A JOURNAL OF NEUROLOGY
Microcystic macular oedema in multiple sclerosis
is associated with disease severity
Jeffrey M. Gelfand,1Rachel Nolan,1Daniel M. Schwartz,2Jennifer Graves1and Ari J. Green1,3
1 Multiple Sclerosis Centre, University of California, San Francisco, Department of Neurology, 400 Parnassus Ave, San Francisco, CA 94143-0114, USA
2 Retinal Service, University of California, San Francisco, Department of Ophthalmology, San Francisco, CA 94143, USA
3 Neuro-Ophthalmology Service, University of California, San Francisco, Department of Ophthalmology, San Francisco, CA 94143, USA
Correspondence to: Ari Green, MD,
UCSF Department of Neurology,
400 Parnassus Ave,
Box 0114, San Francisco,
CA 94143, USA
Macular oedema typically results from blood–retinal barrier disruption. It has recently been reported that patients with multiple
sclerosis treated with FTY-720 (fingolimod) may exhibit macular oedema. Multiple sclerosis is not otherwise thought to be
associated with macular oedema except in the context of comorbid clinical uveitis. Despite a lack of myelin, the retina is a site
of inflammation and microglial activation in multiple sclerosis and demonstrates significant neuronal and axonal loss. We
unexpectedly observed microcystic macular oedema using spectral domain optical coherence tomography in patients with
multiple sclerosis who did not have another reason for macular oedema. We therefore evaluated spectral domain optical
coherence tomography images in consecutive patients with multiple sclerosis for microcystic macular oedema and examined
correlations between macular oedema and visual and ambulatory disability in a cross-sectional analysis. Participants were
excluded if there was a comorbidity that could account for the presence of macular oedema, such as uveitis, diabetes or
other retinal disease. A microcystic pattern of macular oedema was observed on optical coherence tomography in 15 of 318
(4.7%) patients with multiple sclerosis. No macular oedema was identified in 52 healthy controls assessed over the same
period. The microcystic oedema predominantly involved the inner nuclear layer of the retina and tended to occur in small,
discrete patches. Patients with multiple sclerosis with microcystic macular oedema had significantly worse disability [median
Expanded Disability Score Scale 4 (interquartile range 3–6)] than patients without macular oedema [median Expanded Disability
Score Scale 2 (interquartile range 1.5–3.5)], P = 0.0002. Patients with multiple sclerosis with microcystic macular oedema also
had higher Multiple Sclerosis Severity Scores, a measure of disease progression, than those without oedema [median of 6.47
(interquartile range 4.96–7.98) versus 3.65 (interquartile range 1.92–5.87), P = 0.0009]. Microcystic macular oedema occurred
more commonly in eyes with prior optic neuritis than eyes without prior optic neuritis (50 versus 27%) and was associated with
lower visual acuity (median logMAR acuity of 0.17 versus ?0.1) and a thinner retinal nerve fibre layer. The presence of
microcystic macular oedema in multiple sclerosis suggests that there may be breakdown of the blood–retinal barrier and
tight junction integrity in a part of the nervous system that lacks myelin. Microcystic macular oedema may also contribute
to visual dysfunction beyond that explained by nerve fibre layer loss. Microcystic changes need to be assessed, and potentially
adjusted for, in clinical trials that evaluate macular volume as a marker of retinal ganglion cell survival. These findings also have
implications for clinical monitoring in patients with multiple sclerosis on sphingosine 1-phosphate receptor modulating agents.
Keywords: multiple sclerosis; optical coherence tomography; retina; macular oedema
Abbreviations: EDSS = Expanded Disability Score Scale; OCT = optical coherence tomography; RNFL = retinal nerve fibre layer
doi:10.1093/brain/aws098 Brain 2012: 135; 1786–1793 |
Received November 9, 2011. Revised February 23, 2012. Accepted February 24, 2012. Advance Access publication April 25, 2012
? The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, et al.
Quantifying axonal loss after optic neuritis with optical coherence
tomography. Ann Neurol 2006; 59: 963–9.
Costello F, Hodge W, Pan YI, Freedman M, DeMeulemeester C.
Differences in retinal nerve fiber layer atrophy between multiple scler-
osis subtypes. J Neurol Sci 2009; 281: 74–9.
Cunha-Vaz JG, Shakib M, Ashton N. Studies on the permeability of the
blood-retinal barrier. I. On the existence, development, and site of a
blood-retinal barrier. Br J Ophthalmol 1966; 50: 441–53.
Donaldson MJ, Pulido JS, Herman DC, Diehl N, Hodge D. Pars planitis: a
20-year study of incidence, clinical features, and outcomes. Am J
Ophthalmol 2007; 144: 812–7.
Early TreatmentDiabetic Retinopathy
Diabetic Retinopathy Study report number 1. Early Treatment
Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;
FDA. Center for Drug Evaluation and Research (CDER) Peripheral and
Central Nervous System Drugs Advisory Committee Meeting Report.
Fingolimod (NDA 22-527) Background Package, 20 June 2010.
Fisher JB, Jacobs DA, Markowitz CE, Galetta SL, Volpe NJ, Nano-
Schiavi ML, et al. Relation of visual function to retinal nerve fiber
layer thickness in multiple sclerosis. Ophthalmology 2006; 113:
Frohman E, Costello F, Zivadinov R, Stuve O, Conger A, Winslow H,
et al. Optical coherence tomography in multiple sclerosis. Lancet
Neurol 2006; 5: 853–63.
Gaitan MI, Shea CD, Evangelou IE, Stone RD, Fenton KM, Bielekova B,
et al. Evolution of the blood-brain barrier in newly forming multiple
sclerosis lesions. Ann Neurol 2011; 70: 22–9.
Gay D, Esiri M. Blood-brain barrier damage in acute multiple sclerosis
plaques. An immunocytological study. Brain 1991; 114: 557–72.
Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M,
Balcer LJ, et al. Retinal nerve fiber layer is associated with brain atro-
phy in multiple sclerosis. Neurology 2007; 69: 1603–9.
Green AJ, McQuaid S, Hauser SL, Allen IV, Lyness R. Ocular pathology
in multiple sclerosis: retinal atrophy and inflammation irrespective of
disease duration. Brain 2010; 133 (Pt 6): 1591–601.
Hume DA, Perry VH, Gordon S. Immunohistochemical localization of a
macrophage-specific antigen in developing mouse retina: phagocytosis
of dying neurons and differentiation of microglial cells to form a regu-
lar array in the plexiform layers. J Cell Biol 1983; 97: 253–7.
Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P,
et al. A placebo-controlled trial of oral fingolimod in relapsing multiple
sclerosis. N Engl J Med 2010; 362: 387–401.
Kerrison JB, Flynn T, Green WR. Retinal pathologic changes in multiple
sclerosis. Retina 1994; 14: 445–51.
Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, et al.
relapsing-remitting multiple sclerosis: a randomised extension of the
TRANSFORMS study. Lancet Neurol 2011; 10: 520–9.
Kirk J, Plumb J, Mirakhur M, McQuaid S. Tight junctional abnormality in
multiple sclerosis white matter affects all calibres of vessel and is asso-
ciated with blood-brain barrier leakage and active demyelination. J
Pathol 2003; 201: 319–27.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an ex-
panded disability status scale (EDSS). Neurology 1983; 33: 1444–52.
Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple
sclerosis: an overview. Brain Pathol 2007; 17: 210–8.
Lightman S, McDonald WI, Bird AC, Francis DA, Hoskins A, Batchelor JR,
et al. Retinal venous sheathing in optic neuritis. Its significance for the
pathogenesis of multiple sclerosis. Brain 1987; 110 (Pt 2): 405–14.
Mackenzie S, Schmermer C, Charnley A, Sim D, Vikas T, Dumkyj M,
et al. SDOCT imaging to identify macular pathology in patients
with interferonbeta-1a in
diagnosed with diabetic maculopathy by a digital photographic retinal
screening programme. PLoS One 2011; 6: e14811.
Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and com-
plications associated with pars planitis. Ophthalmology 1993; 100:
Marmor MF. Mechanismultiple sclerosis of fluid accumulation in retinal
edema. Doc Ophthalmol 1999; 97: 239–49.
Padden M, Leech S, Craig B, Kirk J, Brankin B, McQuaid S. Differences in
expression of junctional adhesion molecule-A and beta-catenin in mul-
tiple sclerosis brain tissue: increasing evidence for the role of tight
junction pathology. Acta Neuropathol 2007; 113: 177–86.
Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L,
et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the
“McDonald Criteria”. Ann Neurol 2005; 58: 840–6.
Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G,
Calabresi PA. Optical coherence tomography and disease subtype in
multiple sclerosis. Neurology 2007; 69: 2085–92.
Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ,
Vukusic S, et al. Multiple Sclerosis Severity Score: using disability and
disease duration to rate disease severity. Neurology 2005; 64:
Rucker C. Sheathing of the retinal veins in multiple sclerosis. Proceedings
of the Staff Meetings of the Mayo Clinic1944; 19: 176–8.
Runkle EA, Antonetti DA. The blood-retinal barrier: structure and func-
tional significance. Methods Mol Biol 2011; 686: 133–48.
Saab G, Almony A, Blinder KJ, Schuessler R, Brennan DC. Reversible
cystoid macular edema secondary to fingolimod in a renal transplant
recipient. Arch Ophthalmol 2008; 126: 140–1.
Saidha S, Syc SB, Durbin MK, Eckstein C, Oakley JD, Meyer SA, et al.
Visual dysfunction in multiple sclerosis correlates better with optical
coherence tomography derived estimates of macular ganglion cell
layer thickness than peripapillary retinal nerve fiber layer thickness.
Mult Scler 2011a; 17: 1449–63.
Saidha S, Syc SB, Ibrahim MA, Eckstein C, Warner CV, Farrell SK, et al.
Primary retinal pathology in multiple sclerosis as detected by optical
coherence tomography. Brain 2011b; 134 (Pt 2): 518–33.
Salvadori M, Budde K, Charpentier B, Klempnauer J, Nashan B,
Pallardo LM, et al. FTY720 versus MMF with cyclosporine in de
novo renal transplantation: a 1-year, randomized controlled trial in
Europe and Australasia. Am J Transplant 2006; 6: 2912–21.
Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema.
Ophthalmologica 2010; 224 (Suppl. 1): 8–15.
Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, Garcia-Layana A,
Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities
in predicting disease activity in MS. Neurology 2007; 68: 1488–94.
Sugar EA, Jabs DA, Altaweel MM, Lightman S, Acharya N, Vitale AT,
et al. Identifying a clinically meaningful threshold for change in uveitic
macular edema evaluated by optical coherence tomography. Am J
Ophthalmol 2011; 152: 1044–52.
Talman LS, Bisker ER, Sackel DJ, Long DA Jr, Galetta KM, Ratchford JN,
et al. Longitudinal study of vision and retinal nerve fiber layer thickness
in multiple sclerosis. Ann Neurol 2010; 67: 749–60.
ter Braak J, van Herwaarden A. Ophthalmo-encephalomyelitis (Clinical
Augenheilkunde 1933; 91: 316–43.
Tran TH, de Smet MD, Bodaghi B, Fardeau C, Cassoux N, Lehoang P.
Uveitic macular oedema: correlation between optical coherence tom-
ography patterns with visual acuity and fluorescein angiography. Br J
Ophthalmol 2008; 92: 922–7.
Trip SA, Schlottmann PG, Jones SJ, Altmann DR, Garway-Heath DF,
Thompson AJ, et al. Retinal nerve fiber layer axonal loss and visual
dysfunction in optic neuritis. Ann Neurol 2005; 58: 383–91.
Vidovic-Valentincic N, Kraut A, Hawlina M, Stunf S, Rothova A.
Intermediate uveitis: long-term course and visual outcome. Br J
Ophthalmol 2009; 93: 477–80.
Klinische Monatsbla ¨tter
Microcystic macular oedema in multiple sclerosisBrain 2012: 135; 1786–1793 |