confocal microscopy testing for Acanthamoebakeratitis. Two additional patients were diagnosed sequen-tially with herpes simplex keratitis, then Acanthamoebakeratitis, before referral. Polyquaternium-1 exposure withthe use of Opti-Free contact lens solutions and the use ofSystane tear replacement products in patients with ocularsurface disease should be considered in the differentialdiagnosis of course, linear, and dendritiform keratopathy.

References

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Footnotes and Financial Disclosures

Originally received: June 25, 2015.Final revision: October 9, 2015.Accepted: October 28, 2015.Available online: December 11, 2015. Manuscript no. 2015-1061.1 Department of Ophthalmology, Baylor College of Medicine, Houston,Texas.2 Department of Ophthalmology and Visual Science, University of TexasHealth Science Center, Houston, Texas.

Financial Disclosure(s):The author(s) have no proprietary or commercial interest in any materialsdiscussed in this article.

Supported by an unrestricted grant from the Research to Prevent BlindnessFoundation, New York, New York.

Author Contributions:

Conception and design: Matoba, Wilhelmus

Analysis and interpretation: Matoba

Data collection: Matoba, Peterson

Obtained funding: none

Overall responsibility: Matoba, Wilhelmus

Abbreviations and Acronyms:BAK ¼ benzalkonium chloride; DWSCLs ¼ daily wear soft contact len-ses; LSCD ¼ limbal stem cell deficiency.

Correspondence:Alice Y. Matoba, MD, Cullen Eye Institute, Baylor College of Medicine,6565 Fannin Street, NC-205, Houston, TX 77030. E-mail: amatoba@bcm.edu.