Acute Macular Neuroretinopathy: A Review of the Literature

I. Definition, Clinical Diagnosis, and Natural History of AMNR 

Acute macular neuroretinopathy (AMNR) is a rare condition characterized by the sudden onset of mild visual impairment from lesions that occur in the macula of the retina.4 It occurs unilaterally or bilaterally with normal to mildly decreased visual acuity.1, 4, 11, 19, 24, 26, 28, 30 Patients typically present several days or later after the development of multiple, paracentral scotomata in one or both eyes.4, 11, 24, 28

The clinical diagnosis is readily made on the basis of the distinctive lesions of AMNR. Biomicroscopically they typically are multiple, sharply defined, partly confluent, non-elevated, wedge-shaped lesions in a flower petal arrangement around the center of the macula.4, 30 In some cases, the lesions are round or oval and are non-confluent.12 The color of the lesions varies from reddish to purple or brown, depending upon the degree of pigmentation of the fundus.1, 4, 24, 26 Typical, representative lesions of AMNR are shown in Fig. 1.12 The lesions are best seen using red-free light.1, 24, 28 The exact location of the lesions is uncertain,17, 24 but biomicroscopically they appear to be at the level of the outer sensory retinal layers.12, 31 Focal thinning of the inner retina can likewise cause reddish lesions, adding to the uncertainty as to the precise location of the lesions of AMNR. The lesions may develop rapidly or more slowly over days or weeks. Retinal hemorrhages occasionally occur.12 The retinal vessels and optic disk are normal.

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Fig. 1. These photos show the typical appearance of the lesions of acute macular neuroretinopathy. Top left and Top right show the typical dark petal-like oval areas in the macular region along with superficial hemorrhage in both eyes. The second set of photos (Bottom left and Bottom right) show multiple, small, variably sized, dark, round spots, at the level of the outer retina. (Reprinted with permission of CV Mosby Co. from Gass,12 p 695.)

An important diagnostic feature of AMNR is the remarkable correspondence of the lesions with the shape and location of the scotomas that most patients identify on the Amsler grid or by other means of visual field testing.1, 4, 13, 19, 24, 26, 28, 30 The sharply defined reddish lesions corresponding rather precisely with the scotomata suggest that the acute loss of the retinal outer receptor elements is responsible for well-defined zones of outer retinal thinning. Such thinning might be expected to produce reddish lesions in the fundus such as those seen in patients with lamellar and full-thickness holes, and following Berlins edema. Focal thinning of the inner retina, such as occurs in association with cotton-wool infarcts and sickle cell hemogolobinopathy, may also produce focal reddish lesions.14 In some cases this is due to hemosiderin in the outer retinal following retinal hemorrhage.14

Results of fluorescein angiography are typically normal, but there may be slight hypofluorescence of the lesions.4, 24, 26 Resolution of the lesions is possible, and complete recovery has been reported.11, 13, 19 Lesions may persist for as long as 9 years.24

The reddish lesions of AMNR may be mistaken for subretinal blood as appears to be the case of a patient reported by Weinberg and Nerney.37 Patients with smaller lesions may be incorrectly interpreted as having acute posterior multifocal placoid pigment epitheliopathy (APMPPE), acute retinal pigment epitheliitis, or central serous chorioretinopathy (CSC), all of which may be associated with subtle lesions and temporary visual loss in young or middle-aged adults.13 The lesions of AMNR are distinct from these entities in that they tend to be flat or depressed, are outer retinal lesions that are largely confined to the central macular area and are circumscribed and reddish in color (in Caucasians) or dark gray in persons with greater pigmentation. In contrast, APMPPE is characterized by yellow-white, placoid, circumscribed lesions at the level of the retinal pigment epithelium. These lesions have a characteristic non-fluorescent pattern in early phase fluorescent angiography. Acute retinal pigment epitheliitis is unlikely to be a specific disease entity, while CSC is characterized by focal serous detachment of the sensory retina and is typically not confused with AMNR unless the AMNR lesions are especially faint in a patient with loss of central vision.

II. Summary of Reported Cases 

AMNR is rare. Forty-one cases have been reported to date in the English-language medical literature from 1975 through April 2002. These cases are summarized in Table 1. AMNR is seen more frequently in women than men; of the 41 cases, 34 (83%) were in women.1, 4, 10, 11, 17, 19, 24, 26, 29, 30, 31 Women were in their reproductive years, with a mean age of 27 years (range 20–53 years).1, 4, 10, 11, 17, 19, 24, 26, 29, 30, 31 We were unable to identify any published reports of AMNR in children. The causes of AMNR are unknown, but numerous factors have been reported in association with its onset. These factors include oral contraceptives,4, 24 flu-like syndrome,1, 2, 4, 10, 11, 20, 24, 28, 29, 33, 34 contrast media,19 epinephrine,26 trauma,15 a history of headache or migraine headache,24, 30 postpartum hypotension,20 and hypotensive shock.22 AMNR has also been reported in conjunction with multiple evanescent white dot syndrome11 and acute idiopathic blind-spot enlargement.32 These are cases 19 and 20 in Table 1.

Table 1. Cases of AMNR Reported in the Literature

	Case	Author	Sex	Age	Lesion Description	Suspected Etiology	Onset	Amsler Grid	Flourescein Angiogram	Recovery
	1	O'Brien et al.26	F	28	Bilateral macular edema; central red spots; normal retinal vasculature	Ephedrine (25 mg in 1 liter Ringers lactate)	Immediate	Amsler grid demonstrated paracentral scotoma	Faint hypofluorescence after 6 weeks	Persistent scotomata after 3 years
	2	O'Brien et al.26	F	23	Bilateral paracentral scotomas; deep red macular changes	Epinephrine 1 mg IV	Within 12 hours	Amsler grid demonstrated outer retina lesions	Not reported	Not reported
	3	O'Brien et al.26	F	26	Bilateral paracentral scotomas; macular changes	Epinephrine 0.3 cc (1:10,000) 1 dose IV 1 dose subq.	Within 12 hours	Amsler grid demonstrated paracentral scotoma	Faint hypofluorescence corresponding to the lesions	Persistent after 2 months follow-up
	4	Bos and Deutman4	F	29	Bilateral scotomas in both central vision; dark brown reddish lesion in R and L macula; triangular lesion pointed toward fovea	OC use	Sudden	Static perimetry demonstrated scotomas	Normal	Lesions were less obvious
	5	Bos and Deutman4	F	33	L scotoma. R eye normal; dark red spot near fovea	Estrogen use	Sudden	Static perimetry demonstrated scotoma	Dilated perimacular capillaries	1 yr. slightly decreased scotomas
	6	Bos and Deutman4	F	24	Darkish red wedge shaped lesions around R central macula; lesions pointed toward fovea	Enteritis; OC use	Not reported	Amsler grid showed 3 small scotomas	Normal	Persistent scotomata after 1 yr.
	7	Bos and Deutman4	F	30	Maculae showed wedge-shaped lesions in the superficial retinal layers	Influenza a few weeks prior to lesions; OC use	Acute	Paracentral scotomas	Not reported	Paracentral scotomas present after 4 months
	8	Bos and Deutman4	M	23	Darkish red dot in superficial retinal layers	Influenza	Not reported	Perimetry demonstrated visual field defect	No abnormalities	Macular lesion did not change after 2 months
	9	Bos and Deutman4	F	32	Scotomas in both eyes; darkish red triangular lesions pointed toward the R and L macula	Influenza	During influenza	Amsler grid showed paracentral scotoma	Intact retinal pigment epithelium. No flourescein leaks	Slightly decreased scotomas after 6 mos.
	10	Priluck et al.28	M	17	Irregular, dark wedge shaped lesions in deep sensory retina near fovea; some retinal hemorrhage	Flu-like symptoms	Progressive	Amsler grid demonstrated scotomata of R and L eye	Hypofluorescence corresponding to the lesions of deep sensory retina	Persistent scotomas
	11	Guzak et al.19	F	27	Paracentral scotomas in both eyes; radially oriented wedge shaped lesions resembling petals of a flower	Contrast Media Renografin-76; Estrogen use	Within minutes	Amsler grid and Goldmann perimetry demonstrated paracentral scotomata	Hypofluorescence	No scotomas after 1 year
	12	Guzak et al.19	F	24	Dark red macular lesions oriented radially in left eye and distributed geographically in R eye; scotomas in both eyes	Contrast Media Conray-43; Epinephrine; Mononucleosis; OC use	Within 10 hours	Scotomas found on both Amsler grid and Goldmann perimetry tests	Faint hypofluorescence	No change; Pt. claims scotomas less noticeable after 3 months
	13	Miller et al.24	F	26	Irregular dark areas around the fovea in both eyes	Influenza A one day prior to event; OC use	Progressive over 4 days	Amsler grid demonstrated scotoma in both eyes	Normal	Unchanged after 9 months
	14	Miller et al.24	F	23	Darkish red lesions corresponding to the scotomata in R and L eyes	Diabetic retinopathy	Progressive over 2 weeks	Amsler grid demonstrated scotomata	Microaneurysms	Scotomata present after 2 years
	15	Miller et al.24	F	23	Scotomas in both eyes	Headache Hx; OC use	Progressive over 4 weeks	Amsler grid demonstrated scotomata	Normal	After 9 years, L eye scotoma remained, but improved
	16	Miller et al.24	F	25	Several reddish-brown lesions in the macula of both eyes	Influenza-like illness; OC use	Progressive over 1 week	Goldmann fields demonstrated scotoma in left eye	Normal	Scotoma in left eye only but smaller and less dense after 2 years
	17	Miller et al.24	F	27	Parafoveal reddish areas	Influenza-like illness; OC use	Progressive over 3 weeks	Amsler grid demonstrated paracentral scotomata	Not reported	Less pronounced after 9 mos.
	18	Desai et al.6	M	18	Macular edema. Reddish-brown lesions located in outer retina of both maculae	Epinephrine given for allergic food reaction 0.5 ml (1:1000)	Within 3 hours of epinephrine	Amsler grid demonstrated paracentral scotomata	Not reported	Scotomata persisted after 3 months
	19	Gass & Hamed11	F	22	Multiple, variable-sized, round and oval, red-orange lesions; found in outer macula of L eye	Influenza-like illness; Family Hx of diabetes; OC use	Not reported	Amsler grid demonstrated paracentral scotomata	Hypofluorescence in Left eye	Symptoms returned more severe 5 years after initial event
	20	Gass & Hamed11	F	30	Multiple small red-orange lesions in L eye	Unknown	Over a period of one week	Goldman field test demonstrated paracentral scotomas	Multiple hypofluorescence spots	Symptoms persisted after 3 months
	21	Rush30	F	24	Three reddish brown wedges of parafoveal scotomas pointed toward fixation in L eye	Pharyngitis, Migraine Hx; OC use	2 weeks after pharyngitis resolved	Amsler grid demonstrated tear drop parafoveal scotomas	Normal	No change after 6 months of follow up
	22	Rait and Day29	F	21	Subtle red-brown scalloped areas surrounding the fovea of each eye	Respiratory tract infection within days prior to the event; Hx of Migraine with aura; OC use	Sudden onset	Amsler grid and Goldmann demonstrated scotoma	Normal	Scotomas remained after 8 months
	23	Albert1	F	40	Macular lesions representing paracentral scotomas in both eyes	Viral Bronchitis one week earlier; OC use	Sudden onset	Red-free and fundus photographs highlighted lesions	Normal	Did not improve after 18 months
	24	Sieving et al.31	F	20	3 dark burnt orange colored, wedge-shaped, lesions on the nasal side of the fovea in R eye	OC use	Acute	Amsler grid and Goldmann demonstrated 3 paracentral scotomas	Hypofluorescence near the lesions	Scotomata present after 20 months without resolving
	25	Amin et al.2	F	40	Bilateral reddish-brown lesions in the macula	Viral bronchitis 1 week earlier; OC use	Sudden	Red-free frames highlighted the lesions	Normal	Scotomas did not improve after 18 months
	26	Gillies et al.15	M	45	Several oval patches in the nasal fovea	Work related head trauma	Immediate	Amsler grid demonstrated scotoma	Not reported	Clearing of lesions after 6 months
	27	Gillies et al.15	M	17	Wedge-shaped dark lesion in nasal macula	Chest trauma, Car accident	That evening	Amsler grid demonstrated oval scotoma	Not reported	Scotoma smaller after 9 months
	28	Gillies et al.15	M	33	Numerous dark patches at the fovea	Head trauma, Car accident	Progressive over 10 days	Not reported	Not reported	Lost to follow-up
	29	Gillies et al.15	M	53	Curvilinear dark patch at the posterior pole of retina	Car accident, Blunt trauma to chest	Immediate	Visual field test demonstrated scotoma	Not reported	Lost to follow-up
	30	Singh et al.32	F	24	Red-orange lesions of the left macula compatible with AMNR	None	Not reported	Goldmann perimetry showed scotoma	Normal	Lost to follow-up
	31	Gandorfer and Ulbig10	F	23	Bilateral, central wedge shaped, well defined reddish-brown lesions in the macula	Flu-like symptoms in week earlier; OC use for several years	Sudden onset	Only scanning laser opthalmoscopy disclosed precise areas of lesions	Normal	Did not improve during 6 months time
	32	Feigl and Hass8	F	33	Red-brown lesions in the macula area	Flu-like disease one week earlier	Sudden onset	Visual field test demonstrated paracentral scotomata	Normal	Not reported
	33	Kerrison et al.20	F	25	Bilateral, reddish, petaloid, macular lesions	Episode of postpartum hypotension	Acute onset	Dilated fundus examination and Amsler grid demonstrated areas of lesions	Choroidal filling defects nasal to the fovea of right eye	Not reported
	34	Tingsgaard et al.33	F	21	Bilateral paracentral scotomata	Flu-like symptoms; OC use	Acute onset	Amsler grid identified small semilunar scotomata	Normal	Some improvement within two weeks
	35	Leys et al.22	F	22	Paracentral cloverlike lesions in right eye	Hypotensive shock; Epinephrine; OC use	Acute onset	Amsler grid and Visual field demonstrated dense central scotoma	Slight hypofluorescence in early phases	Improvement after 6 months
	36	Leys et al.22	F	26	Dark scotoma in left eye	Hypotensive shock; Epinephrine	Acute onset	Goldman Perimetry demonstrated scotoma	Hypofluorescence corresponding to scotoma	Scotoma still present after 6 months
	37	Van Herck et al.34	F	50	Paracentral dark red spot overlying macula in left eye	Bronchitis	Sudden onset	Amsler grid demonstrated scotoma	Slight hypofluorescence corresponding to scotoma	Scotoma still present after 1 year, but less dense
	38	Van Herck et al.34	F	23	Paracentral dark wedge shaped spot above fovea in left eye	Influenza syndrome	Sudden onset	Amsler grid demonstrated scotoma	Normal	No change after 6 weeks
	39	Van Herck et al.34	F	47	Paracentral dark-red, wedge-shaped lesion above fovea in left eye	Influenza and headache	Sudden onset	Amsler grid demonstrated lesions	Normal	Loss to follow-up
	40	Van Herck et al.34	F	20	Multiple parafoveal wedge-shaped lesions in both eyes	Influenza; headache; possible reaction to antiviral medication; OC	Sudden onset	Amsler grid demonstrated multiple scotomas in both eyes	Normal	No change after 3 weeks
	41	Gomez-Torreiro et al.17	F	27	Temporal paracentral reddish orange lesions in left eye	None	Sudden onset	Amsler grid demonstrated lesion	Normal	Some improvement after 3 years

OC = oral contraceptives.

Oral contraceptive use was reported in 17/34 (50%) cases in women.1, 4, 8, 10, 11, 19, 20, 22, 24, 26, 29, 30, 31, 33, 34 The high frequency of oral contraceptive use is not surprising, because most women are in their reproductive years when oral contraceptive use is common. The types of oral contraceptives used prior to about 1985 consisted of high dose (≥50 μg) estrogen preparations compared to the low-dose (20–30 μg) preparations used today. These earlier drugs could be related to risk of AMNR if this lesion has a vascular etiology, because high dose oral contraceptives have been associated with an increased risk of thromboembolic disorders.35 Two women (6%) were taking estrogen supplementation when they were diagnosed with AMNR.4, 19 It is unclear whether oral contraceptive use or estrogen supplementation increases the risk of AMNR, because controlled studies have not been done. It has been suggested that hormonal status may be a predisposing factor.11 This would be consistent with the female predominance of this lesion.

An infectious process may also be a risk factor for AMNR. Of the 41 cases, 18 (44%) had a history of an influenza-like syndrome prior to their ocular event. 1, 2, 4, 10, 11, 20, 24, 28, 29, 33, 34 Cases of pharyngitis,30 mononucleosis,19 and enteritis4 have also been reported. It is unclear whether there is a viral etiology for AMNR, and there is not enough information to determine if the cases clustered during the cyclical winter outbreaks of influenza. Studies that include a sufficient number of cases with appropriate control groups are needed to determine whether a viral illness is a risk factor for AMNR or merely an incidental observation. It is interesting, however, that almost one-half of the cases had a respiratory or “influenza-like” illness less than one week prior to their diagnosis. Influenza causes severe and protracted coughing which might produce a substantial increase in retinal pressure, causing damage to the retinal blood barrier. This mechanism is similar to that proposed by Gillies et al.,15 in which an increase in intravascular pressure from coughing can produce enough force to distend the retinal blood vessels. If the risk of AMNR is proven to be increased with influenza, the agents used to treat influenza should also be investigated as possible causative factors. It may also be that some cases of AMNR are the result of acute immune damage to the receptor cells that contain an intracellular virus.

Epinephrine or ephedrine administration has been associated with four cases (10%) of AMNR independent of concomitant hypotension or contrast media.6, 26 Two additional cases were reported following epinephrine administration as treatment for an acute shock-like episode.22 The reported intravenous doses of epinephrine range from 0.5 cc (1:1000)6 to 10 mg.22 In two cases (one epinephrine and one ephedrine) the drugs were given inadvertently.26 The time required for visual disturbances to develop after administering epinephrine ranged from seconds to nearly 24 hours.26 A search for reactions to epinephrine reported to the FDA's Adverse Events Reporting System (AERS) revealed 902 adverse event reports of all types filed from 1980 to 1997. Of the 902 epinephrine reactions, three were reported as ocular reactions: one “retinal disease” and two “vision abnormality”. Neither the dose nor the route of administration of epinephrine was reported.

The biological effects of epinephrine are well known. Epinephrine produces a vasoconstrictive effect on the vasculature of the retina. The decrease in blood supply to the retina may cause either transient ischemia, in which the compromised tissue will eventually heal or permanent damage if the ischemia is severe. If the lesions of AMNR are located in the outer retina, which most observations support, then retinal vascular changes are unlikely to be the cause of the lesions. If AMNR is primarily a result of ischemia, it would be more likely related to changes in blood flow in the choroid than in the retina. On the other hand, the absence of acute changes in the retinal pigment epithelium adjacent to the red lesions argues against choroidal ischemia as the mechanism. Thus, whether AMNR lesions are the result of ischemic change, or some other mechanism, is uncertain. With regard to epinephrine, it has been suggested that it may have a direct interactive effect on rhodopsin in the photoreceptor cells of the macula,6 but it is unlikely that this would cause such circumscribed lesions.

Some interesting differences were noted in comparing the 18 cases whose AMNR followed an influenza-like syndrome and the four cases following epinephrine exposure. The onset in “influenza cases” was sometimes progressive over days to weeks but could also be sudden. All of the epinephrine cases were of sudden onset. In the “influenza cases”, 8/18 (44%) were bilateral, whereas all of the epinephrine cases were bilateral. Finally, none of the epinephrine cases were reported to resolve over the time that they were observed, while several of the “influenza cases” showed improvement.

AMNR has been reported to occur after exposure to intravenous contrast agents. Guzak et al.19 describes two cases, both women, who experienced altered vision immediately after the administration of contrast agents for computerized tomography. One woman received Renografin-60, the other received Conray-73. Both of these agents are iodine contrast materials. Both women's allergic reactions to the contrast agents were successfully treated with intravenous epinephrine. The fact that the visual symptoms began immediately after exposure to the contrast agent, but before they received epinephrine, strongly supports a causal role for the contrast material. It is thought that these reactions were idiosyncratic.19 It is not reported whether the women had a prior respiratory infection. A search for reactions to either of these two contrast agents reported to the FDA's AERS revealed 3,615 reports for reactions of all types filed from 1980 to 1997. Only two of these adverse events involved the eye. The reported adverse reaction for Renografin-60 was an “oculogyric crisis”. The report for Conray-43 was a “vision abnormality” that was not further described. Clearly, AMNR is a rare adverse reaction to contrast agents as no reports were identified in the AERS.

Gillies et al.15 describes four cases in men of traumatic retinopathy with characteristics resembling AMNR (Table 1). Two of the four patients sustained a head injury and the other two had blunt trauma to the chest. None of the four patients experienced direct injury to the eye or orbital area. The authors hypothesize that an increase in thoracic pressure due to trauma, straining, or coughing causes a sudden increase in intravascular pressure, resulting in a breakdown of the capillary blood–retinal barrier. They propose that the peculiar wedge-shaped findings observed in AMNR may be due to the difference in the surface area of the blood vessels in the retina. The surface area in the outer macula, which houses the larger blood vessels, will allow the escape of more fluid compared to the smaller vessels found in the fovea, thus producing the wedge-shaped lesions pointing toward the fovea. These are the only results relating AMNR to trauma that we were able to locate in the published literature, and it is possible that they are not “true” cases of AMNR.

Whether there is an association between migraine and AMNR remains unclear. Of the 41 cases, 3 (7%) had a history of either migraine or headaches. Migraine with and without aura has been reported to cause both transient and permanent scotomas23, 25, 36 and other permanent visual defects, including complete blindness.3, 5, 9, 18, 27 The prevalence of visual field defects increases with age and duration of migraine.21 Most visual problems reported in migraineurs are in those who experience retinal migraine. Retinal migraine is defined as a transient or permanent visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migraine.25 Retinal migraine is reported to cause acute and permanent scotomatas7, 16, 21, 25 but has not been specifically associated with the characteristic lesions of AMNR.

The length of follow-up of the 41 cases described in the table ranged from 3 weeks to 7 years. Among these 41 cases, 54% (22/41) showed no improvement, whereas 29% (12/41) showed some degree of improvement. The outcome was unknown in 7 of the cases.

III. Summary 

Acute macular neuroretinopathy is a rare condition that had been reported primarily among young women in their reproductive years. The symptoms usually include the onset of temporary or permanent vision loss associated with paracentral scotomas that occur either unilaterally or bilaterally. The hallmark lesions of this condition are dark-reddish brown and wedge- or oval-shaped. The lesions typically point toward the fovea and appear as teardrops or petals. Amsler grid or Goldmann perimetry identify the scotomas associated with these lesions. AMNR has been reported in association with epinephrine, intravenous iodine contrast agents, oral contraceptives, influenza-like illnesses, and trauma. AMNR has also been reported in association with two other ocular syndromes, multiple evanescent white dot syndrome and idiopathic blind spot enlargement syndrome. Migraine itself is reported to cause similar ocular disorders and may be a risk factor for AMNR. Differences were observed in the presentation and natural history of AMNR cases depending on whether they were associated with influenza-like illness or with epinephrine exposure. Such differences may reflect alternative mechanisms for damage or varying degrees of involvement in the macula.

An infectious process seems to be a promising etiological association, since 18/41 (44%) had a history of an influenza-like illness less than one week prior to their ocular event. Identifying the times of the year in which these cases of AMNR occurred would at least make it possible to evaluate whether the flu-like illnesses were consistent with the expected frequency for that time of year (e.g., a winter distribution of cases). Because of the rarity of AMNR, controlled studies of possible causal factors will be difficult to conduct. Such studies provide the best opportunity, however, to determine whether factors reported in association with the onset of AMNR are in excess of what would be expected or are merely the same as occur in similar persons without AMNR.

The diagnosis of AMNR should be considered in young, female patients who present with acute onset of multiple, paracentral scotomas and especially in those who have recently experienced an acute viral-like illness. A definitive diagnosis is made using red-free light to examine the retina. AMNR may be self-limiting or may persist, and there is no treatment. Future research may better elucidate the factors that precipitate this condition.

Method of Literature Search 

This review included all published case reports of AMNR in the English-speaking literature from 1975 through April 2002. The following databases were searched: Pubmed and Medline. The keywords included acute macular neuroretinopathy, macula, etiology, and retinal diseases. Textbooks that included information on diseases of the macula were examined for relevant reports, and published reports identified through the reference lists of other articles were also included. Only non-English language papers were excluded.