Ophthalmology

Volume 117, Number 6, June 2010

(range, 9.0102.9) grams and the mean duration of treatment was 21.817.0 (range, 655) months. None of the
patients had prior or coexisting treatment with other chemotherapeutics or had radiotherapy. The patients did not
have any history of ocular surgery, ocular/systemic diseases, or a history of topical/systemic drug use or contact
lens wear that would alter the ocular surface. Informed
consents were obtained from all subjects. Examination procedures were ethic board reviewed. The criteria for the
diagnosis of MGD were described as follows: (1) occluded
meibomian gland (MG) orifices; (2) cloudy/inspissated
glandular secretion following digital pressure on the tarsus
of the eyelids; (3) presence of keratinization or displacement of the mucocutaneous junction; (4) absence of inflammatory skin disorders such as atopic dermatitis, seborrhea
sicca, and rosacea; (5) absence of trachoma, ocular cicatritial pemphigoid, chemical, thermal, or radiation injury; and
(6) absence of excessive meibomian lipid secretion (seborrheic MGD).4 The patients underwent tear lipid layer interferometry, tear evaporation rate measurements from the
ocular surface (TEROS), tear collection for tegafur (FT207) concentration assessment by gas chromatography,
tear film break-up time (BUT) measurements, vital stainings of the ocular surface, Schirmer test I without anesthesia, in vivo laser confocal microscopy, transillumination of the eyelids with a transilluminator or infrared
meibography, and the MG expressibility test. The degree
of MG dropout and MG expressibility were scored as
described previously.4
The FT-207 concentrations measured during drug ingestion
ranged between 908 and 3631 ng/ml (mean, 2013.21014.8
ng/ml). FT-207 was undetectable in tears when the patients
were on a rest period from S-1. Slit-lamp microscopy disclosed complete occlusion of MG orifices with numerous
pigmentary deposits and unexpressible glands in all patients
(Figure 1; available at http://aaojournal.org). Meibography
revealed marked loss of glandular structures in patients compared to controls (Figure 2; available at http://aaojournal.org).
Three patients had canalicular stenosis/obstruction and 4
eyes had epithelial crack lines. The mean TEROS, corneal
fluorescein staining scores, BUT, the mean acinar unit density and the mean acinar unit diameter in in vivo confocal
microscopy were significantly worse in S-1 users compared
with the controls (Table 1; available at http://aaojournal.org).
Such in vivo confocal microscopy findings together with
observations of periglandular inflammation, fibrosis, and
glandular atrophy provided further evidence on S-1 induced
changes in the MGs (Fig 3; available at http://aaojournal.
org). Corneal and MG disease did not respond well to
conventional MGD treatment for at least 2 months with lid
hygiene/warming/nonpreserved artificial tears and sodium
hyaluronate eye drops (Table 2; available at http://aaojournal.
org). S-1 treatment was observed to induce irreversible MG
damage evidenced by lack of improvement in confocal
microscopy and infrared meibography even after cessation
of S-1 therapy in the 6 patients in remission from their
primary disease.
The mechanism by which S-1 induces these changes
remains unknown but direct toxicity from the drug in tears
is a possibility. In summary, oncology and ophthalmology

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health care personnel should be aware that S-1 may induce

MGD, corneal epithelial damage, and evaporative dry eye
disease which require careful follow up of cancer patients
receiving this treatment.
YUKIHIRO MATSUMOTO, MD
MURAT DOGRU, MD
ENRIQUE ADAN SATO, MD
OSAMA M. A. IBRAHIM, MD
YUKAKO TATEMATSU, MD
YOKO OGAWA, MD
KAZUO TSUBOTA, MD
Tokyo, Japan
References
1. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of
a novel form of an oral 5-fluorouracil derivative (S-1) directed
to the potentiation of the tumor selective cytotoxicity of
5-fluorouracil by two biochemical modulators. Anticancer
Drugs 1996;7:548 57.
2. Hirata K, Horikoshi N, Aiba K, et al. Pharmacokinetic study
of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer
Res 1999;5:2000 5.
3. Esmaeli B, Golio D, Lubecki L, Ajani J. Canalicular and nasolacrimal duct blockage: an ocular side effect associated with the
antineoplastic drug S-1. Am J Ophthalmol 2005;140:3257.
4. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes
and discomfort in patients with meibomian gland dysfunction.
Arch Ophthalmol 1995;113:1266 70.

Subconjunctival Hemorrhage and

Conjunctivochalasis
Dear Editor:
We note with interest the paper by Mimura et al1 reporting
an association between subconjunctival hemorrhage (SCH)
and conjuntivochalasis (CCh).
They conclude that CCh may have an important role in
the pathogenesis of SCH.
This study reports an association between SCH and CCh;
however, this does not establish causation. It could be
argued, for example, that the presence of SCH worsens the
grade of CCh instead of CCh causing SCH.
However, we would like to highlight a paper published
in 2005 that also indicates that CCh may play a role in the
pathogenesis of SCH.2 This was an observational case
series that reported 5 patients with circumferental drainage blebs following trabeculectomy and multiple inferior
SCH. These patients had significant CCh due to their
circumferential blebs, and 4 of the patients experienced 4
or more SCH.
A possible explanation is that a bulge of bullous conjunctiva may form into a fold between the lids during
blinking and that conjunctival vessels folded and compressed during a blink become damaged and bleeds. Other
possible explanations include eyelid rubbing associated
with irritated conjunctiva or traction on a trapped conjunctiva
fold during REM sleep. Degenerative structural changes of the
conjunctiva found in Cache3 or altered fibrous connections

Letters to the Editor

between the conjunctiva and Tendons capsule may also contribute to the pathogenesis of SCH.
SIMON NICHOLAS, FRANZCO
ANTHONY WELLS, FRANZCO
Wellington, New Zealand
References
1. Mimura T, Usui T, Yamasaki S, et al. Subconjunctival hemorrhage and conjunctivochalasis. Ophthalmology 2009;116:
1880 6.
2. Wells A, Marks J, Khaw P. Spontaneous inferior subconjunctival haemorrhages in association with circumferential drainage blebs. Eye 2005;19:269 72.
3. Watanabe A, Yokoi N, Kinoshita S, et al. Clinicopathologic
study of conjunctivochalasis. Cornea 2004;23:294 8.

Author reply
Dear Editor:
We appreciate the comments expressed by Drs. Nicholas
and Wells regarding our manuscript about Subconjunctival
hemorrhage (SCH) and conjunctivochalasis (CCh) by
Mimura et al1 published in the October 2009 issue.
We agree with Drs. Nicholas and Wells in thinking that
the presence of SCH worsens the grade of CCh instead of
CCh causing SCH. Additionally, we agree with their view
that a conjunctival bulge may develop into a fold between
the lids during blinking, and that conjunctival vessels folded
and compressed during a blink may become damaged and
bleed.2 To clarify the role of CCh in the induction of SCH,
we compared the severity of CCh between fellow eyes of
patients with SCH and eyes of healthy subjects and found
the grade was higher in the fellow eyes in patients with SCH
than in the eyes of healthy subjects (data not shown).
Therefore, our results, as well as theirs, suggest that there is
a mutual causal relationship between SCH and CCh.
The comments of Drs. Nicholas and Wells are very
helpful and enhance the understanding of the relationship
between SCH and CCh.
TATSUYA MIMURA, MD, PHD
SHIRO AMANO, MD, PHD
Tokyo, Japan

was associated with significantly shorter survival at 2 years

after AGV placement. The authors suggested that this was
related to exuberant tissue fibrosis around the AGV as a
result of MMC-induced tissue death.
The dissemination of outcome data for a reasonably
specific group of patients in a rare situation is valuable, and
we agree that the evidence so far does not support the use of
intraoperative MMC in improving outcomes for eyes with
AGV implantation, with failure most likely due to tissue
fibrosis. However, we do not believe that the poorer survival
in the MMC group can be attributed to scarring secondary to
cell death from intraoperative MMC.
The body of evidence so far in clinical and laboratory
studies is fairly conclusive for the role of MMC in downregulating fibrosis. MMC is an alkylating agent that inhibits
fibroblast proliferation and also induces fibroblast apoptosis.2,3 Cell apoptosis incites minimal inflammation,4 and
therefore would unlikely drive fibroblast proliferation and
subsequent fibrosis. Although we cannot be completely sure
as to the anti-fibrotic effects of MMC on conjunctival and
Tenons fibroblasts for this cohort of patients (younger than
2 years of age), it would be extremely unlikely for the effect
of MMC to be different for different age groups.
A more likely explanation for the results lies in the study
design. As already highlighted by the authors, the main
limitations of the study were its retrospective nature, relatively small sample size, surgeon preference for MMC use,
and selection bias (more difficult glaucoma cases, most
notably Peters anomaly, in the MMC group). It is therefore
not unreasonable to assume that the eyes receiving MMC
were already at higher risk for failure MMC was applied
intraoperatively in these eyes to try to reduce this risk. There
is also the possibility of genetic influences on outcomes. For
instance, mutations in the PAX6 gene associated with Peters anomaly may also affect the wound-healing process.
Nevertheless, it would be of interest to evaluate the
histopathology and genetics for this population of patients
in future studies to shed more light on this issue.
GHEE SOON ANG, FRCOPHTH
Wellington, New Zealand
JONATHAN G. CROWSTON, FRCOPHTH, FRANZCO, PHD
Melbourne, Australia

References
1. Mimura T, Usui T, Yamagami S, et al. Subconjunctival hemorrhage and conjunctivochalasis. Ophthalmology 2009;116:
1880 86.
2. Wells AP, Marks J, Khaw PT. Spontaneous inferior subconjunctival haemorrhages in association with circumferential
drainage blebs. Eye 2005;19:269 72.

Pediatric Ahmed Valves

Dear Editor:
We read with interest the article by Al-Mobarak and Khan
regarding the effect of mitomycin-C (MMC) in Ahmed
glaucoma valve (AGV) implantation outcomes for patients
younger than 2 years of age.1 The results from this retrospective study indicated that intraoperative use of MMC

ANTHONY P. WELLS, FRANZCO

Wellington, New Zealand
References
1. Al-Mobarak F, Khan AO. Two-year survival of Ahmed
valve implantation in the first 2 years of life with and
without intraoperative mitomycin-C. Ophthalmology 2009;
116:18625.
2. Crowston JG, Akbar AN, Constable PH, et al. Antimetaboliteinduced apoptosis in Tenons capsule fibroblasts. Invest Ophthalmol Vis Sci 1998;39:449 54.
3. Seong GJ, Park C, Kim CY, et al. Mitomycin-C induces the
apoptosis of human Tenons capsule fibroblast by activation of
c-Jun N-terminal kinase 1 and caspase 3 protease. Invest
Ophthalmol Vis Sci 2005;46:354552.

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