Multimodal Imaging In Acute Macular Neuroretinopathy

A variety of imaging modalities, from fundus photos through adaptive optics, can be useful in diagnosis.

ANTHONY JOSEPH, MD · EHSAN RAHIMY, MD · K. BAILEY FREUND, MD · DAVID SARRAF, MD

First described by Bos and Deutman in 1975,¹ acute macular neuroretinopathy (AMN) is a rare retinal disorder, the understanding of which has evolved with imaging technology in ophthalmology.

While a mechanism to explain the development of this disease has been elusive, an underlying ischemic etiology has been suspected on the basis of the risk factors for this disorder, which include oral contraceptive use^1,2 and hypotension,³ as well as agents that cause vasoconstriction, such as caffeine,^4,5 epinephrine,⁶ and adrenaline.⁷

The original description of AMN highlighted dark, wedge-shaped intraretinal lesions in the macula pointing toward the fovea and sparing the retinal pigment epithelium.^1,8 The disease process was initially thought to involve the inner layers of the retina. However, advanced imaging modalities, such as spectral-domain OCT, have shown disruption of the ellipsoid zone to be a characteristic finding in AMN, prompting the authors to rename the condition acute macular outer retinopathy (AMOR).^9,10

More recently, Fawzi et al¹¹ performed complex multimodal imaging of eight patients with AMN, with two eyes in their series demonstrating more superficial involvement at the level of the outer plexiform layer (OPL) and Henle’s fiber layer (HFL) early in the course of disease.

It is clear that the understanding of AMN continues to evolve as retinal imaging becomes more refined. Moreover, the classic retinal lesions are often very subtle or even absent on clinical examination. Therefore, adjunctive imaging plays a vital role in diagnosis and management.

This article will review the current state of multimodal imaging in AMN and describe the new imaging findings that have led to a greater insight and understanding of the mechanisms at play in this complex disease.

CLINICAL PRESENTATION AND COLOR FUNDUS PHOTOGRAPHY

Acute macular neuroretinopathy typically presents in young or middle-aged women with the acute onset of mildly decreased vision in one or both eyes. Patients have noted one or multiple paracentral scotomas in the affected eyes.

As previously mentioned, the classic funduscopic finding is the presence of one or multiple dark, relatively well-defined, wedge-shaped intraretinal lesions pointing to the fovea, often in a flower petal arrangement (Figures 1A and 1B).^1,8 These lesions spare the RPE and retinal vessels, and their color may vary from red to purple or brown, depending on the degree of fundus pigmentation.^1,2,8,14

Figure 1. Color fundus images of a right (A) and left (B) eye from two patients displaying multiple dark, relatively well-defined, wedge-shaped intraretinal lesions pointing to the fovea in a flower petal arrangement. Note the reddish color of the lesion varies depending on the level of background fundus pigmentation.

These lesions are often very subtle and are better seen using red-free light (Figures 2A and 2B, page 42).^2,12-14 In isolated cases, intraretinal hemorrhage has been reported in association with the wedge-shaped AMN lesion, suggesting a vascular occlusive or vasculopathic etiology.¹⁵

One of the hallmark clinical features of AMN is the consistent correlation between the lesions in the macula and the shape and location of scotomas identified with Amsler grid testing or automated perimetry.^{1,2,8,12-14,16} This finding supported the idea that involvement of the outer retina contributed to the characteristic macular lesions before this was more conclusively demonstrated with OCT.

FA, ICG A, AND FAF

Fluorescein angiography, indocyanine green angiography, and fundus autoluorescence findings in AMN have traditionally been unremarkable, although these techniques have still been considered useful in excluding other conditions that present in a similar fashion.¹⁷

Patients with multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy, and punctate inner choroidopathy may also present with paracentral scotomas and temporary vision loss, accompanied by subtle lesions in the macula.^14,17

Additionally, the reddish lesions of AMN may be mistaken for subretinal blood or choroidal neovascularization. Although AMN lesions may show slight hypofluorescence with FA,^1,2,14,16 they do not demonstrate the characteristic FA, ICGA, and FAF patterns of these other conditions.

More recently, Sarraf et al¹⁵ demonstrated subtle retinal capillary abnormalities with high-magnification FA images in a case of early AMN. This was one of several factors that led the authors to propose that ischemia of the deep capillary plexus may be the etiology of this disorder.

NEAR INFRARED

While the clinical examination findings in AMN are often quite subtle, near-infrared (NIR) reflectance imaging usually shows characteristic dark gray, paracentral lesions, which typically point toward the foveal center (Figure 2C).^11,18-20 As this condition progresses, these gray hyporeflective lesions can increase in intensity (Figure 2D) and can extend laterally (Figure 2E), before eventually fading (Figure 2F).

Some reports have suggested the hyporeflective lesions on NIR imaging may be persistent long-term markers for this condition.¹¹ NIR is becoming an important adjunct in diagnosing AMN, especially in cases in which the lesions are not visible clinically or with color fundus photographs.

OCT AND PATHOGENESIS

While NIR is helpful in detecting AMN lesions, OCT is the most useful tool for the diagnosis and evaluation of patients. The OCT findings of AMN were first documented using time-domain OCT, showing a band of abnormal increased hyper-reflectivity internal to the RPE.²¹

Later, ultra–high-resolution OCT revealed focal outer nuclear layer (ONL) thinning and ellipsoid zone disruption 10 days after symptom onset.²² Subsequently, Hughes et al¹⁰ used high-resolution Fourier-domain OCT to demonstrate focal ellipsoid zone disruption and ONL thinning, proposing AMOR to describe the lesion more accurately.

Recently, authors have reported that AMN lesions may develop at the OPL/ONL junction with associated outer macular disruption.^11,18 Fawzi et al.¹¹ performed complex multimodal imaging of patients with AMN, demonstrating acute paracentral band-like hyper-reflective plaques at the ONL/OPL junction on SD-OCT (Figure 2G), indicating disruption of photoreceptor cell bodies and their axons.

With resolution of this ONL/OPL hyper-reflectivity, thinning of the ONL was noted. Changes developed in the outer segments of the photoreceptors and their junction with the RPE, including disruption of the ellipsoid and interdigitation zones and thinning of the photoreceptor outer segments (Figures 2H and 2I).

Figure 2. Baseline color fundus (A) and red-free (B) images demonstrating a superficial, hyporeflective, wedge-shaped retinal lesion superonasal to the fovea in the right eye of a patient with AMN. Baseli e near-infrared (NIR) reflectance image (C) showing a gray teardrop-shaped lesion with corresponding spectral-domain OCT (G), demonstrating a band-like hyper-reflective lesion at the level of the outer plexiform layer with an intact ellipsoid zone and early disruption of interdigitation zone. Two-week follow-up NIR reflectance with increased intensity of the teardrop lesion (D) and corresponding SD-OCT (H) showing resolution of the hyper-reflective lesion at OPL and thinning of the outer nuclear layer (ONL) and ellipsoid zone and interdigitation zone disruption. One-month followup NIR reflectance with lateral extension of the teardrop lesion (E) and SD-OCT (I) with a corresponding spread of interdigitation zone disruption. Six-week follow-up NIR reflectance with a persistent teardrop lesion (F) and corresponding SD-OCT (J) revealed the reconstitution of the ellipsoid zone and persistent thinning of the ONL and outer segments.

CREDIT: WOLTERS KLUWER

Thinning of the ONL and disruption of the interdigitation zone persisted even after normalization of the ellipsoid zone (Figure 2J), an important finding differentiating AMN from MEWDS, in which outer segment abnormalities on OCT typically normalize completely after the acute episode.²³

Persistence of the gray hyporeflective lesions on NIR and persistent interdigitation zone disruption and ONL thinning on OCT seem to be long-term markers for AMN and may explain permanent symptomatic scotomas in some cases.

Figure 3. Near-infrared reflectance (A) image of the right eye of a patient with paracentral acute middle maculopathy (PAMM), showing a subtle, gray, paracentral lesion involving the inferior fovea. Spectral-domain OCT (B) through the lesion showing a hyper-reflective, band-like plaque at the level of the inner nuclear layer (INL), which led to significant INL thinning.

AMN AND PAMM

More recently, Sarraf et al¹⁵ identified characteristic AMN lesions involving the middle layers of the retina at the level of the inner nuclear layer (INL), a novel SD-OCT finding referred to as paracentral acute middle maculopathy (PAMM), attributed to ischemia of the superficial capillary plexus (SCP).

These hyper-reflective bandlike plaques were noted to have many of the same characteristics of the aforementioned AMN lesions, but on SD-OCT extended from the border of the OPL to the most superficial edge of the INL and lead to corresponding thinning of the INL in all cases (Figure 3B). The precise alignment of these INL lesions with the SCP supports occlusion of the SCP as an etiology.

In contrast, AMN lesions of the OPL/ONL region are aligned with the deep capillary plexus (DCP), which is located in the outer most portion of the INL. The OPL is comprised of photoreceptor axon terminals, which lie adjacent to the DCP in a watershed region.

Consequently, the OPL and the region immediately below it may be especially vulnerable to ischemic insults to the DCP. Subsequent axonal and outer segment disruption and death may develop as evidenced by the ellipsoid zone and interdigitation zone abnormalities that occur with these types of lesions.

The more classic AMN lesions attributed to ischemic insult of the DCP have been seen in young female patients, the traditional demographic of AMN, while PAMM lesions attributed to ischemic insult of the SCP were observed in middle-aged and older men with vasculopathic risk factors, such as hypertension.¹⁵

Thus, while the two lesions have many similar features, PAMM lesions aligned with the SCP may indicate a different disease process, in which the characteristic SD-OCT findings may be comparable to a deep cotton wool spot.

Certainly, as OCT technology continues to improve and is used in conjunction with other imaging modalities, we will continue to learn more about the factors underlying AMN and related conditions.

OPHTHALMIC ADAPTIVE OPTICS

Owing to its advanced resolution, OCT has become a standard tool to evaluate the retina in AMN, although monochromatic aberrations in the eye limit its lateral resolution.

Adaptive optics (AO) is a technique that compensates for these aberrations, allowing for visualization of the photoreceptor mosaic in the retina.^24-27 In other conditions, AO imaging has been reported to reveal photoreceptor abnormalities that were not otherwise discernible with OCT.^28-30

The use of AO in AMN is relatively new with few reports in the literature. Hansen et al²⁵ used an AO scanning light ophthalmoscope to show preferential disruption of cone photoreceptor structure within a region of decreased retinal sensitivity as measured with microperimetry.

Similarly, Sarraf et al¹⁵ reported one case in which AO confirmed the presence of reduced cone density, corresponding to a dark lesion visualized on NIR. In that case, the area of disruption of the cone mosaic on AO was more widespread than the lesion visualized with NIR, while it confirmed at a cellular level what had been seen on OCT.

Along with improving OCT technology, AO appears to offer another useful tool in the study of AMN and perhaps in the detection of subclinical cases.

CONCLUSION

Progress in multimodal imaging has helped refine our understanding of the pathophysiology of AMN and has dramatically enhanced diagnostic sensitivity. In some cases of AMN, funduscopic abnormalities may be nearly absent and fundus photography may be essentially normal.

We have seen a shift toward the use of NIR to detect the characteristic lesions that typically point toward the foveal center. OCT has shown a spectrum of interesting findings, including hyper-reflective band-like lesions at the level of the OPL and Henle’s layer associated with INL thinning and outer macular disruption. Similar lesions identified at the level of the INL have been termed paracentral acute middle maculopathy or PAMM and may represent a variant of AMN or a distinct form of retinal ischemic disease.

As multimodal imaging techniques continue to advance, allowing us to identify more subtle cases, we may find that AMN is not as rare a disorder as previously thought. Moreover, we may be able to better identify the risk factors and etiologies in what is more convincingly a condition with underlying ischemic etiology. RP

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