EDITORIALS

Paracentral Acute Middle Maculopathy and Acute

Macular Neuroretinopathy: Related and Distinct
Entities
KUNAL K. DANSINGANI AND K. BAILEY FREUND

HE HISTORY OF MEDICINE IS CHARACTERIZED BY DIS-

covery, subclassification, reorganization, and bifurcation of physiological concepts or pathologic

entities, driven by advances in investigative technologies
or by recognition of clinical details previously overlooked.
The story of paracentral acute middle maculopathy
(PAMM) is no exception. While it was initially described
by Sarraf and associates as a variant of acute macular neuroretinopathy (AMN), it is becoming increasingly evident
that PAMM should be considered a clinical finding related
to ischemia of the deep retinal circulation, not a specific
retinal disease.
In this issue of the Journal, Chen and associates describe
the occurrence of PAMM in 9 patients with diverse risk factors for retinal ischemia, including diabetes mellitus,
hypertension, hyperlipidemia, sickle cell disease, a flu-like
illness, and transient orbital compression.1 Additionally,
they report that PAMM lesions occurring in a patient with
recent motor vehicle trauma are indistinguishable from
polygonal Purtscher flecken, suggesting that certain lesions
in Purtscher retinopathy might in fact be lesions of
PAMM. Their findings significantly expand the known spectrum of etiologies that underlie PAMM and require a shift in
consideration of PAMM from a disease entity to a newly
recognized clinical finding with a wider differential diagnosis
that warrants further medical investigations and optimization
of systemic risk factors. Moreover, as PAMM lesions are being discovered with relative rapidity in an array of systemic
diseases, it appears that PAMM is likely to be more common
than the wider ophthalmic community currently appreciates.
In a previous report, Yu and associates described
the occurrence of PAMM in 35 patients with retinal
See accompanying article on page 26.
Accepted for publication May 4, 2015.
From Vitreous Retina Macula Consultants of New York (K.K.D.,
K.B.F.), LuEsther T. Mertz Retinal Research Center, Manhattan Eye,
Ear and Throat Hospital (K.K.D., K.B.F.), and Department of
Ophthalmology, New York University School of Medicine (K.B.F.),
New York, New York; and Moorfields Eye Hospital, London, United
Kingdom (K.K.D.).
Inquiries to K. Bailey Freund, Vitreous Retina Macula Consultants of
New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail:
kbfnyf@aol.com
0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2015.05.001

2015 BY

arterial occlusive disease and hypothesized that transient

ischemia of the intermediate and deep capillary plexuses
may account for PAMM. They described the PAMM
lesion as a deeper form of the more familiar cottonwool spot.2 In the acute phase, a cotton-wool spot
presents as a fluffy white nonexudative focal loss of transparency in the nerve fiber layer due to ischemic
axoplasmic stasis.3 After resolution, the cotton-wool
spot leaves a focus of inner retinal thinning or depression.
The relative subtlety of PAMM lesions when compared
with cotton-wool spots may be due to differences in
neurosensory architecture and optical characteristics
between inner plexiform, outer plexiform, and nerve fiber
layers, the latter of which contains the longest axons,
which are perpendicularly oriented to the axis of visualization and least translucent to visible light.
The organization of the retinal microcirculation into superficial, intermediate, and deep capillary plexuses is well
known from histologic and confocal imaging studies.46
The localization of PAMM lesions mostly within the inner
nuclear layer bordered by the intermediate and deep
capillary plexus etiologically implicates these vascular
layers, but the precise hemodynamic factors leading to
their occurrence remain incompletely understood.
The recent discovery of PAMM in patients with sickle
cell retinopathy, not only by Chen and associates1 but
also by Ilginis and associates,7 provides some insight into
its underlying mechanism. The capillary-occlusive manifestations of sickle cell retinopathy are attributed to the
change in aspect ratio and loss of compliance of erythrocytes as they enter a zone of reduced oxygen tension. It is
therefore believed that retinal vascular occlusive and
neovascular events in sickle cell retinopathy occur in the
peripheral retina because these areas are perfused by the
smallest capillaries, which are most distally located from
the oxygen source, the so-called watershed zones. The
observation that PAMM can occur parafoveally in sickle
cell patients, and even in the papillomacular bundle, suggests that the middle retina, distal in circulatory terms relative to the inner retinal circulation and to the
choriocapillaris, does indeed represent a functional watershed zone in the anteroposterior axis.

ELSEVIER INC. ALL

RIGHTS RESERVED.

Hemoglobinopathies vary in their predilection for

neovascular complications and severe, vision-threatening
retinopathy, and the Hb-SC variant carries the highest
risk. It would be interesting to find out whether the risk distribution of PAMM lesions across different hemoglobinopathies is similar to that of classical sickle cell retinopathy
and whether PAMM lesions antecede and predict the
development of classical sickle cell retinopathy.
Our view of the relationship between PAMM and AMN
is evolving as we question whether they are truly distinct
entities. In 1975, Bos and Deutman described a series of
patients, mostly young female subjects, who presented
with well-defined central scotomata that mapped to radially oriented perifoveal wedge-shaped lesions of AMN.8
They reported from biomicroscopic observations that
AMN appeared to involve the superficial retinal layers,
but imaging of AMN with time-domain optical coherence
tomography (OCT) demonstrated that these lesions in fact
reside in the outer retina.9 The superiority of near-infrared
reflectance over red-free imaging in demonstrating AMN
was not reported until 2007.10
With the application of ultrahigh-resolution and
spectral-domain OCT, further studies reported that
AMN lesions specifically involve the outer plexiform and
outer nuclear layers, where they manifest as hyperreflective
bands with associated ellipsoid disruption, subsequent loss
of hyperreflectivity, and a legacy of permanent thinning
of the outer nuclear layer.11
Subclassification of AMN was proposed in 2013 by Sarraf
and associates,12 who designated the outer plexiformouter
nuclear layer lesions as type 2 and described PAMM as a
new type 1 variant, with its characteristic parafoveal
hyperreflective band on spectral-domain OCT, mostly at
the level of the inner nuclear layer. The PAMM variant
was also noted to occur more commonly in older patients,
mostly male, with vasculopathic risk factors.12 By contrast,
AMN continues to be relatively rare and to have a demographic and risk profile that is distinctly different from
that of PAMM. Acute macular neuroretinopathy occurs
more commonly in younger female subjects who often
have had a recent history of a hypotensive or hypertensive
episode induced by febrile illness, trauma, or medication.
The pathogenesis of AMN remains unknown, although
our knowledge of the clinical circumstances surrounding
its onset, and of the affected demographic, might inform
our hypotheses. Andrews and associates have demonstrated
immunohistochemically that the distribution of markers of
mitochondrial enzyme activity in the axons of the Henle

fiber layer is biased toward the outer retina/photoreceptors,13 implying that these axons may lie on the functional
circulatory watershed between the choriocapillaris and the
most distal reaches of the deep capillary plexus. It is
possible that while PAMM results from occlusive events
of the retinal arterial tree, AMN results from a simultaneous
hypoperfusion more proximally at the level of the
ophthalmic artery that leads to reduced perfusion of both
the deep capillary plexus and choriocapillaris. The severity
of ischemia in the deep capillary plexus in AMN may not
be sufficient to produce PAMM lesions but, combined
with choriocapillaris ischemia, may reach the threshold
to cause AMN at the functional anteroposterior watershed.
If this is the case, it would place AMN at the mild end of a
perfusion spectrum defined in its worst manifestation by
conditions that cause simultaneous infarcts of the retina
and choroid, albeit with differing cellular pathology (eg, giant cell arteritis). Supporting the requisite for simultaneous
effects on both retinal and choroidal circulations in the
pathogenesis of AMN is the observation that even in complete central retinal artery occlusion, spectral-domain
OCT typically shows minimal outer retinal involvement.
Optical coherence tomography angiography (OCTA) is
a new modality that represents time-based changes in
reflectivity of intravascular components as quantifiable
flow maps with depth resolution.14 In the immediate future,
OCTA promises to reveal new information about retinal
capillary function in health and disease, with quantitative
indices.15
The application of new modalities, diagnostic or therapeutic, increases the collective knowledge of diseases and
informs the constantly evolving systems of classification
that we employ. At present we do not possess the tools
for restorative intervention at the capillary level, and there
is therefore no specific treatment for AMN or PAMM. It
remains to be seen whether a deeper understanding of these
conditions as capillaropathies further subclassifies them
or reunites them as having a common mechanism and
potential for intervention.
The relatively recent description of PAMM, together
with rapidly growing interest in studying it over the last
23 years, suggests that it is more common than previously
thought and that it accounts for visual debilitation in a
significant number of patients for whom definitive diagnosis may previously have been elusive. Its association
with an expanding spectrum of systemic risk factors makes
it an important finding with which all ophthalmologists
should attain familiarity.

THE AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Financial disclosures: Dr Freund is a consultant for Genentech (South San Francisco, California), Optovue (Fremont, California), Heidelberg Engineering
(Heidelberg, Germany), Optos (Marlborough, Massachusetts), and Thrombogenics (Leuven, Belgium). Funding support: LuEsther T. Mertz Retinal
Research Center, Manhattan Eye, Ear and Throat Hospital, New York, and the Macula Foundation, Inc, New York, New York, USA. The funding organization had no role in the conception, design, or production of this editorial. Both authors attest that they meet the current ICMJE requirements to qualify
as authors.

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REFERENCES
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deep capillary ischemia in retinal artery occlusion. Am J
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3. Schmidt D. The mystery of cotton-wool spots - a review of
recent and historical descriptions. Eur J Med Res 2008;
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4. Foreman DM, Bagley S, Moore J, Ireland GW, McLeod D,
Boulton ME. Three dimensional analysis of the retinal
vasculature using immunofluorescent staining and confocal
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5. Dorrell MI, Friedlander M, Smith LEH. Retinal vascular
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6. Tan PE, Yu PK, Balaratnasingam C, et al. Quantitative
confocal imaging of the retinal microvasculature in the human retina. Invest Ophthalmol Vis Sci 2012;53(9):57285736.
7. Ilginis T, Keane PA, Tufail A. paracentral acute middle
maculopathy in sickle cell disease. JAMA Ophthalmol 2015.

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8. Bos PJ, Deutman AF. Acute macular neuroretinopathy. Am J

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coherence tomography angiography. JAMA Ophthalmol 2015.

EDITORIAL

Biosketch
Kunal K. Dansingani studied medicine at Cambridge and at the Royal Free Hospital and UCL Medical School, London. He
completed postgraduate training in Ophthalmology in the UK, through the Royal College of Ophthalmologists, London,
and fellowships in medical and surgical retina at Moorfields Eye Hospital, where he then held a faculty position for 2 years as
a locum consultant in vitreo-retinal surgery. He is currently spending a research sabbatical as an international fellow with
the Vitreous Retina Macula Consultants of New York. His special interests include management of complex medical and
surgical retinal disease, surgical instruction, and retinal imaging.

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Biosketch
K. Bailey Freund, MD, is a Clinical Professor of Ophthalmology at New York University School of Medicine and a senior
partner at Vitreous Retina Macula Consultants of New York. Dr Freund is on the Editorial Board of the journal Retina. He
has authored over 200 peer-reviewed scientific manuscripts and numerous book chapters. He is a recipient of the Young
Investigator Award from the Macula Society.

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