EDITORIALS

Paracentral Acute Middle Maculopathy and AcuteMacular Neuroretinopathy: Related and Distinct

Entities

KUNAL K. DANSINGANI AND K. BAILEY FREUND

T HE HISTORY OF MEDICINE IS CHARACTERIZED BY DIS-

covery, subclassification, reorganization, and bifur-cation of physiological concepts or pathologic

entities, driven by advances in investigative technologiesor by recognition of clinical details previously overlooked.The story of paracentral acute middle maculopathy(PAMM) is no exception. While it was initially describedby Sarraf and associates as a variant of acute macular neuro-retinopathy (AMN), it is becoming increasingly evidentthat PAMM should be considered a clinical finding relatedto ischemia of the deep retinal circulation, not a specificretinal disease.

In this issue of the Journal, Chen and associates describethe occurrence of PAMM in 9 patients with diverse risk fac-tors for retinal ischemia, including diabetes mellitus,hypertension, hyperlipidemia, sickle cell disease, a ‘‘flu-likeillness,’’ and transient orbital compression.1 Additionally,they report that PAMM lesions occurring in a patient withrecent motor vehicle trauma are indistinguishable frompolygonal Purtscher flecken, suggesting that certain lesionsin Purtscher retinopathy might in fact be lesions ofPAMM. Their findings significantly expand the known spec-trum of etiologies that underlie PAMM and require a shift inconsideration of PAMM from a disease entity to a newlyrecognized clinical finding with a wider differential diagnosisthat warrants furthermedical investigations and optimizationof systemic risk factors. Moreover, as PAMM lesions are be-ing discovered with relative rapidity in an array of systemicdiseases, it appears that PAMM is likely to be more commonthan the wider ophthalmic community currently appreciates.

In a previous report, Yu and associates describedthe occurrence of PAMM in 35 patients with retinal

arterial occlusive disease and hypothesized that transientischemia of the intermediate and deep capillary plexusesmay account for PAMM. They described the PAMMlesion as a deeper form of the more familiar ‘‘cotton-wool spot.’’2 In the acute phase, a cotton-wool spotpresents as a fluffy white nonexudative focal loss of trans-parency in the nerve fiber layer due to ischemicaxoplasmic stasis.3 After resolution, the cotton-woolspot leaves a focus of inner retinal thinning or depression.The relative subtlety of PAMM lesions when comparedwith cotton-wool spots may be due to differences inneurosensory architecture and optical characteristicsbetween inner plexiform, outer plexiform, and nerve fiberlayers, the latter of which contains the longest axons,which are perpendicularly oriented to the axis of visuali-zation and least translucent to visible light.The organization of the retinal microcirculation into su-

perficial, intermediate, and deep capillary plexuses is wellknown from histologic and confocal imaging studies.4–6

The localization of PAMM lesions mostly within the innernuclear layer bordered by the intermediate and deepcapillary plexus etiologically implicates these vascularlayers, but the precise hemodynamic factors leading totheir occurrence remain incompletely understood.The recent discovery of PAMM in patients with sickle

cell retinopathy, not only by Chen and associates1 butalso by Ilginis and associates,7 provides some insight intoits underlying mechanism. The capillary-occlusive mani-festations of sickle cell retinopathy are attributed to thechange in aspect ratio and loss of compliance of erythro-cytes as they enter a zone of reduced oxygen tension. It istherefore believed that retinal vascular occlusive andneovascular events in sickle cell retinopathy occur in theperipheral retina because these areas are perfused by thesmallest capillaries, which are most distally located fromthe oxygen source, the so-called watershed zones. Theobservation that PAMM can occur parafoveally in sicklecell patients, and even in the papillomacular bundle, sug-gests that the middle retina, distal in circulatory terms rela-tive to the inner retinal circulation and to thechoriocapillaris, does indeed represent a functional water-shed zone in the anteroposterior axis.

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 ofOphthalmology, New York University School of Medicine (K.B.F.),New York, New York; and Moorfields Eye Hospital, London, UnitedKingdom (K.K.D.).

Inquiries to K. Bailey Freund, Vitreous Retina Macula Consultants ofNew York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail:kbfnyf@aol.com

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2015.05.001

1! 2015 BY ELSEVIER INC. ALL RIGHTS RESERVED.

Hemoglobinopathies vary in their predilection forneovascular complications and severe, vision-threateningretinopathy, and the Hb-SC variant carries the highestrisk. It would be interesting to find out whether the risk dis-tribution of PAMM lesions across different hemoglobinop-athies is similar to that of classical sickle cell retinopathyand whether PAMM lesions antecede and predict thedevelopment of classical sickle cell retinopathy.

Our view of the relationship between PAMM and AMNis evolving as we question whether they are truly distinctentities. In 1975, Bos and Deutman described a series ofpatients, mostly young female subjects, who presentedwith well-defined central scotomata that mapped to radi-ally oriented perifoveal wedge-shaped lesions of AMN.8

They reported from biomicroscopic observations thatAMN appeared to involve the superficial retinal layers,but imaging of AMN with time-domain optical coherencetomography (OCT) demonstrated that these lesions in factreside in the outer retina.9 The superiority of near-infraredreflectance over red-free imaging in demonstrating AMNwas not reported until 2007.10

With the application of ultrahigh-resolution andspectral-domain OCT, further studies reported thatAMN lesions specifically involve the outer plexiform andouter nuclear layers, where they manifest as hyperreflectivebands with associated ellipsoid disruption, subsequent lossof hyperreflectivity, and a legacy of permanent thinningof the outer nuclear layer.11

Subclassification of AMNwas proposed in 2013 by Sarrafand associates,12 who designated the outer plexiform–outernuclear layer lesions as ‘‘type 2’’ and described PAMM as anew ‘‘type 1’’ variant, with its characteristic parafovealhyperreflective band on spectral-domain OCT, mostly atthe level of the inner nuclear layer. The PAMM variantwas 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 demo-graphic and risk profile that is distinctly different fromthat of PAMM. Acute macular neuroretinopathy occursmore commonly in younger female subjects who oftenhave had a recent history of a hypotensive or hypertensiveepisode induced by febrile illness, trauma, or medication.

The pathogenesis of AMN remains unknown, althoughour knowledge of the clinical circumstances surroundingits onset, and of the affected demographic, might informour hypotheses. Andrews and associates have demonstratedimmunohistochemically that the distribution of markers ofmitochondrial enzyme activity in the axons of the Henle

fiber layer is biased toward the outer retina/photorecep-tors,13 implying that these axons may lie on the functionalcirculatory watershed between the choriocapillaris and themost distal reaches of the deep capillary plexus. It ispossible that while PAMM results from occlusive eventsof the retinal arterial tree, AMN results from a simultaneoushypoperfusion more proximally at the level of theophthalmic artery that leads to reduced perfusion of boththe deep capillary plexus and choriocapillaris. The severityof ischemia in the deep capillary plexus in AMN may notbe sufficient to produce PAMM lesions but, combinedwith choriocapillaris ischemia, may reach the thresholdto cause AMN at the functional anteroposterior watershed.If this is the case, it would place AMN at the mild end of aperfusion spectrum defined in its worst manifestation byconditions that cause simultaneous infarcts of the retinaand choroid, albeit with differing cellular pathology (eg, gi-ant cell arteritis). Supporting the requisite for simultaneouseffects on both retinal and choroidal circulations in thepathogenesis of AMN is the observation that even in com-plete central retinal artery occlusion, spectral-domainOCT typically shows minimal outer retinal involvement.Optical coherence tomography angiography (OCTA) is

a new modality that represents time-based changes inreflectivity of intravascular components as quantifiableflowmaps with depth resolution.14 In the immediate future,OCTA promises to reveal new information about retinalcapillary function in health and disease, with quantitativeindices.15

The application of new modalities, diagnostic or thera-peutic, increases the collective knowledge of diseases andinforms the constantly evolving systems of classificationthat we employ. At present we do not possess the toolsfor restorative intervention at the capillary level, and thereis therefore no specific treatment for AMN or PAMM. Itremains to be seen whether a deeper understanding of theseconditions as ‘‘capillaropathies’’ further subclassifies themor reunites them as having a common mechanism andpotential for intervention.The relatively recent description of PAMM, together

with rapidly growing interest in studying it over the last2–3 years, suggests that it is more common than previouslythought and that it accounts for visual debilitation in asignificant number of patients for whom definitive diag-nosis may previously have been elusive. Its associationwith an expanding spectrum of systemic risk factors makesit an important finding with which all ophthalmologistsshould attain familiarity.

THEAUTHORSHAVE COMPLETEDAND SUBMITTED THE ICMJE FORM FORDISCLOSUREOF POTENTIAL CONFLICTSOF 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 RetinalResearch Center, Manhattan Eye, Ear and Throat Hospital, New York, and the Macula Foundation, Inc, New York, New York, USA. The funding orga-nization had no role in the conception, design, or production of this editorial. Both authors attest that they meet the current ICMJE requirements to qualifyas authors.

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REFERENCES

1. Chen X, Rahimy E, Sergott RC, et al. Spectrum of retinalvascular diseases associated with paracentral acute middlemaculopathy. Am J Ophthalmol 2015;160(1):26–34.

2. Yu S, Pang CE, Gong Y, et al. The spectrum of superficial anddeep capillary ischemia in retinal artery occlusion. Am JOphthalmol 2015;159(1):53–63.e1-2.

3. Schmidt D. The mystery of cotton-wool spots - a review ofrecent and historical descriptions. Eur J Med Res 2008;13(6):231–266.

4. Foreman DM, Bagley S, Moore J, Ireland GW, McLeod D,Boulton ME. Three dimensional analysis of the retinalvasculature using immunofluorescent staining and confocallaser scanning microscopy. Br J Ophthalmol 1996;80(3):246–251.

5. Dorrell MI, Friedlander M, Smith LEH. Retinal vasculardevelopment. In: Joussen AM, Gardner TW, Kirchhof B,Ryan SJ, eds. Retinal Vascular Disease. Berlin, Heidelberg,New York: Springer-Verlag; 2007:29–30.

6. Tan PE, Yu PK, Balaratnasingam C, et al. Quantitativeconfocal imaging of the retinal microvasculature in the hu-man retina. Invest Ophthalmol Vis Sci 2012;53(9):5728–5736.

7. Ilginis T, Keane PA, Tufail A. paracentral acute middlemaculopathy in sickle cell disease. JAMA Ophthalmol 2015.

8. Bos PJ, Deutman AF. Acute macular neuroretinopathy. Am JOphthalmol 1975;80(4):573–584.

9. Feigl B, Haas A. Optical coherence tomography (OCT) inacute macular neuroretinopathy. Acta Ophthalmol Scand2000;78(6):714–716.

10. Corver HD, Ruys J, Kestelyn-Stevens AM, De Laey JJ,Leroy BP. Two cases of acute macular neuroretinopathy.Eye (Lond) 2007;21(9):1226–1229.

11. Fawzi AA, Pappuru RR, Sarraf D, et al. Acute macular neuro-retinopathy: long-term insights revealed by multimodal imag-ing. Retina 2012;32(8):1500–1513.

12. Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middlemaculopathy: a new variant of acute macular neuroretinop-athy associated with retinal capillary ischemia. JAMAOphthalmol 2013;131(10):1275–1287.

13. Andrews RM, Griffiths PG, Johnson MA, Turnbull DM. His-tochemical localisation of mitochondrial enzyme activity inhuman optic nerve and retina. Br J Ophthalmol 1999;83(2):231–235.

14. Tokayer J, Jia Y, Dhalla AH, Huang D. Blood flow velocityquantification using split-spectrum amplitude-decorrelationangiography with optical coherence tomography. BiomedOpt Express 2013;4(10):1909–1924.

15. Nagiel A, Sadda SR, Sarraf D. A promising future for opticalcoherence tomography angiography. JAMAOphthalmol 2015.

VOL. 160, NO. 1 3EDITORIAL

Biosketch

Kunal K. Dansingani studied medicine at Cambridge and at the Royal Free Hospital and UCLMedical School, London. Hecompleted 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 asa locum consultant in vitreo-retinal surgery. He is currently spending a research sabbatical as an international fellow withthe Vitreous Retina Macula Consultants of New York. His special interests include management of complex medical andsurgical retinal disease, surgical instruction, and retinal imaging.

3.e1 JULY 2015AMERICAN JOURNAL OF OPHTHALMOLOGY

Biosketch

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

VOL. 160, NO. 1 3.e2EDITORIAL