AIM: To review the clinical characteristics, diagnosis, and visual outcome in patients with non-contact

lensrelated Acanthamoeba keratitis and compare the findings with reported series of contact

lens associated Acanthamoeba keratitis. METHODS: Medical and microbiology records of 39

consecutive patients with a diagnosis of Acanthamoeba keratitis, at a tertiary eyecare centre in India

between January 1996 and June 1998, were analysed retrospectively. RESULTS: A majority of the

patients presented with poor visual acuity and large corneal stromal infiltrates (mean size 38.20 (SD

26. 18) mm). A predisposing factor was elicited in 19/39 (48.7%) patients (trauma 15, dirty water

splash three, leaf juice one). None of the patients had worn contact lenses. Most patients (26/39 (66.

6%)) came from a low socioeconomic background. Complaint of severe pain was not a significant

feature and radial keratoneuritis was seen in 1/39 (2.5%) patients. A ring infiltrate was present in

41.1% of cases. A clinical diagnosis of fungal keratitis was made in 45% of the patients before they

were seen by us. However, all patients were diagnosed microbiologically at our institute based on

demonstration of Acanthamoeba cysts in corneal scrapings (34/39) and/or culture of Acanthamoeba

(34/39). Treatment with biguanides (PHMB, 15/38 (39.4%), PHMB with CHx, 23/38 (60.5%), one patient

did not return for treatment) resulted in healing with scar formation in 27 out of 31(87.0%) followed up

patients (mean time to healing 106.9 days). Overall visual outcome was poor with no statistical

difference between cases diagnosed within 30 days (early) or 30 days after (late) start of symptoms.

The visual outcome in cases requiring tissue adhesive (five) and keratoplasty (three) was also poor.

CONCLUSIONS: This is thought to be the largest series of cases of Acanthamoeba keratitis in non-

contact lens wearers. In such cases, the disease is advanced at presentation in most patients,

pathognomonic clinical features are often not seen, disease progression is rapid, and visual outcome is

usually poor. Possible existence of Acanthamoeba pathotypes specifically associated with non-contact

lens keratitis and unique to certain geographical areas is suggested.

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Headnote

Abstract

Aim-To review the clinical characteristics, diagnosis, and visual outcome in patients with non-contact

lensrelated Acanthamoeba keratitis and compare the findings with reported series of contact

lensassociated Acanthamoeba keratitis.

Method-Medical and microbiology records of 39 consecutive patients with a diagnosis of

Acanthamoeba keratitis, at a tertiary eyecare centre in India between January 1996 and June 1998,

were analysed retrospectively.

Headnote

Results-A majority of the patients presented with poor visual acuity and large corneal stromal

infiltrates (mean size 38.20 (SD 26.18) mm). A predisposing factor was elicited in 19!39 (48.7%)

patients (trauma 15, dirty water splash three, leaf juice one). None of the patients had worn contact

lenses. Most patients (26!39 (66.6%)) came from a low socioeconomic background. Complaint of

severe pain was not a significant feature and radial keratoneuritis was seen in 1/39 (2.5%) patients. A

ring infiltrate was present in 41.1% of cases. A clinical diagnosis of fungal keratitis was made in 45% of

the patients before they were seen by us. However, all patients were diagnosed microbiologically at

our institute based on demonstration of Acanthamoeba cysts in corneal scrapings (34/ 39) and/or

culture of Acanthamoeba (34! 39). Treatment with biguanides (PHMB, 15!38 (39.4%), PHMB with CHx,

23/38 (60.5%), one patient did not return for treatment) resulted in healing with scar formation in 27

out of 31 (87.0%) followed up patients (mean time to healing 106.9 days). Overall visual outcome was

poor with no statistical difference between cases diagnosed within 30 days (early) or 30 days after

(late) start of symptoms. The visual outcome in cases requiring tissue adhesive (five) and keratoplasty

(three) was also poor.

Headnote

Conclusion-This is thought to be the largest series of cases of Acanthamoeba keratitis in non-contact

lenswearers. In such cases, the disease is advanced at presentation in most patients, pathognomonic

clinical features are often not seen, disease progression is rapid, and visual outcome is usually poor.

Possible existence of Acanthamoeba pathotypes specifically associated with non-contact lenskeratitis

and unique to certain geographical areas is suggested.

(Br J Ophthalmol 2000;84:1103-1108)

From a historical perspective Acanthamoeba keratitis has been described as a recent epidemic.1 It has

been recognised in almost all parts of the world.2-6 Evidence from several studies has suggested

soft contact lenswear as the greatest risk factor7 8 although some studies have reported the

development of Acanthamoeba keratitis in patients with no apparent predisposing factor.4 9 With most

of the literature focusing on contact lensrelated Acanthamoeba keratitis, ophthalmologists may

hesitate to diagnose this entity in patients without lenses. Chynn et al10 reported some of the

differences between contact lensand noncontact lensrelated Acanthamoeba keratitis in a small

number of patients. Mean time to diagnosis was significantly longer and visual outcome was

significantly lower in non-contact lensusers compared with those who wore contact lenses. The study

recommended the need for increased suspicion of Acanthamoeba keratitis in patients who did not

present with the obvious risk factor of contact lenses. On the basis of our experience, on a much larger

scale, with Acanthamoeba keratitis unrelated to contact lenswear, we support the above contention

and report in this study 39 cases of Acanthamoeba keratitis in non-contact lensusers. We present the

clinical characteristics, diagnostic methods, treatment schedules, and outcome in these cases and

discuss our findings in the context of reported series of Acanthamoeba keratitis in patients

using contact lenses.

Patients and methods

All patients treated for Acanthamoeba keratitis between January 1996 and June 1998 were included in

the study. The clinical and microbiology records were reviewed retrospectively. Information obtained

from the clinical records included age, sex, socioeconomic status, medical history including

predisposing risk factors, duration and type of symptoms, prior diagnosis and treatment, presenting

ocular findings, ocular treatment, and final visual outcome.

Laboratory data of all patients were sought from microbiology records. Results of smear examinations

of corneal scrapings which included Gram stain, Giemsa stain, and potassium hydroxide with calcofluor

white (KOH+CFV) stain were noted. Culture results indicating any significant growth of bacteria,

fungus, or Acanthamoeba were recorded along with the in vitro sensitivity test results. Cultures in all

cases had included a variety of media, such as sheep blood agar (aerobic, anaerobic), chocolate agar,

brain-heart infusion broth, thioglycollate broth, Sabouraud's dextrose agar, and non-nutrient agar with

Escherichia coli overlay, allowing for the growth of bacteria, fungus, or Acanthamoeba. Significance

was assigned to the bacterial or fungal growth if the same organism had grown in more than one

medium or a similar organism was seen in the smears of corneal scrapings. All organisms including

Acanthamoeba were identified using standard procedures.11

Once the diagnosis was established by microbiological investigation the treatment was started with

polyhexamethylene biguanide 0.02% (PHMB, Baquasil, ICI, USA) and/or chlorhexidine digluconate

0.02% (CHx, Sigma, C-9394) instilled half hourly to the affected eye day and night for 2-3 days (usually

as an inpatient) and then 1 hourly for a week. The frequency of instillation of the biguanides was

reduced to 3 or 4 hourly per day according to clinical response over subsequent weeks and continued

after resolution of inflammatory signs for 2-3 weeks. In 18 (46.1 %) cases Neosporin ointment

(neomycin, Dominion) was added at night. Concomitant bacterial infection was treated with

ciprofloxacin 0.3% eye drops and modified if required according to the sensitivity results from the

laboratory. Topical cycloplegics and oral analgesics were used in most cases. Steroids were not used in

any case.

For analysis, the patients were divided into two groups according to the time between the onset of

symptoms and diagnosis of Acanthamoeba keratitis (initiation of antiamoebic treatment). The "early"

category consisted of patients who were diagnosed within 1 month of onset of symptoms and the

remaining were labelled as "late".

Results

Over a span of 2 1/2 years, we treated 39 eyes of 39 patients with Acanthamoeba keratitis. Table 1

shows the demographic data of these patients. The laboratory data are listed in Table 2.

More males than females (23:16) were affected, though the difference was not significant (p =

0.2945). Mean age of patients was 36.8 years with a range of 18-70 years.

All except six patients had received ophthalmic attention before reporting to our cornea service and

were being treated for presumed bacterial, fungal, or viral keratitis based on clinical features. None

had been investigated microbiologically. The most common clinical suspicion was of fungal keratitis

( 15/33, 45.4%). Viral keratitis was suspected in only four cases. One patient was clinically suspected

to have Acanthamoeba keratitis and was receiving PHMB.

None of the patients in our series wore contact lenses. While 15 patients gave a history of definite

trauma with either vegetative matter, stone, or dust, three patients reported splashing unclean water

into the eyes along with trauma. In one patient, a suspected foreign body on the cornea was removed

with the tongue. The same patient used extract of some herbs in the eye before seeing a doctor who

treated her for bacterial keratitis. In 20 (51.2%) patients no definite risk factor could be elicited from

the history.

SIGNS AND SYMPTOMS

All patients presented to us with redness, watering, and decrease in vision. Ocular pain

disproportionate to the degree of keratitis was not noted for any of the patients. Various clinical signs

noted in our patients are shown in Table 3. Radial keratoneuritis, which has been described as specific

for the diagnosis of Acanthamoeba keratitis, was seen in only one patient. Anterior stromal infiltrates

were present in all patients except one in the late group who had a corneal scar with oedema. A ring

infiltrate was present in 41.1 % of the patients and was the presenting feature more often (45.8%) in

the early than the late group (33.3%). The difference was not statistically significant (p = 0.6617). Less

specific signs such as satellite stromal infiltrates, diffuse stromal infiltrates, and endothelial plaques

were seen in many of the patients with no significant difference between the early and late groups.

One patient in the early group presented with dendritiform epithelial lesion mimicking viral keratitis.

More than half of the patients (53.8%) had anterior chamber reaction with hypopyon ranging from

trace to 3.5 mm.

DIAGNOSIS

Diagnosis in all cases was based on the demonstration of Acanthamoeba cysts or trophozoites in

corneal scrapings by smear examination and/or culture. Twenty four of 39 (61.5%) patients were

diagnosed within a month (early) and 15 (38.5%) cases were diagnosed 1 month (late) after start of

symptoms. Twenty nine (74.3%) cases were positive for Acanthamoeba both on smear examination

and culture where as five each were detected either by culture or smear (Table 2). Among 34 smear

positive cases, KOH+CFW stain detected cysts in all cases. Fewer cases showed cysts in corneal

scrapings by Gram and Giemsa stain (26/34 (76.4%) and 23/34 (67.6%) respectively). Bacterial growth

along with Acanthamoeba was seen in five cases in the early group and four cases in late group. The

bacterial co-isolates were mainly low virulence organisms such as Staphylococcus epidermidis (6/9)

and Corynebacterium species (2/9). Staphylococcus aureus was isolated in one case.

TREATMENT OUTCOME

Anti-Acanthamoeba treatment with cationic antiseptics (PHMB and/or CHx) was initiated in all cases as

soon as the microbiological diagnosis was made. The therapeutic strategy and outcome in all patients

is shown in Figure

1. In 27 out of 31 patients followed up (87.0%) the corneal infiltrate resolved following medical

treatment in a mean time of 106.9 (9-281) days. Seven patients were lost to follow up, four of whom

were refused admission for financial reasons, and three patients left against medical advice after being

treated for 5-7 days. Post-treatment visual acuity was recorded in 14 early and 13 late cases. Visual

acuity before and after treatment in early and late cases is shown in Figure 2. Improvement in visual

acuity following treatment was seen in 35.7% (5/14) of early and 30.7% (4/13) of late cases (p=0.891).

Application of tissue adhesive (n-butyl cynoacrylate tissue adhesive) with bandage contact lenswas

performed in five cases (four in late, one in early) for extreme thinning or perforation less than 2 mm

in size. After prolonged medical therapy with PHMB and CHx (mean 88 days) the infiltrates resolved

with scarring and vascularisation in all. However, the final visual acuity remained poor (PL]PR three,

HM one, and 6/36 one). Paramedian tarsorrhaphy was performed for associated lagophthalmos in one

patient. Therapeutic penetrating keratoplasty (PK) was performed in three cases in the early group

owing to large infiltrate at the time of presentation which failed to respond even on intensive medical

therapy. The outcome of surgical excision however, was not encouraging. One patient required limbus

to limbus graft 7 days after presentation. The graft developed an infiltrate in the immediate

postoperative period followed by corneal perforation and pseudocornea formation. The graft failed in

the second patient, and in the third patient there was choroidal detachment with vitreous opacities

resulting ultimately in phthisis. Development of vitreous opacities and scleral involvement was noted

in one patient who ultimately required evisceration.

Discussion

Corneal ulceration is a major cause of monocular blindness in developing countries. A recent report

from this centre, in a well conducted survey of an urban population in south India, listed corneal

blindness as the third major cause of visual disability and blindness.12 Incidence of corneal ulcers in

south India has been estimated to be 11.3 per 10 000 population and has been referred to as a

blinding disease of epidemic proportions.13 Epidemiology and aetiology of corneal ulceration in south

India has already been published14 wherein 1% of culture positive cases were caused by

Acanthamoeba. The reported incidence of Acanthamoeba keratitis in India varies from 1-3% in various

published14 15 and unpublished series. Of note, barring single case reports in contact lenswearers,16

17 all reported cases are predominantly seen in non-contact lenswearers.1 14 15 While Sharma et al4

reported complete healing in four out of five adequately followed up cases (treated with

neosporin/miconazole/ ketoconazole) they did not comment on visual outcome. Likewise, none of the

other studies14 15 has dwelt on clinical features, treatment schedule, or visual outcome.

Consequently, such data are severely lacking from this part of the world.

On the other hand, some reports from the USA10 and the UK18 have described the disease in non-

contact lenswearers. While contributing significantly to the understanding of Acanthamoeba keratitis in

non-contact lenswearers, both these studies were encumbered by relatively small sample size. To the

best of our knowledge, the present study is the largest series of patients with non-contact lensrelated

Acanthamoeba keratitis.

Diagnosis of Acanthamoeba keratitis, based on clinical features, was made only in one out of 33

patients by physicians who had treated these patients before they were seen by us. The majority of

these patients (15/33(45.4%)) were treated as fungal keratitis which is different from what has been

reported for patients with contact lensrelated Acanthamoeba keratitis who generally undergo

treatment for herpes simplex keratitis before the microbiological diagnosis is made.19 The presence of

satellite stromal infiltrates and endothelial exudates in some of our patients points more towards

fungal aetiology. Additional reason for underdiagnosis of Acanthamoeba keratitis could have been the

relatively high incidence of fungal keratitis in India (50%),14 and lack of enough reports of

Acanthamoeba keratitis in noncontact lenswearers. Radial keratoneuritis, described as typical for

Acanthamoeba keratitis, was also uncommon in our patients. Visual loss in contrast with severe pain

was the predominant symptom in our series. Absence of complaints of pain disproportionate to clinical

features in our patients is probably related to absence of keratoneuritis. Although predilection of

Acanthamoeba to neural tissue has been demonstrated,20 it is possible that the same is not seen with

all species and pathotypes of Acanthamoeba.

Contact lenswear does not emerge as an important risk factor for Acanthamoeba keratitis in our

population. This can probably be attributed to the relatively few people who are exposed to contact

lenswear in this country. In 20/39 (51.2%) of the patients in this series a definite risk factor that led to

Acanthamoeba keratitis could not be elicited. In previously published reports of this entity in non-

contact lenswearers from India' and elsewhere,10 18 trauma and exposure to contaminated water

have been identified as major risk factors. Use of traditional eye medicine may be added as another

risk factor though this was reported in just one patient in this series. A recent study from south India

reported use of traditional eye medicine by 47.7% of patients with keratitis in a rural setting.21

However, the lone patient with Acanthamoeba keratitis in their series had not used any traditional

medicine. It is possible that some of our patients experienced events that were too trivial to

remember. The low socioeconomic background of our patients (26/39(66.6%)) may be a contributory

factor. The innocuous habit of splashing water into the eye following dust fall may not be remembered

by the patients and cannot be ruled out in our patients. On the other hand, it is also possible that

particularly virulent strains of Acanthamoeba adhere to and invade normal corneal epithelium, a

possibility suggested by the electron microscopy study of Neiderkorn et al22 which showed rigid host

specificity of A castellanii to intact Chinese hamster, pig, and human corneas in vitro.

In this series the diagnosis and initiation of treatment was delayed in 38.5% of patients by more than

30 days. This is in contrast with contact lensrelated Acanthamoeba keratitis. Radford et al18 reported

that diagnosis was established within 1 month in 89% of contact lensrelated cases. This delayed

diagnosis could have been because of lack of severe pain and low socioeconomic status of most of our

patients. Compared with Acanthamoeba keratitis in contact lenswearers, severe corneal features were

noted in our patients at presentation. The stromal infiltrates, even in early cases, varied in size from

11.9-88 mm (mean 38.3 (SI? 20.6) mm ). Large ulcer size and central location in 22/24 (91.6%)

patients in the early group and 13/15 (86.6%) in late group account for the overall poor visual outcome

in our patients. Though we found the final visual outcome better in cases diagnosed early than late,

the difference was not signifcant (p=0.891), which is in contrast to other studies which have shown a

significant difference.10 18 23 While Radford et al18 related the less assured visual outcome in

patients with no contact lenshistory to delayed diagnosis we believe that this is also related to the

presence of more severe disease in these patients. Wide variability in virulence among the strains of

Acanthamoeba in different geographical areas, as well as differences in host immune responses, may

contribute to the variability in clinical presentation. In the patients in this series, a rapid progression of

the corneal pathology leading to early and severe damage to corneal tissues is seen. This is in contrast

with slow progress of the disease in contact lensrelated keratitis where a marked stromal involvement

may not be obvious until 6 weeks or more.24 Though the host factors may have an important part to

play, variability among different strains can not be ruled out. Co-infection with bacteria may be

another explanation in this setting; however, in this series there were only nine (23%) cases with

mixed infection with bacteria.

Microbiological diagnosis in this series was satisfactory in majority of the patients with the organisms

being demonstrated in smears and cultures. In 32/34 cases the first scraping yielded a positive result

leaving only two requiring rescrapes. As reported earlier,25 KOH+CFW staining of corneal scrapings

proved to be the most rewarding of all methods for the diagnosis of Acanthamoeba keratitis. With

increased awareness and better diagnostic facilities in this part of the world, the incidence of

Acanthamoeba keratitis is likely to be reported more often in non-contact lenswearers which may

contrast with the decrease in the number of cases reported from developed countries.18

The final visual outcome, as measured by resolution of the infiltrate and healing of the ulcer, was

achieved in 27/31 (87.0%) patients with no significant difference between early and late cases. Use of

cationic antiseptics (PHMB and CHx) has resulted in a dramatic improvement in the clinical

management of Acanthamoeba keratitis. We used PHMB in 15/38 (39.4%) and CHx with PHMB in 23/38

(60.5%) patients. Neosporin was used only during sleeping hours in a limited number of patients which

may not have played a significant part in control of infection. Although combination therapy with PHMB

and propamidine has been reported earlier23 the choice of combination therapy with PHMB and CHx

was based on in vitro observation of low MCC (minimum cysticidal concentration) of PHMB and CHx

and the reported synergistic activity of both.26 The mean duration of treatment in our patients was

106.9 days which is comparable with the duration reported (135 days) forcontact lenswearers,18 23

thereby suggesting that though the clinical features were severe time taken to respond to medical

therapy was not unduly long. This also suggests that the susceptibility of Acanthamoeba to biguanides

in our series is similar to what has been reported from contact lenswearers.

Studies are taking place at our centre to determine susceptibility of Acanthamoeba isolates from non-

contact lenswearers to various antimicrobials and the results (unpublished) support this hypothesis.

Although the visual outcome was poor, a clinical resolution of infiltrate was obtained in majority of the

patients with a promise of good vision following optical corneal graft at a later stage. Increased

awareness may enable early and frequent recognition and proper management of this devastating

corneal disease in patients other than contact lenswearers.

Financial support: Hyderabad Eye Research Foundation, Hyderabad, India.

Footnote

1 Schaumberg DA, Snow KK, Dana MR. The epidemic of Acanthamoeba keratitis: where do we stand?

Cornea 1998;17:3-10.

2 Radford CF, Bacon AS, Dan jKG, et al. Risk factors far Acanthamoeba keratitis in contact lensusers: a

casecontrol study. BM$ 1995;310:1567-70.

3 Kamel AB, Norazah A. First case of Acanthamoeba keratitis in Malaysia. Trans R Soc Trop Med Hyg

1995;89:652,

4 Sharma S, Srinivasan M, George C. Acanthamoeba keratitis in non-contact lenswearers. Arch

Ophthalmol 1990;108: 676-8.

Footnote

5 Tay-kearney ML, McGhee CN, Crawford GJ, et al. Acanthamoeba keratitis: a masquerade of

presentation in six cases. Aust NZ3` Ophthalmol 1993;21:237-44.

6 Stehr-Green JK, Bailey TM, Visvesvara GS. The epidemiology of Acanthamoeba keratitis in the United

States. Am J Ophthalmol 1989;107:331-6.

7 Stehr-Green JK, Bailey TM, Brandt FH, et al. Acanthamoeba keratitis in soft contact lenswearers. A

case control study. LAMA 1987;258:57-60.

8 Buehler PO, Schein OD, Stamler JF, et al. The increased risk of ulcerative keratitis among disposable

softcontact lensusers. Arch Ophthalmol 1992;110:1555-8.

9 Auran JD, Starr MB, Jakobiec FA. Acanthamoeba keratitis: a review of the literature. Cornea 1987;6:2-

26.

10 Chynn EW, Lopez MA, Pavan-Langston D, et al. Acanthamoeba keratitis. Contact lensand

non contact lenscharacteristics. Ophthalmology 1995;102:1369-73.

11 Murray PR, Baron EJ, Pfaller MA, et al. Manual of clinical microbiology. 6th ed. Washington DC; ASM

Press, 1995.

12 Dandona L, Dandona R, Naduvilath TJ, et al. Is current eye-care-policy focus almost exclusively on

cataract adequate to deal with blindness in India? Lancet 1998;351: 1312-16.

13 Whitcher JP, Srinivasan M. Corneal ulceration in the developing world-a silent epidemic. Br a

Ophthalmol 1997;81: 622-3.

Footnote

14 Srinivasan M, Gonzales CA, George C, et at. Epidemiology and aetiological diagnosis of corneal

ulceration in Madurai, South India. Br3' Ophthalmol 1997;81:965-71.

15 Davamani F, Gnanaselvam J, Anandakarman K, et al. Studies on the prevalence of Acanthamoeba

keratitis in and around Chennai. Ind 3 Med Microbiol 1998;16:152-3.

16 Singh S, Sachdeva MPS. Acanthamoeba keratitis. BMJ 1994;309:273.

17 Srinivasan M, Channa P, Raju CV, et al. Acanthamoeba keratitis in hard contact lenswearer.

Indian ]` Ophthalmol 1993;41:187-8.

18 Radford CF, Lehmann O, Dart JKG. Acanthamoeba keratitis: multicentre survey in England 1992-6.

Brt` Ophthalmol 1998;82:1387-92.

19 Lindquist TD. Treatment of Acanthamoeba keratitis. Cornea 1998;17:11-16.

20 Pettit DAD, Williamson J, Cabrol GA, et al. In vitro destruction of nerve cell cultures by

Acanthamoeba spp. J parasitol 1996;82:769-77.

21 Prajna NV, Pillar MR, Manimegalai TK, ez al. Use of traditional eye medicines by corneal ulcer

patients presenting to a hospital in South India. Indian 3 Ophthalmol 1999; 47:15-18.

22 Niederkorn JY, Ubelaker JE, McCulley JP, et al. Susceptibility of corneas from various animal species

to in vitro binding and invasion by Acanthamoeba castellani. Invest Ophthalmol Vis Sci 1992;33:104-

12.

Footnote

23 Duguid IGM, Dart JKG, Morlet N, et al. Outcome of Acanthamoeba keratitis treated with

polyhexamethyl biguanide and propamidine. Ophthalmology 1997;104: 1587-92.

24 Illingworth CD, Cook SD. Acanthamoeba keratitis. Surv Ophthalmol 1998;42:493-508.

Footnote

25 Wilhelmus KR, Osato MS, Font RL, et al. Rapid diagnosis of Aacanthamoeba keratitis using

calcofluor white. Arch Ophthalmol 1986;104:1309-12.

26 Angel JT; Gabriel MM, Wilson LA, et al. Effect of polyhexamethylene biguanide and chlorhexidine on

four species of Acanthamoeba in vitro. Curr Eye Res 1996;15:225-8.

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The effect of senofilcon A contact lenses compared to habitual contact lenses on ocular discomfort during exposure to a controlled adverse environmentOusler, George W, III; Anderson, Russell T; Osborn, Kathrine E. Current Medical Research and Opinion 24.   2  (Feb 2008): 335-41.

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OBJECTIVE: Contact lens wear is often associated with signs and symptoms of ocular dryness. These

drying effects can be exacerbated by certain environmental factors such as low humidity, wind, and

visual tasks. The objective of the study was to compare the ability of senofilcon A contact lenses to

subjects' habitual contact lenses to provide relief from the subjects' perceived ocular discomfort

during contact lens wear in adverse environmental conditions. RESEARCH DESIGN AND METHODS:

Eleven subjects completed a single-center, double-masked, randomized, cross-over, pilot clinical trial.

At the qualification visit, and subsequently wearing senofilcon A study lenses (ACUVUE OASYS

Brand Contact Lenses with HYDRACLEAR Plus) and control (habitual) lenses at the following visits,

subjects underwent a total of three 75-min Controlled Adverse Environment (CAE) exposures. The

primary efficacy variable measured during the 2-week, 3-visit trial was subject-reported ocular

discomfort during CAE exposure measured on a five-point scale from 0 (none) to 4 (worst). The

endpoint of ocular discomfort was evaluated using a two-sided t-test based on a longitudinal linear

mixed model. Lenses were also evaluated for safety, and all adverse events were monitored. RESULTS:

Subjects reported a significantly better mean comfort score when wearing senofilcon A contact

lenses (1.62 +/- 0.71 units) compared to the mean comfort score reported when wearing

habitual lenses (2.21 +/- 0.80 units) over the course of an entire CAE exposure (p = 0.0068). During

exposure, senofilcon A lenses also yielded significantly better mean overall discomfort scores versus

no lenses (2.73 +/- 0.79 points, p < 0.0001). CONCLUSIONS: Senofilcon A contact lenses provided

greater relief of subjective ocular discomfort associated with lens wear in adverse environmental

conditions than that afforded by both the habitual lenses of contact lens wearers as well as with

no contact lens wear. These results should be verified in a larger, appropriately-powered study.

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Headnote

Key words: Contact lens- Controlled adverse environment (CAE) - Dry eye - Ocular discomfort

Senofilcon A

ABSTRACT

Objective: Contact lenswear is often associated with signs and symptoms of ocular dryness. These

drying effects can be exacerbated by certain environmental factors such as low humidity, wind, and

visual tasks. The objective of the study was to compare the ability of senofilcon A contact lensesto

subjects' habitual contact lensesto provide relief from the subjects' perceived ocular discomfort

during contact lenswear in adverse environmental conditions.

Research design and methods: Eleven subjects completed a single-center, double-masked,

randomized, cross-over, pilot clinical trial. At the qualification visit, and subsequently wearing

senofilcon A study lenses(ACUVUE OASYS Brand Contact Lenseswith HYORACLEAR Plus*) and control

(habitual) lensesat the following visits, subjects underwent a total of three 75-min Controlled Adverse

Environment (CAE) exposures. The primary efficacy variable measured during the 2-week, 3-visit trial

was subject-reported ocular discomfort during CAE exposure measured on a five-point scale from 0

(none) to 4 (worst). The endpoint of ocular discomfort was evaluated using a two-sided t-test based on

a longitudinal linear mixed model. Lenseswere also evaluated for safety, and all adverse events were

monitored.

Results: Subjects reported a significantly better mean comfort score when wearing senofilcon

A contact lenses(1.62 ± 0.71 units) compared to the mean comfort score reported when wearing

habitual lenses(2.21 ± 0.80 units) over the course of an entire CAE exposure (p = 0.0068). During

exposure, senofilcon A lensesalso yielded significantly better mean overall discomfort scores versus

no lenses(2.73 ± 0.79 points, p < 0.0001).

Conclusions: Senofilcon A contact lensesprovided greater relief of subjective ocular discomfort

associated withlenswear in adverse environmental conditions than that afforded by both the

habitual lensesof contact lenswearers as well as with no contact lenswear. These results should be

verified in a larger, appropriately-powered study.

Introduction

Contact lensesare becoming more and more prevalent alternatives to traditional forms of refractive

correction - estimates suggest that at least 34 million Americans currently wear contactlenses1.

Roughly 85% of those individuals wear soft contact lenses, primarily silicone hydrogel lenses1. Despite

apparently healthy eyes and normal pre-ocular tear films, contact lenswearers frequently complain of

sensations of ocular discomfort and dryness associated with wearing their lenses.

The symptomatology associated with contact lenswear can be observed in large-scale studies. In a

study of 1092 current lenswearers, 23% of patients reported dryness, 13% reported discomfort, and

27% reported experiencing at least 2 h of uncomfortable lenswear daily2. Further studies suggest that

at least 50% or 52% of lenswearers have some dryness-related symptoms2,3. This can make contact

lenswear difficult and unfavorable for some patients. A recent survey indicates that 26.3%

of contactwearers are dissatisfied with their contact lenses, while another 24.1% permanently

discontinue lenswear, with dryness and discomfort symptoms being the primary self-reported

reasons4.

A number of mechanisms may potentially account for the subjective symptoms of discomfort common

inlenswearers. When placed on the eye, contact lensescan induce changes to the tear film, which may

induce symptoms of dry eye. The placement of a soft contact lenson the eye often disrupts the tear

film (specifically the lipid layer which is responsible for retarding evaporation) sufficiently enough to

greatly increase tear evaporation rates5. As measured by a study using evaporimetry, tear

evaporation was on average 60.3% higher in 30% relative humidity (RH) and 60.4% higher in 40% RH

during contact lenswear than 30-min afterlensremoval6. Lenswearers exhibited on average 57.5%

higher tear evaporation rates in 30% RH and 134.8% higher tear evaporation rates in 40% RH than did

non contactwearers in the same conditions6. It is believed that increased tear film evaporation can

lead to elevated tear osmolarity, which in turn is associated with symptoms and clinical signs of ocular

drying7,8.

It is evident from the fluctuations in tear evaporation rate brought about by changes in relative

humidity that environmental factors can considerably impact dryness symptoms during lenswear. In

addition to humidity, variables such as air movement (wind), temperature, and blink-rate altering

visual activities such as reading and computer use may exacerbate signs and symptoms of dryness

in contactwearers as they do in dry eye patients9,10. Many of these factors are difficult to avoid - they

are often present in offices, households, or other daily environments. Studies have found that as air

temperature and relative humidity decrease, the tear films of soft contactwearers thin, their break-up

times decrease, and subjective reports of dryness increase11,12. One trial reported that exposure to

artificial wind brought about thinning of the tear film, increased tear evaporation, and increased

dryness scores in soft contact lenspatients13. Additionally, ocular sensitivities to common pollutants

such as cigarette smoke and common cosmetic products applied in the vicinity of the eyes are

correlated with dry eye symptomatology in patients that wear soft contactlenses14.

The variability and modifiability of the signs and symptoms of dryness during lenswear can create a

difficult scenario for the evaluation of investigational contact lenses, rewetting solutions, and cleaning

solutions. The environmental and behavioral differences among subjects create a challenge in

establishing a reliable baseline and an accurate evaluation of study materials. Therefore, when

evaluating an investigational lensor solution for its effects on dryness during lenswear, these sources

of variation should ideally be reduced as much as possible via regulation of the subjects' environment

and activities.

Given the similarities of manifestations of dryness caused by lenswear to the signs and symptoms of

dry eye, the Controlled Adverse Environment (CAE) model could prove a useful tool for investigating

dryness duringlenswear. Typically incorporated into trials studying dry eye, the CAE is used to

exacerbate dry eye symptoms in a repeatable, controlled manner by closely regulating humidity,

temperature, airflow, lighting, and visual tasking15. The same environmental factors that can

contribute to dryness symptoms in contact lenswearers are those controlled in the CAE, which

suggests the appropriateness of the model for evaluation oflenswearers. Acute ocular drying

conditions are optimized in the CAE by using appropriate exposure times and requiring subjects to

perform a visual task16. The CAE is representative of adverse environmental conditions encountered

throughout the daily life of contact lenswearers (i.e., riding on an airplane, working on a computer, low

humidity office environments, etc).

In light of the scope of drying symptoms associated with soft contact lensuse, the development of

alenscapable of minimizing these symptoms could be valuable to wearers of soft contact lenses. The

novel softcontact lensmaterial senofilcon A has been indicated to show promising reduction of dry eye

symptoms incontact lenswearers. Research suggests that the combination of characteristics including

high oxygen transmissibility, a low wetting angle, a mid-level modulus and low coefficient of friction of

senofilcon A may be related to reduction in hyperemia and improved comfort and lid sensation with

blinking17. This study was designed to evaluate the incidence of ocular drying symptoms during CAE-

exposure of the novel soft contact lensmaterial senofilcon A (ACUVUE[dagger] OASYS[double dagger]

Brand Contact Lenseswith HYDRACLEAR§ Plus) as compared to patients' habitual contact lenses.

Participants and methods

This was a single-center, double-masked, randomized, cross-over, 3-visit, pilot clinical trial lasting

approximately 2 weeks. Institutional review board (IntegReview Ethical Review Board, Austin, TX, USA)

approval was obtained prior to study initiation, and all participants were recruited via IRB-approved

telephonecontactfrom a pre-existing database, then provided written informed consent before

receiving study-relatedproceduresor treatment. Prior to Visit 1, a statistical plan included in the study

protocol detailed that a two-sided t-test would be used to evaluate the results for all efficacy variables.

This was accomplished with a longitudinal linear mixed model that considered lens, time, and lensby

time interaction as fixed effects and subject as a random effect.

Participants were current soft contact lenswearers with histories of perceived ocular discomfort

duringlenswear in windy or dry environments. Subjects were eligible for inclusion if at least 18 years of

age and willing to submit to a urine pregnancy test at the initial visit if of childbearing potential. All slit

lamp exams were performed by trained ophthalmologists and optometrists. Key exclusion criteria

included: active ocular infections or inflammation, significant Meibomian Gland Dysfunction as

determined by the investigator, ophthalmic medication use during the study, active seasonal ocular

allergies, LASIK surgery, any medical condition (such as diabetes) that could affect study parameters,

and punctal plug placement within 30 days of the first study visit. Subjects were not permitted to use

rewetting drops or tear substitutes for at least 12 h prior to Visits 1, 2, and 3, nor were subjects

allowed to wear contact lensesfor at least 72 h prior to each of the three visits.

After qualifying at Visit 1 (Day O), subjects were randomized using a cross-over design and by an

independent person to receive either senofilcon A soft contact lensesor their habitual lensesduring CAE

exposure at Visit 2 (Day 7 ± 2) and then were crossed over to wear the comparative lensduring CAE

exposure at Visit 3 (Day 14 ± 2). The visit structure and proceduresare presented in Figure 1.

Visit 1 (Day 0) - eligibility visit

After informed consent was obtained, consenting subjects provided demographic data, medical

history, and medication history, and confirmed that they had not worn contact lenseswithin 72 h of the

visit. Prior to ocular exams, individuals reported their ocular discomfort on a standardized five point

scale from O (none) to 4 (worst), and completed a subjective questionnaire that asked subjects to

report the amount of time that they experienced comfortable lens-wear and the total amount of wear

time with their habitual lenses, which were then converted to a percentage by a technician.

These procedureswere followed by baseline ophthalmic safety examinations: visual acuity (using the

Early Treatment of Diabetic Retinopathy Study method) for which subjects wore their prescription

eyeglasses, and slit lamp biomicroscopy. Tear meniscus height and conjunctival redness were also

evaluated as part of the initial slit lamp exam.

Tear film break-up time (TFBUT) was assessed after 5μL of 2% unpreserved sodium fluorescein was

instilled into the lower palpebral conjunctiva of each eye by the investigator16. After determination of

mean break-up time in each eye, the evaluator graded staining of the three corneal regions and the

two conjunctival regions using a slit lamp with a Wratten yellow No. 12 filter, on a standardized five-

point 0 (none) to 4 (worst) scale. Next, 10 μL of 1% unpreserved lissamine was instilled into the lower

palpebral conjunctiva of each eye. Immediately following lissamine instillation the investigator graded

the staining of the corneal (inferior, superior, and central) and conjunctival (nasal and temporal)

regions, again using the same standardized scale from O (none) to 4 (worst) points. Slit lamp exams

and diagnostics at this and subsequent visits were performed by the same masked investigator.

Following initial ophthalmic exams, subjects were required to wait for 10min prior to entering the CAE.

A technician queried patients as to their ocular discomfort (on the previously mentioned 0-4 point

comfort scale) in both eyes individually upon entering the CAE and at 5 min intervals for a span of 75

min. The scale was explained to patients by trained technicians, who also recorded the discomfort

scores reported by the subjects; reference cards detailing the five point scale from 0 (none) to 4

(worst) scale were kept in plain view of the subjects for easy reference during their exposure. Those

qualifying patients who experienced a symptomatic reaction (reported 3 or 4 on the ocular discomfort

scale) while in the CAE underwent the same diagnostic and safety proceduresas they did prior to entry

after their 75-min exposure: visual acuity, slit lamp biomicroscopy, tear meniscus evaluation,

conjunctival redness, TFBUT, and corneal and conjunctival staining (using fluorescein and lissamine

green dyes, respectively). Subjects that met all inclusion criteria were randomized, assigned subject

numbers, and instructed not to wear contact lensesat least 72h before the next visit, nor to use

artificial tears at least 12h before the next visit.

Visit 2 (Day 7 ± 2)

At the beginning of the second visit, subject medical and medication histories were updated, and it

was confirmed that subjects had not worn contact lensesin the past 72h, nor used artificial tears in the

past 12h. As at the first visit, subjects provided an initial ocular discomfort score, underwent visual

acuity assessment, slit lamp biomicroscopy, tear meniscus and conjunctival redness evaluations,

TFBUT, and then had fluorescein and lissamine staining graded by the investigator. After vital dye

staining, subjects' eyes were washed with saline, and after a 15-min wait, they were fitted with a new

pair of either their habitual contact lensesor the studylenses(senofilcon A). An additional 10-min wait

was followed by assessments of visual acuity, contrast sensitivity (using a Pelli-Robson chart),

and lensfit acceptability, prior to a subject's entering the CAE. The CAE discomfort

reporting procedurewas the same as at Visit 1, except that the patient was wearing lensesin the

adverse environment - discomfort scores were reported upon entering the chamber, and at 5-min

intervals for the 75-min duration of the exposure. After exiting, patients again had their visual acuity

and contrast sensitivity tested with the lensesin their eyes, and following these tests, had

their lensesremoved by the investigator. The second visit finished with slit lamp biomicroscopy, tear

meniscus evaluation, conjunctival redness determination, TFBUT, and vital dye staining.

Visit 3 (Day 14 ± 2)

The proceduresperformed at the third visit were identical to those performed at the second visit, with

the exception that, during the 75-min CAE exposure, subjects wore the lenses(either habitual or

senofilcon A) that they did not wear at Visit 2. This was determined by randomization, as this was a

double-masked study. Following the final slit lamp exams, any subjects of childbearing potential took a

pregnancy test, and all subjects were exited from the study.

Results

There were no clinically or statistically significant changes in any of the safety parameters (evaluation

of the cornea, conjunctiva, anterior chamber, iris, lens, lids, and visual acuity) during the study, and of

the three adverse events reported - one subject had a sore throat, one had a fever, and one reported

cold symptoms - none were serious, and none were judged to have any relation to the investigational

device.

Data from all subjects receiving study devices (11 subjects) were considered evaluable for efficacy

analysis. Of the 11 participants completing the study, 27.3% were between 20 and 29 years of age,

18.2% were 30-39 years of age, and 54.5% 40-49 years of age; the mean age was 36.6 years. Of the

subjects, 81.8% were female.

Ocular discomfort during exposure to the controlled adverse environment was the primary efficacy

variable for this study, and as noted in the methods, subjects reported comfort scores upon entering

the CAE, and at 5-min intervals for a 75-min span during exposure. This was conducted at each of the

three visits - once with subjects wearing no lenses, once wearing a new pair of their habitual contact

lenses, and once wearing senofilcon Acontact lenses. The mean scores and trendlines for all time

points for the three CAE exposures for no-lens, habitual lens, and senofilcon A lens, respectively, are

displayed graphically in Figure 2. A subjective grade of 0 on the 0-4 discomfort scale was indicative of

no ocular discomfort, p-values for ocular discomfort were obtained using a two-tailed t-test from a

longitudinal linear mixed model in order to determine significance. Multiplicity correction was not

conducted due to the pilot nature of this study.

All patient reported discomfort scores increased significantly as CAE exposure time increased (p <

0.001) which demonstrates the model works as intended. Patients reported better mean discomfort

scores across all time points during CAE exposure while wearing senofilcon A lenses(1.62 ± 0.71

points) than they did while wearing their habitual contact lenses(2.21 ± 0.80 points, p = 0.0068).

Senofilcon A lensesalso yielded significantly better mean overall discomfort scores versus

no lenses(2.73 ± 0.79 points, p < 0.0001). These data are reported in Table 1.

Secondary efficacy variables measured for the purposes of the study were conjunctival redness, tear

film breakup time, contrast sensitivity, composite fluorescein staining, and composite lissamine green

staining. No statistically significant differences or trends were found between the senofilcon

Alensesand subjects' habitual contact lensesfor any of these secondary measures, either pre-or post-

CAE exposure.

Discussion

When wearing senofilcon A contact lenses, subjects in this study reported significantly lower subjective

ocular discomfort scores during exposure to a controlled adverse environment than they did when

wearing their habitual contact lenses. There were no safety issues witii either the experimental or

habitual lenses.

Previous research has suggested the propensity of contact lenswear to instigate symptoms and signs

of ocular dryness. This is at least partially attributable to the disruption of normal tear film layers and

structure - leading to more rapid tear break-up and evaporation - that can occur when any sort

ofcontact lensis placed on the pre-corneal tear film. The ability of environmental conditions to

contribute to and exacerbate this contact-lens-related dryness has also been clinically supported11-13.

In fact, discomfort during lenswear is the leading cause of contact lensdiscontinuation - roughly 51% of

lapsed lenswearers cite discomfort as the primary reason18. The most common type of discomfort

reported as a reason for discontinuing lenswear was dryness (40%)18. So it appears the development

of a contact lensless prone to causing the discomfort associated with ocular dryness would be a

favorable development for contactwearers. Logically, patients would be less likely to discontinue

from contact lenswear when wearing such a lens.

Studies have also demonstrated the modifiability of signs and symptoms of lens-related dryness by

modulating certain environmental inputs, such as wind (air flow), temperature, and relative

humidity11-13. Acute exposure to low humidity or high air flow conditions can increase dryness, thin

the pre-corneal tear film, and quicken tear film break-up time in soft contactwearers11,12. The break-

up time changes may be due in part to the escalation of tear film evaporation that occurs in contact-

lenswearers in lower humidity environments6. Normally the thin outer lipid layer of the tear film is

responsible for slowing or preventing the evaporation of the aqueous tear film components, but

a contact lenscan interfere with the lipid layer.

In one trial, 112 symptomatic contactwearers were refitted with senofilcon A lenses: 75% reported less

dryness, 88% reported that they had experienced a higher level of comfort, and 76% had fewer hours

of uncomfortable lenswear daily2. Also in this study, there were no significant differences in clinical

signs between senofilcon A lensesand subjects' habitual lenses, so there is no reason to believe any

type of softcontact lensis harsher to the ocular epithelium, tear film, or visual system during this

protocol. Senofilcon A proved a safe lensmaterial for the purposes of this trial. The main study

limitation incurred in this study was the small sample size.

Soft contact lensmaterials have previously demonstrated a susceptibility to environmental factors

which can lead to clinical signs normally associated with dry eye4,6. Soft contact lensesin general are

commonly associated with ocular dryness symptoms, and several studies support the idea that these

symptoms can be acutely exacerbated by several of the same environmental factors that a controlled

adverse environment (CAE) model regulates, namely air flow, relative humidity, and temperature12-

14,16. For this reason it is notable that senofilcon A demonstrated statistically significant

improvements over other soft lensesworn by subjects in terms of subjective ocular discomfort during

CAE exposure in the course of this study. Most importantly, on average over the course of the 16 time

points collected during exposure to the CAE, senofilcon A lensesyielded a lower mean discomfort score

than did either no lensesor subjects' habitual lenses, with statistical significance in both cases.

Conclusion

Soft contact lenswear is often associated with signs and symptoms of ocular dryness, often

exacerbated acutely by environmental factors. The results of this study suggest that the new contact

lensmaterial senofilcon A may lessen die acute symptomatology associated with exposure to adverse

environmental conditions. Patients seemed to experience less subjective discomfort while wearing

senofilcon A contact lenses, as used according to diis protocol, than they did either while wearing

no lensesor while wearing their habitual contact lensesin a controlled adverse environment. Further

clinical research should be conducted to verify the results.

Acknowledgments

Declaration of interest: This study was supported by funding from VISTAKON, a division of Johnson &

Johnson Vision Care, Inc., Jacksonville, FL, USA. GWO and RTA had no financial interest in the outcome

of the study. KEO is an employee of VISTAKON.

Footnote

*ACUVUE, ACUVUE OASYS and HYDRACLEAR are trademarks of VISTAKON, a division of Johnson &

Johnson Vision Care, Inc., Jacksonville, FL, USA

[dagger] ACUVUE is a registered trademark of VISTAKON, a division of Johnson & Johnson Vision Care,

Inc., Jacksonville, FL, USA

[double dagger] ACUVUE OASYS is a trademark of VISTAKON

§ HYDRACLEAR is a trademark of VISTAKON

References

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4116_5, Accepted for publication: 21 November 2007

Published Online: 10 December 2007

doi:10.1185/030079908X260826

AuthorAffiliation

George W. Ousler III(a), Russell T. Anderson(a) and Kathrine E. Osborn(b)

a ORA Clinical Research and Development, North Andover, MA, USA

b Vistakon, A Division of Johnson & Johnson Vision Care, Inc., Jacksonville, FL, USA

Address for correspondence: George W. Ousler III, BS, ORA Clinical Research and Development, 863

Turnpike Street, North Andover, MA 01845, USA. Tel.: +1 978 685 8900; Fax: +1 978 689 0020;

gousler@oraclinical.com

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