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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Multiple sclerosis is a disease of the CNS characterized by
immune-mediated injury, demyelination and neuroaxonal loss
(Lassmann et al., 2007). Despite a lack of myelin, which is thought
to contain the principal target(s) of immune activation in multiple
sclerosis, the retina is a site of neuronal and axonal loss in multiple
sclerosis (Trip et al., 2005; Costello et al., 2006; Fisher et al.,
2006; Gordon-Lipkin et al., 2007; Pulicken et al., 2007; Green
et al., 2010; Talman et al., 2010; Saidha et al., 2011b). The
retina is also a site of inflammation and blood–retinal barrier dis-
ruption in multiple sclerosis (Rucker, 1944; Lightman et al., 1987;
Kerrison et al., 1994, Green et al., 2010). As in the brain, retinal
inflammation in multiple sclerosis is most prominent in the peri-
vascular space and can sometimes be identified on clinical exam-
ination in the form of retinal periphlebitis (ter Braak and van
Herwaarden, 1933; Rucker, 1944; Lightman et al., 1987), a find-
ing associated with greater overall multiple sclerosis disease activity
(Sepulcre et al., 2007). Inflammation and microglial activation are
also evident within the parenchyma of the inner retina in multiple
sclerosis (Green et al., 2010), but this pathological finding has not
yet been confirmed in a clinical setting. Given that the retina is
unmyelinated, exploring how retinal inflammation arises in mul-
tiple sclerosis may yield insights about the relationship between
inflammation and neurodegeneration in the disease.
Optical coherence tomography (OCT) is a non-invasive tech-
nique in which the backscatter of infrared light directed against
a target tissue is used to generate cross-sectional images (Frohman
et al., 2006). Advances in spectral domain OCT afford faster scan
times, automation of data collection and superior structural reso-
lution. OCT in multiple sclerosis has traditionally been used as a
measure of axonal loss, with numerous studies demonstrating
thinning of the peripapillary retinal nerve fibre and a reduction
in total macular volume (Trip et al., 2005; Costello et al., 2006,
2009; Fisher et al., 2006; Pulicken et al., 2007; Burkholder et al.,
2009; Talman et al., 2010; Saidha et al., 2011a). Recent work
using OCT also demonstrates that there is thinning of the retinal
ganglion cell, inner and outer nuclear layers in multiple sclerosis
(Saidha et al., 2011b).
Macular oedema, the collection of fluid within the retina, has a
number of potential causes, such as diabetes, uveitis, retinal vein
occlusion and age-related macular degeneration (Early Treatment
Diabetic Retinopathy Study Research Group, 1985; Marmor,
1999; Tran et al., 2008; Scholl et al., 2010; Sugar et al., 2011).
In multiple sclerosis, cystoid macular oedema can occur in patients
being treated with fingolimod, an oral sphingosine 1-phosphate
receptor modulator (Cohen et al., 2010; Kappos et al., 2010).
Cystoid macular oedema is also a known complication of uveitis
and pars planitis in multiple sclerosis (Malinowski et al., 1993). In
the absence of uveitis,fingolimod
comorbidity, however, macular oedema is not thought to be asso-
ciated with multiple sclerosis.
OCT has been shown to be a robust technique for identifying
macular oedema (Mackenzie et al., 2011; Sugar et al., 2011).
Microcystic macular oedema on spectral domain OCT was clinic-
ally observed in a subset of patients with multiple sclerosis imaged
in our laboratory who did not have another reason to have macu-
lar oedema, such as symptomatic uveitis, diabetes or fingolimod
exposure. Macular oedema was not observed on histopathology at
autopsy of patients who died with multiple sclerosis, but this ap-
proach may have been limited by fixation, sectioning and time of
sampling (Green et al., 2010). We therefore analysed retinal spec-
tral domain OCT images in consecutive patients with multiple
sclerosis for the presence of microcystic macular oedema and
examined correlations between microcystic macular oedema and
both visual and ambulatory disability in a cross-sectional analysis.
Materials and methods
The neurodiagnostics laboratory at the University of California, San
Francisco Multiple Sclerosis Centre provides a spectral domain OCT
service for patients with neurological disease. The study base for this
cross-sectional analysis was consecutive patients with multiple sclerosis
referred for spectral domain OCT imaging at the University of
California, San Francisco Multiple Sclerosis Centre as a standard evalu-
ation for multiple sclerosis in our clinic between January 2010 and
August 2011. Spectral domain OCT images of 52 healthy controls
without known neurological or ophthalmological disease, some of
who were friends or spouses of patients with multiple sclerosis, were
also examined for evidence of microcystic macular oedema. All par-
ticipants provided written informed consent, and the University of
California, San Francisco Committee on Human Research approved
the study protocol.
Participants classified as having multiple sclerosis satisfied 2005
International Panel diagnostic criteria (Polman et al., 2005). Participants
were excluded if there was any history of a comorbidity that could
plausibly account for the presence of macular oedema, including a
prior history of uveitis (n = 8), diabetes (n = 4), retinal vein occlusion,
age-related macular degeneration (n = 1), retinal infection (n = 1), ret-
inal surgery (n = 1), retinitis pigmentosa (n = 2), cataract surgery (within
1 year) or intraocular malignancy (n = 1). Participants with a history of
glaucoma were also excluded to minimize possible confounding for
correlations with retinal nerve fibre layer (RNFL) thickness and visual
function. Subtype and stage of multiple sclerosis were assigned by the
treating multiple sclerosis specialists and confirmed by the study inves-
tigators through medical record review. A history of acute demyelinat-
ing optic neuritis, defined clinically as a subacute episode of visual
blurring or loss associated with eye pain, was determined by the treat-
ing multiple sclerosis specialist and confirmed by study investigators
through subject interview and medical record review. Disease duration
was defined as the time from the first clinical symptom attributable to
multiple sclerosis to the date of OCT evaluation. The Expanded Disabil-
ity Score Scale (EDSS) (Kurtzke, 1983) was assigned by the treating
multiple sclerosis specialist and confirmed by the study investigators
through medical record review (and not calculated during the time of
an acute relapse). The Multiple Sclerosis Severity Score, a predictor of
future disability in multiple sclerosis, was calculated from the EDSS and
clinical disease duration (Roxburgh et al., 2005).
High contrast visual acuity was measured using a computerized Early
Treatment Diabetic RetinopathyStudy chart (ProVideo system,
Microcystic macular oedema in multiple sclerosis Brain 2012: 135; 1786–1793 |
INNOVA Systems). For statistical analysis, visual acuity was converted
from the Snellen to the LogMAR scale, which was calculated as the
negative log (base 10) of the decimal value of the Snellen acuity. A
LogMAR value of 0 is equivalent to 20/20 vision, with positive values
indicating less than 20/20 vision and negative values indicating better
than 20/20 vision. Slit-lamp examinations and dilated retinal ophthal-
moscopy were not routinely performed.
Spectral domain optical coherence
Spectral domain OCT was performed using the Spectralis OCT system
(Heidelberg Engineering). For evaluation of the macula and macular
volume measures, raster scans of the macula (20 ? 15?) consisting of
19 line scans were obtained. For circumpapillary measurements of
RNFL, the peripapillary RNFL was measured at a distance of 3.4mm
from the centre of the papilla. Prior to analysis, RNFL thickness was
calculated using the provided software, with quality control measures
including confirmation of accurate inner limiting membrane identifica-
tion and absence of other significant retinal pathology. Furthermore,
scans with insufficient signal to noise ratio or edge detection/retinal
thickness algorithm failure were excluded and measurements were
repeated until a good quality image was achieved. Automatic real-time
is a method for maintaining OCT B-scan alignment and registration
during image acquisition on the Spectralis OCT. The automatic
real-time number is the number of B-scans averaged to produce the
final image. In Spectralis OCT the quality number is a measure of
signal strength. Our laboratory standard includes a target automatic
real-time number of 48 for raster scans of the macula and a quality
number of 20.
Microcystic macular oedema was defined as cystic, lacunar areas of
hyporeflectivity with clear boundaries (Brar et al., 2010) on spectral
domain OCT macular volume images, excluding lesions due to speckl-
ing artefact. Scans reported as demonstrating microcycstic macular
oedema were additionally confirmed by a retinal specialist (D.M.S.),
blinded to neurological history. For confirmation we required that
microcystic abnormalities be unequivocally identified on two adjacent
B-scans and on two separate acquisitions.
Differences in demographic variables between patients with multiple
sclerosis with and without macular oedema were analysed using the
student’s t-test for age, the ?2test for sex and the Wilcoxon Rank
Sum test for EDSS, Multiple Sclerosis Severity Score and disease
duration (non-parametric analysis). Differences in optic neuritis history
between eyes with and without macular oedema were analysed using
the ?2test. Multiple linear regression was used to examine differences
in visual acuity, RNFL and macular volume between the groups of eyes
with and without microcystic macular oedema, adjusting for age, sex,
disease duration and optic neuritis. To account for within-patient
inter-eye correlations, the standard error was adjusted for possible
clustering using the clustered sandwich estimator ordinary least
squares method. A P-value of 50.05 was interpreted as significant.
Statistical analyses were performed using Stata 12.0 (Statacorp).
Microcystic macular oedema was observed in 15 of 318 (4.7%)
unique, consecutive patients with multiple sclerosis over the
20-month study period. The microcystic oedema was bilateral in
five patients. Six additional patients with multiple sclerosis
exhibited various manifestations of macular oedema on spectral
domain OCT, but were excluded from analysis due to a history
of diabetes, viral retinitis, retinitis pigmentosa and prior ocular
radiation. None of the patients with microcystic macular oedema
were taking fingolimod at the time of baseline OCT scanning or
had taken fingolimod prior to the baseline scan. None of 52
unaffected controls [mean age 36.9 years (standard deviation,
SD 11.8), 56% female, logMAR acuity median ?0.12 (interquar-
tile range ?0.3 to ?0.12)] had evidence of microcystic macular
oedema on spectral domain OCT.
As illustrated in Fig. 1, the microcystic oedema predominantly
involved the inner nuclear layer of the retina and tended to occur
in small, discrete patches. The microcysts ranged in size from
?20 ? 30mm to ?70 ? 90mm along the x–y axis. Below the micro-
cysts, lower reflectance (darker colour on spectral domain OCT)
was observed in deeper retinal layers, which is indicative of sha-
dowing and supportive of the presence of fluid in the inner nuclear
layer. The location of microcystic oedema detected ranged from the
foveal centre to as far as 2300mm from the fovea, but most of the
oedema occurred ?500–1800mm from the foveal centre and vari-
ably affected all quadrants. In three eyes with microcystic changes
in the inner nuclear layer, there was concomitant involvement of
the outer nuclear layer (Fig. 1G), which was directly foveal (140–
300mm from the foveal centre) in one patient and 800–900mm
from the fovea in the others. Two eyes with microcystic oedema
in the inner nuclear layer also exhibited mild involvement in the
ganglion cell layer. An epiretinal membrane was noted in 2 of the
15 patients with multiple sclerosis with microcystic oedema, one of
which demonstrated minimal retina traction (not thought to be
significant enough to cause oedema). None of the patients with
microcystic macular oedema had evidence of hyaloid membrane
traction. None of the patients with microcystic macular oedema
had evidence of retinal periphlebitis.
Patients with multiple sclerosis with microcystic macular oedema
(Table 1) tended to be slightly older and have longer disease dur-
ations than patients with multiple sclerosis without macular
oedema, but these differences were not statistically significant.
Patients with multiple sclerosis with microcystic macular oedema
had significantly worse disability (as measured by median EDSS)
than patients with multiple sclerosis without macular oedema [4
(interquartile range, IQR 3–6) versus 2 (IQR 1.5–3.5), P = 0.0002;
Table 1 and Fig. 2]. Adjustment for age and disease duration using
a logistic regression model did not change the results. Patients
with multiple sclerosis with microcystic macular oedema also had
higher Multiple Sclerosis Severity Scores than patients without
oedema [6.47 (IQR 4.96–7.98) versus 3.65 (IQR 1.92–5.87),
P = 0.0009; Table 1], indicating a higher risk of future disability.
Visual acuity was more impaired in eyes with microcystic macu-
lar oedema (median logMAR acuity of 0.17, which is equivalent to
a Snellen acuity of about 20/30) than multiple sclerosis eyes with-
out oedema (median logMAR acuity of ?0.1). Even so, one-third
of multiple sclerosis eyes with microcystic macular oedema had a
visual acuity better than 20/25. Visual acuity impairment remained
associated with microcystic macular oedema after adjustment for
optic neuritis history and age, sex, disease duration and RNFL
Brain 2012: 135; 1786–1793J. M. Gelfand et al.
thickness in a linear regression model (P = 0.02), and in a model
adjusting for RNFL thickness as a categorical variable (75mm and
below versus 475mm) given possible threshold effects of RNFL
loss on visual dysfunction (Costello et al., 2006).
A history of optic neuritis was more common in eyes with mi-
crocystic macular oedema than eyes without oedema (Table 2).
The optic neuritis was acute (within 14 days) in a single patient
with microcystic oedema and in the others occurred a median of
Figure 1 Microcystic macular oedema on spectral domain optical coherence tomography in multiple sclerosis. (A–H) Seven different
patients with multiple sclerosis; B is a magnified view of A. The microcysts predominantly involved the inner nuclear layer of the retina
(asterisks). For comparison purposes, I is a representative scan without macular oedema in a patient with relapsing-remitting multiple
sclerosis and J is a representative scan from an unaffected control. Note that the retinal nerve fibre layer (short arrow) is thinner in the
patient with multiple sclerosis (I) than in the control participant (J). An epiretinal membrane is noted in H (wide arrow).
Microcystic macular oedema in multiple sclerosis Brain 2012: 135; 1786–1793 |
3 years prior to scanning (IQR 1–11 years, range 0.5–31 years).
The patient with a recent acute optic neuritis had just completed a
course of corticosteroids; a second patient with microcystic
oedema received a dose of monthly pulse steroids 2 months
prior to OCT scanning; a third patient received a course of intra-
venous pulse steroids 5 months prior; and a fourth patient
received steroids 7 months prior; none of the other 11 patients
with microcystic macular oedema had received corticosteroids for
more than a year prior to OCT scanning.
The total RNFL was thinner in eyes with microcystic macular
oedema (median 66mm) than multiple sclerosis eyes without
oedema (median 87mm) (Table 1). The total RNFL was also thin-
ner in eyes with microcystic macular oedema after adjustment for
age, sex, disease duration and history of symptomatic optic neur-
itis in that eye (P50.001). Macular volume trended lower in eyes
with microcystic oedema than multiple sclerosis eyes without
oedema, but after adjustment for history of optic neuritis, this
was not significant (P = 0.3).
Longitudinal spectral domain OCT scanning was available on a
convenience sample of six of the 15 patients with microcystic
macular oedema. Microcystic changes appeared to be dynamic
over time, improving in size, appearance and area of involvement
in some patients and becoming more prominent in others (Fig. 3).
The microcystic oedema improved in two of the patients (com-
pletely resolving in one), was relatively stable in one and worsened
in the three others (median follow-up time 9.5 months, range 3–
12 months). Two of the six patients with longitudinal follow-up of
microcystic macular oedema elected to proceed with fingolimod
therapy—the macular oedema was stable in one patient at 9
months of follow-up and slightly more prominent in the other
patient at 3 months of follow-up, with no significant change in
Microcystic macular oedema, predominantly involving the inner
nuclear layer of the retina, was observed in a subset of patients
with multiple sclerosis with no other identifiable cause. The pres-
ence of microcystic macular oedema was associated with greater
overall disability(EDSS), disease severity
Severity Score), reduced visual acuity and occurred more com-
monly in eyes with prior optic neuritis.
Table 1 Patients with multiple sclerosis with and without microcystic macular oedema
without oedema (n = 303)
Patients with multiple
sclerosis with microcystic
macular oedema (n = 15)
Age (years), mean (SD)
Disease duration (years), median (IQR)
EDSS, median (IQR)
Multiple Sclerosis Severity Score, median (IQR)
Multiple sclerosis subtype, n (%)
Clinically isolated syndrome
Relapsing-remitting multiple sclerosis
Secondary-progressive multiple sclerosis
Primary-progressive multiple sclerosis
Progressive-relapsing multiple sclerosis
Percentages do not add up to 100 due to rounding.
a Student’s t-test.
c Wilcoxon Rank Sum test.
Figure 2 Microcystic macular oedema in multiple sclerosis is
associated with greater disability (EDSS). The P-value was cal-
culated by the Wilcoxon Rank Sum test. The line in the centre of
the box indicates the median and the shaded box denotes the
IQR. The whiskers denote minimum and maximum values,
excluding outliers (defined as 41.5 times the lower and upper
Brain 2012: 135; 1786–1793J. M. Gelfand et al.
In a large series of patients with macular oedema evaluated in a
subspecialty retina clinic, microcysts involving the inner nuclear
layer were observed on spectral domain OCT in a quarter of
eyes demonstrating diffuse fluorescein leakage (a marker of
blood–retinal barrier breakdown) (Brar et al., 2010). Microcysts
were not detected on fluorescein angiography in any of those
cases, possibly due to the lower spatial resolution of fluorescein
angiography compared with spectral domain OCT, even when
performed using a scanning laser ophthalmoscope (Brar et al.,
2010). These observations further illustrate the importance of
source image analysis of retinal OCT in multiple sclerosis and
not just a review of automated quantitative algorithms. Increases
in macular volume are sometimes used as a marker for macular
oedema (Sugar et al., 2011), but macular volumes tended to be
lower in eyes with microcystic macular oedema than eyes without
oedema in our cross-sectional analysis. This is likely to be attrib-
utable to microcystic oedema occurring more frequently in eyes
with prior optic neuritis, a well-established cause of macular
volume loss (Trip et al., 2005; Pulicken et al., 2007; Burkholder
et al., 2009).
In Phase III trials of fingolimod, a sphingosine 1-phosphate re-
ceptor modulator used as disease modifying therapy in multiple
sclerosis, cystoid macular oedema was observed in 0–0.5% of pa-
tients randomized to the 0.5mg dose and 0.7–1% of patients
randomized to the 1.2mg dose (Cohen et al., 2010; Kappos
et al., 2010; Khatri et al., 2011). Macular oedema was also
observed in renal transplant patients taking fingolimod (Salvadori
et al., 2006; FDA, 2010). Screening and follow-up testing in those
studies, however, wereperformed
time-domain OCT platforms that lack the resolution to readily
identify the kinds of microcysts described here. Fingolimod-
associated macular oedema is thought to be reversible with treat-
ment cessation (Saab et al., 2008), but at least one patient with
multiple sclerosis with cystoid macular oedema on fingolimod ther-
apy required surgery to repair a full-thickness macular hole (FDA,
2010). Whether the initiation of fingolimod augments or acceler-
ates pre-existing microcystic macular oedema in multiple sclerosis
is unknown. Spectral domain OCT screening of patients with mul-
tiple sclerosis prior to fingolimod initiation may be helpful to detect
baseline microcystic macular oedema and track associations with
Figure 3 Microcystic macular oedema worsened at 5 months of
follow-up in one patient (A and B), with an increase in macular
volume from 3.14 to 3.19mm3, while improving at 12 months
of follow-up in another patient (C and D), with a decrease in
macular volume from 3.01 to 2.99mm3. In A and B, the auto-
matic real-time was 70 and quality was 26 and 22, respectively.
In C and D, the automatic real-time was 30 and the quality was
29 and 22, respectively.
Table 2 Ocular parameters in patients with multiple sclerosis with and without microcystic macular oedema
Eyes without macular
oedema (n = 606)
Eyes with microcystic
macular oedema (n = 20)a
Prior symptomatic optic neuritis in that eye, n (%)
Total RNFL thickness (mm), mean (SD)
Macular volume (mm3), mean (SD)
Foveal thickness (mm), mean (SD)
Visual acuity (logMAR), median (IQR)
?0.1 (?0.1 to 0)
0.17 (0 to 0.4)
a Excluding fellow eyes in patients with unilateral microcystic macular oedema.
c Linear regression, with the standard error adjusted for possible clustering at the patient level (within-patient inter-eye correlations).
d Linear regression of differences in visual acuity between groups, adjusting for RNFL thickness, optic neuritis history in that eye, age, sex and disease duration, with the
standard error adjusted for possible clustering at the patient level (within-patient inter-eye correlations).
Microcystic macular oedema in multiple sclerosisBrain 2012: 135; 1786–1793 |
Macular oedema typically results from breakdown of the blood–
retinal barrier (Marmor, 1999). The blood–retinal barrier is analo-
gous to the blood–brain barrier, with shared biochemical and
molecular mechanisms for maintenance of endothelial tight
junctions (Cunha-Vaz et al., 1966; Runkle and Antonetti, 2011).
Disruption of the blood–brain barrier is a pathological and radio-
logical hallmark of acute multiple sclerosis plaques (Gay and Esiri,
1991; Gaitan et al., 2011). Histopathological evidence of blood–
brain barrier leakage is also evident in normal appearing white
matter in multiple sclerosis (Kirk et al., 2003; Padden et al.,
2007). The cause of microcystic macular oedema in multiple scler-
osis is unknown, but if it relates to blood–retinal barrier disruption,
possibly due to subclinical uveitis or retinitis (Donaldson et al.,
2007; Vidovic-Valentincic et al., 2009), it would suggest that
breakdown of tight junction integrity in multiple sclerosis may
also occur in an area of the nervous system without myelin.
One possible explanation for how this may occur is that retinal
neuronal and axonal injury could lead to release of cellular distress
signals, which, in turn, could lead to focal intraretinal microglial
activation and inflammation. This could cause local blood–retinal
barrier disruption and fluid accumulation with cystic changes
within the retina. Another possible mechanism is that blood–retinal
barrier breakdown may occur concurrently with blood–brain bar-
rier breakdown, as evidenced by the association of multifocal sites
of leakage on fluorescein angiography in some patients with acute
optic neuritis (Lightman et al., 1987).
The inner nuclear layer is a prominent site of retinal inflamma-
tion and microglial activation in multiple sclerosis (Green et al.,
2010). Inner nuclear layer thinning in multiple sclerosis is also
associated withgreater disease
Severity Score) (Saidha et al., 2011b). A mixed retinal phenotype
with inner and outer nuclear layer thinning associated with RNFL
and ganglion cell layer and inner plexiform layer thinning was also
recently described in multiple sclerosis (Saidha et al., 2011a). The
predominance of microcystic changes within the inner nuclear
layer raises the hypothesis that microcystic macular oedema may
be a clinical correlate of inner nuclear inflammation and microglial
activation in multiple sclerosis. Microglia in the retina are concen-
trated within two parallel networks in the inner and outer plexi-
form layers (Hume et al., 1983), which are the layers that lie
immediately adjacent to the inner nuclear layer. Longitudinal stu-
dies will be needed to determine if macular oedema is associated
with neuronal loss in the inner nuclear layer or possibly transsy-
naptic degeneration. If such an association exists, it may help to
account for the recently described macular thinning phenotype of
retinal neuronal loss in a subset of patients with aggressive mul-
tiple sclerosis (Saidha et al., 2011b).
One of the most significant advances in retinal OCT imaging in
recent years is the combination of the spectral domain technique
with automated image registration. This enables dramatically
increased imaging speed, which provides the capability to repeat-
edly sample individual B-scans and average these multiple snap-
shots into a crisper composite image by reducing signal to noise
(which is the concept of the automatic real-time measure on the
Heidelberg spectral domain OCT platform used in this study).
While the use of high automatic real-time sequences improves
accuracy of retinal thickness measures, too high an automatic
real-time can have the paradoxical effect of over-averaging under-
lying retinal pathology, potentially leading to obscuration of micro-
cystic changes. Averaging B-scans without real-time tracking
would also be likely to make microcystic changes more difficult
to resolve. Incorporation of macular volume scans with less aver-
aging into the standard OCT protocol for evaluation of patients
with multiple sclerosis may help to improve detection of macular
This study has some important limitations. Fluorescein angiog-
raphy was not performed as part of the study protocol. Future
studies examining this phenotype of microcystic macular oedema
in multiple sclerosis would benefit from the inclusion of fluorescein
angiography, as leakage of fluorescein would be direct evidence of
breakdown of the blood–retinal barrier. As spectral domain OCT
examines only a limited area of retina (with poor coverage of the
retinal periphery), our methods are also likely to underestimate
the prevalence of microcystic retinal oedema in multiple sclerosis.
The inclusion of imaging at greater eccentricity from the fovea in
future studies would also provide added coverage to screen for
microcystic changes in retinal regions not included in macular OCT
scans. The dynamic nature of microcystic retinal oedema in mul-
tiple sclerosis could also bias the results towards under-sampling as
this was a cross-sectional analysis. As patients with a prior history
of uveitis were excluded from this analysis, the prevalence of
microcystic macular oedema in multiple sclerosis overall may also
be underestimated. It is also possible that unrecognized comorbid-
ities not detected through routine clinical evaluation contributed to
the formation of microcystic macular oedema in these patients.
If this finding is confirmed in other studies, microcystic macular
oedema may prove to be a clinically and mechanistically meaning-
ful marker of disease activity in multiple sclerosis. Further research
is needed to understand why microcystic macular oedema in mul-
tiple sclerosis occurs and whether microcystic oedema could also
be a potentially reversible cause of visual dysfunction in multiple
American Academy of Neurology Clinical Research Training Fel-
lowship (to J.M.G.); National Institutes of Health (KL2 RR-
024130), Howard Hughes Medical Institute Physician Scientist
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Klinische Monatsbla ¨tter
Microcystic macular oedema in multiple sclerosisBrain 2012: 135; 1786–1793 |