Funding/Support: This work was supported in part by

250 an unrestricted grant from Research to Prevent Blind-

225
Before treatment ness to the New England Eye Center and Department of
Mean Choroidal Thickness, µm Ophthalmology, Tufts University School of Medicine, by
200 3 mo
grants R01-EY11289-25, R01-EY13178-10, R01-
175
6 mo EY013516-07, and R01-EY019029-02 from the Na-
150 12 mo tional Institutes of Health and FA9550-10-1-0551 and
125 FA9550-10-1-0063 from the Air Force Office of Scien-
100
tific Research, and by the Massachusetts Lions Clubs.
75 1. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science.
P <.05
1991;254(5035):1178-1181.
50 2. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain
T 2.5 T 2.0 T 1.5 T 1.0 T 0.5 Fovea N 0.5 N 1.0 N 1.5 N 2.0 N 2.5
optical coherence tomography. Am J Ophthalmol. 2008;146(4):496-500.
Location 3. Manjunath V, Taha M, Fujimoto JG, Duker JS. Choroidal thickness in nor-
mal eyes measured using Cirrus HD optical coherence tomography. Am
J Ophthalmol. 2010;150(3):325-329, e1.
Figure 2. Mean choroidal thickness over all locations measured in 500-µm 4. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging op-
intervals, 2500 µm temporal (T) and nasal (N) to the fovea before treatment tical coherence tomography of the choroid in central serous chorioretinopathy.
and 3, 6, and 12 months after the first treatment. Note that the N Retina. 2009;29(10):1469-1473.
measurements are thinnest where the T measurements are thickest. The 5. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA. An
numbers next to the T and N locations indicate millimeters. essential role for RPE-derived soluble VEGF in the maintenance of the
choriocapillaris. Proc Natl Acad Sci U S A. 2009;106(44):18751-18756.
6. Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S. Changes in choriocap-
essary to determine whether there is a dose response. An- illaris and retinal pigment epithelium in age-related macular degeneration.
other limitation to this prospective investigation was that Mol Vis. 1999;5:35.
there was no standard protocol for the initiation of therapy
or the timing and number of injections.
The use of anti-VEGF for the treatment of neovascu- Management of Fingolimod-Associated
lar AMD has been shown to improve visual acuity and is Macular Edema
currently being used extensively for this purpose. In our
study, there was significant thinning of the choroid in
patients with neovascular AMD treated with anti-
VEGF. This may have implications for long-term cho-
roidal function.
Lauren Branchini, MD
F ingolimod is the first orally active drug ap-
proved for the management of relapsing-
remitting multiple sclerosis (MS).1 Its immuno-
suppressive action is related to downregulation of
sphingosine 1–phosphate receptor 1 on lymphocytes,
Caio Regatieri, MD, PhD which inhibits their egress from lymphoid tissues.2 Macu-
Mehreen Adhi, MBBS lar edema (ME) is an infrequent adverse effect of fingo-
Ignacio Flores-Moreno, MD limod, usually occurring within 3 months of initiation
Varsha Manjunath, MD of treatment and resolving on cessation of fingolimod.1
James G. Fujimoto, PhD We report a case of ME in a patient with MS receiving
Jay S. Duker, MD fingolimod and its successful management by topical anti-
inflammatory drugs.
Published Online: March 14, 2013. doi:10.1001
/jamaophthalmol.2013.692 Report of a Case. A 67-year-old woman had decreased
Author Affiliations: Department of Ophthalmology, New vision in her right eye. She began treatment with fingo-
England Eye Center, Tufts Medical Center, Boston (Drs limod, 0.5 mg/d, 6 months earlier for chronic relapsing-
Branchini, Regatieri, Adhi, Manjunath, and Duker) and remitting MS. She denied history of other systemic ill-
Department of Electrical Engineering and Computer Sci- ness or previous ocular disease and was taking no
ence, Research Laboratory of Electronics, Massachu- concurrent medications.
setts Institute of Technology, Cambridge (Dr Fuji- On examination, her best-corrected visual acuity
moto); and Department of Ophthalmology, University (BCVA) was 6/7.5 OD and 6/6 OS. Intraocular pressure
Hospital of Albacete, Albacete, Spain (Dr Flores- was 14 mm Hg OU. Anterior segment examination find-
Moreno). ings were normal. Funduscopy and optical coherence to-
Correspondence: Dr Duker, New England Eye Center, mography showed macular cystic changes in her right
800 Washington St, Boston, MA 02111 (jduker eye (Figure 1, week 0). A provisional diagnosis of fin-
@tuftsmedicalcenter.org). golimod-associated ME (FAME) was made.
Author Contributions: Dr Duker had full access to all Because the patient wished to continue treatment with
the data in the study and takes responsibility for the in- fingolimod, she began topical treatment with ketorolac
tegrity of the data and the accuracy of the data analysis. tromethamine, 0.5%, and dexamethasone suspension,
Conflict of Interest Disclosures: Dr Fujimoto receives 0.1%, both 4 times daily in her right eye. After 1 month,
royalties from intellectual property owned by Massachu- BCVA remained at 6/7.5 OD but worsened to 6/9 OS, cor-
setts Institute of Technology and licensed to Carl Zeiss responding to optical coherence tomographic findings of
Meditech Inc and has stock options in Optovue Inc. Dr resolving ME in her right eye with progression in her left
Duker receives research support from Carl Zeiss Medi- untreated eye (Figure 1, week 4). To exclude other causes
tech Inc, Optovue Inc, and Topcon Medical Systems Inc. of ME, fluorescein angiography was performed, demon-

JAMA OPHTHALMOL/ VOL 131 (NO. 5), MAY 2013 WWW.JAMAOPHTH.COM

694

©2013 American Medical Association. All rights reserved.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Edinburgh Library User on 02/02/2015
 OD OS

Week 0
Week 4
Week 23
Week 35

Figure 1. Optical coherence tomographic images showing cystoid macular edema initially affecting the right eye (OD) at week 0, which improved on treatment
with topical dexamethasone and ketorolac tromethamine. At week 4, topical treatment was extended to the previously untreated left eye (OS), which had begun to
display cystic changes. Macular edema improved after topical treatment was increased to every 2 hours at week 23. At week 35, 5 weeks after cessation of
fingolimod use, macular edema had completely resolved.

strating late-phase leakage of dye in the left central macula
(Figure 2). At this stage, topical ketorolac and dexa-
methasone were prescribed for both eyes twice daily with
temporary improvement of BCVA to 6/7.5 OU after 3
weeks. Increased instillation frequency of topical anti-
inflammatory eyedrops (initially 4 times daily, then ev-
ery 2 hours) led to resolution of ME (Figure 1, week 23)
with improvement of BCVA to 6/6 OU. Unfortunately,
attempts at weaning topical anti-inflammatory drugs failed
while the patient continued to use fingolimod. After con-
sultation with her neurologist, a decision was made to
cease fingolimod use, resulting in resolution of her ME
5 weeks later (Figure 1, week 35).
Comment. Fingolimod-associated ME is observed in up
to 0.5% of patients with MS receiving fingolimod.3 The
proposed pathophysiological mechanism behind FAME
is loss of sphingosine 1–phosphate receptor 1 signaling
in endothelial cells, subsequent downregulation of ad-
hesion complexes, and enhanced vascular permeability.4
In previous reports, FAME resolved after cessation of
fingolimod use.3,5 Because our patient’s neurological symp-
toms were well controlled and she wished to continue treat-
ment with fingolimod, we elected to manage her FAME
with topical medications. Our patient was partially re-
sponsive to topical nonsteroidal anti-inflammatory drugs
and glucocorticoids since attempts at dose reduction led
to exacerbation of FAME. The mechanism behind this re-
sponsiveness is unclear, but we speculate that an inflam-
matory component may have contributed in this case. Topi-
cal nonsteroidal anti-inflammatory drugs have been
successfully used to manage cystoid ME.6 More recently,
Afshar et al7 successfully managed FAME with topical non-
steroidal anti-inflammatory drugs. Further clinical trials
may assist in optimizing management of FAME without
cessation of fingolimod use.
Although not present in our case, optic neuritis is a
diagnostic consideration in patients with MS who have
visual disturbance. This may be differentiated from ME
by the presence of a relative afferent pupillary defect, dys-
chromatopsia, and ocular pain on eye movements.3 An-
other possibility is that the ME may be unrelated to fin-
golimod use. Microcystic ME, predominantly affecting
the inner nuclear layer, is reported in 4.7% of patients
with MS and is more common in eyes with a history of
optic neuritis.8 We cannot exclude preexisting micro-
cystic ME because our patient was receiving fingolimod
prior to her first clinic attendance and she did not have
pretreatment optical coherence tomographic investiga-
tions, even though ophthalmological evaluation is rec-
ommended by the manufacturer prior to commence-
ment of fingolimod treatment. Additionally, the frequency

JAMA OPHTHALMOL/ VOL 131 (NO. 5), MAY 2013 WWW.JAMAOPHTH.COM

695

©2013 American Medical Association. All rights reserved.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Edinburgh Library User on 02/02/2015

OD OS
A 2. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking
B
Figure 2. Fundus photographs (A) and fluorescein angiograms (B) of the
right (OD) and left (OS) eyes 1 month after commencing topical treatment
with anti-inflammatory drugs. Late-phase fluorescein leakage is observed in
the left macula.
of FAME in patients with preexisting microcystic ME is
unknown as previous clinical trials used time-domain op-
tical coherence tomography, which was not sufficiently
sensitive to detect microcystic ME.8
In conclusion, our observations suggest that inflam-
mation may contribute to the pathogenic pathway of
FAME. Topical anti-inflammatory drugs may be useful
in managing patients with FAME when cessation of fin-
golimod use is not desired. Our case also illustrates the
importance of regular ophthalmological review of pa-
tients receiving fingolimod.
Jeanie Chui, MBBS, PhD
Geoffrey K. Herkes, MBBS, PhD
Andrew Chang, MBBS, PhD
Published Online: March 28, 2013. doi:10.1001
/jamaophthalmol.2013.47
Author Affiliations: Sydney Retina Clinic and Day Sur-
gery (Drs Chui and Chang), Department of Neurology,
Royal North Shore Hospital (Dr Herkes), and Northern
Clinical School, University of Sydney (Dr Herkes), Syd-
ney, Australia.
Correspondence: Dr Chang, Sydney Retina Clinic and
Day Surgery, Level 13, 187 Macquarie St, Sydney, Aus-
tralia (achang@sydneyretina.com.au).
Author Contributions: Dr Chang had full access to all
the data in the study and takes responsibility for the in-
tegrity of the data and the accuracy of the data analysis.
Conflict of Interest Disclosures: Dr Herkes chairs the
Advisory Committee for Prescription Medicines of the
Therapeutic Goods Administration of the Common-
wealth of Australia. Dr Chang has been a consultant for
Novartis, Bayer, and Alcon.
Previous Presentation: This paper was presented at the
44th Annual Scientific Congress of the Royal Australian
and New Zealand College of Ophthalmologists; Novem-
ber 26, 2012; Melbourne, Australia.
JAMA OPHTHALMOL/ VOL 131 (NO. 5), MAY 2013
696
©2013 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Edinburgh Library User on 02/02/2015
1. Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group. A placebo-
controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med.
2010;362(5):387-401.
by sphingosine-1-phosphate receptor agonists. Science. 2002;296(5566):346-
349.
3. Jain N, Bhatti MT. Fingolimod-associated macular edema: incidence, detec-
tion, and management. Neurology. 2012;78(9):672-680.
4. Oo ML, Chang SH, Thangada S, et al. Engagement of S1P1-degradative mecha-
nisms leads to vascular leak in mice. J Clin Invest. 2011;121(6):2290-2300.
5. Turaka K, Bryan JS. Does fingolimod in multiple sclerosis patients cause macu-
lar edema? J Neurol. 2012;259(2):386-388.
6. Hariprasad SM, Akduman L, Clever JA, Ober M, Recchia FM, Mieler WF.
Treatment of cystoid macular edema with the new-generation NSAID nepa-
fenac 0.1%. Clin Ophthalmol. 2009;3:147-154.
7. Afshar AR, Fernandes JK, Patel RD, et al. Cystoid macular edema associated
with fingolimod use for multiple sclerosis. JAMA Ophthalmol. 2013;131(1):
103-107.
8. Gelfand JM, Nolan R, Schwartz DM, Graves J, Green AJ. Microcystic macular
oedema in multiple sclerosis is associated with disease severity. Brain. 2012;
135(pt 6):1786-1793.
COMMENTS AND OPINIONS
Validity of the Results
of a Contact Lens Sensor?
W e read with great interest the study by Man-
souri et al titled “Continuous 24-Hour Moni-
toring of Intraocular Pressure Patterns With
a Contact Lens Sensor: Safety, Tolerability, and Repro-
ducibility in Patients With Glaucoma.”1
The authors describe their results about safety and tol-
erability of the contact lens sensor (CLS) Triggerfish (Sen-
simed AG) in 40 eyes of 40 patients either with glau-
coma or suspected of having glaucoma. Safety and
tolerability were good. We, too, could find the same sat-
isfying results in our patients (so far 30 eyes, one of us
[C.F.] 3 times).2
In addition, the authors studied the reproducibility of
the measurements by repeating their examinations 1 week
apart. The Pearson correlation showed an overall corre-
lation of r=0.59, determined as fair to good. We studied
the reproducibility in only 5 subjects (young, healthy eyes;
not for 24 hours, but for 2 hours) and found the same
results.3
Besides safety, tolerability, and reproducibility, one very
important quality is yet missing: the validity of the re-
sults gained by the CLS in young subjects as well as in
elderly patients with and without glaucoma. Leonardi et
al, the “inventors” of this CLS, (only) performed mea-
surements in juvenile porcine eyes by inducing very short-
acting spikes of intraocular pressure (IOP) (injection and
ejection to ⫾10 mm Hg within 50 seconds4 or ⫹3 mm Hg
within 5 seconds5) and reported excellent results.
We performed a similar experiment in 1 enucleated
human eye but increased the IOP stepwise by 5 mm Hg
using a pump for much longer periods (30 minutes). We
could not obtain the expected stepwise profile by means
of the CLS.6
No further experimental studies have been pub-
lished on the validity of the results of the CLS so far. We
therefore built a setup of 5 young subjects with healthy
eyes in whom we measured the IOP in one eye with ap-
WWW.JAMAOPHTH.COM