Acute Macular Neuroretinopathy (AMN) — Comprehensive Disease Research Report

1. Disease Information

Overview: Acute macular neuroretinopathy (AMN) is a rare, acquired retinal disorder characterized by acute-onset paracentral scotomas accompanied by distinctive reddish-brown, wedge-shaped ("petaloid" or teardrop-configured) lesions in the macula, with apices pointing toward the fovea. It was first described by Bos and Deutman in 1975. It is now understood as a disorder of the outer retina caused by ischemia affecting the deep capillary plexus (DCP) and/or choriocapillaris (Orphanet ORPHA:488239; PMID: 26973287).

Key identifiers: - Orphanet: ORPHA:488239 - MONDO: Indexed in MONDO Disease Ontology (referenced via NORD/MONDO partnership; specific MONDO ID not independently confirmed in available sources — verify against current MONDO release) - ICD-10-CM: H35.89 (Other specified retinal disorders) is the most commonly cited code; some sources list it under H35.3 (Degeneration of macula and posterior pole) — coding conventions vary by institution - OMIM: No dedicated OMIM entry identified; AMN is not classified as a monogenic/Mendelian disorder - MeSH: Retinal Diseases (broader term); no AMN-specific MeSH descriptor identified in search - Suggested MONDO/HPO cross-reference terms below

Synonyms: AMN; acute macular neuroretinopathy of Bos and Deutman; "type 2 AMN" is sometimes used loosely for a related but distinct entity (paracentral acute middle maculopathy, PAMM) — see Section 6/8 for the AMN/PAMM spectrum debate.

Evidence base: Information is derived predominantly from aggregated case series, case reports, and one major systematic literature review (Bhavsar et al., Surv Ophthalmol 2016;61(5):538-65, PMID: 26973287, pooling 156 eyes from 101 published cases), rather than large-scale registries or EHR-based cohort studies. No disease registry or biobank specific to AMN was identified. A retrospective single-center study also reported an increase in visits coded for AMN during the COVID-19 pandemic (0.66/100,000 visits in 2019 to 8.97/100,000 in 2020), suggesting some administrative/EHR-level data exists but is not aggregated into a public registry.

Sources: - Orphanet: Acute macular neuroretinopathy - Acute macular neuroretinopathy: A comprehensive review of the literature - PubMed (PMID 26973287) - NORD/MONDO: acute macular neuroretinopathy - ICD10Data H35.89

2. Etiology

Disease causal factors: AMN is understood as a primarily mechanistic/vascular disorder — microvascular ischemia of the retinal deep capillary plexus and/or inner choroid/choriocapillaris — rather than a genetic or single-infectious-agent disease. It is best conceptualized as a final common pathway triggered by diverse systemic insults that transiently compromise perfusion to the outer retina.

Risk factors (environmental/clinical — no confirmed genetic risk loci identified in literature searched): - Preceding viral or flu-like illness (influenza, dengue, SARS-CoV-2, other febrile illnesses) - Oral contraceptive pill use - Vaccination (including COVID-19 mRNA and adenoviral vector vaccines — multiple case reports) - Sympathomimetic/vasoactive drug exposure: intravenous epinephrine, ephedrine - Hypovolemia, systemic shock, hypotension - Pregnancy - Excessive caffeine intake - Trauma (including head injury; associated with Purtscher retinopathy) - Intravenous contrast administration - Migraine history - Prothrombotic states, including antiphospholipid antibodies - Demographics as risk modifiers: young age, female sex, non-Latino white race are overrepresented in case series (see Section 9)

Protective factors: No genetic or environmental protective factors have been identified or studied in the literature; this is consistent with AMN's classification as an acquired, trigger-driven microvascular event rather than a disease with defined susceptibility/resistance alleles.

Gene-environment interactions: Not established. No GWAS, CTD, or PheGenI data specific to AMN were found. The described "risk factors" are exclusively environmental/physiological triggers layered onto a presumed baseline vascular vulnerability of the deep capillary plexus/choriocapillaris (a watershed, low-flow vascular bed), rather than documented gene × environment interactions.

Sources: - Acute macular neuroretinopathy: A comprehensive review — PubMed - Multimodal imaging of type 2 AMN in a young woman — PMC - Acute macular neuroretinopathy in dengue virus serotype 1 — PMC - Bilateral AMN after Oxford-AstraZeneca COVID-19 vaccine — PMC

3. Phenotypes

Onset/severity/progression: Onset is acute (days), typically following a systemic trigger by 1–7 days (e.g., mean 2.8 ± 2.5 days post-COVID-19 PCR positivity in one series). Severity is variable — visual acuity is "often only mildly affected" since lesions are typically paracentral rather than foveal, but permanent paracentral scotomas are common even when acuity recovers well. Course is typically stable-to-slowly-improving: lesions and associated OCT/IR changes evolve over weeks to months, with scotomas persisting indefinitely in many patients even as visual acuity improves. Bilateral involvement occurs in ~54% of cases (Bhavsar et al. review of 156 eyes/101 cases).

Quality of life impact: Persistent paracentral scotomas can impair reading and fine visual tasks despite preserved central acuity; no formal EQ-5D/SF-36 disease-specific QOL data were identified in the literature searched.

Sources: - Acute macular neuroretinopathy: A comprehensive review — PubMed - Occult Acute Macular Neuroretinopathy — PMC - The characteristics of AMN following COVID-19 infection — PMC

4. Genetic/Molecular Information

Not applicable / not established. AMN has no known causal genes, pathogenic variants, chromosomal abnormalities, or Mendelian inheritance pattern. No entries were found in OMIM, ClinVar, or HGMD specific to AMN as a genetic disease. It is classified as an acquired microvascular retinopathy, not a genetic disorder. The only quasi-genetic association in the literature is an acquired autoantibody state (antiphospholipid antibodies) as a prothrombotic risk factor, which is an immunologic/hematologic risk factor rather than a germline genetic cause.

• Causal genes: None identified
• Modifier genes: None identified
• Epigenetic information: No epigenetic studies of AMN were found
• Chromosomal abnormalities: None reported

This section should likely be flagged as "not applicable" in the disease knowledge base entry, distinguishing AMN clearly from inherited macular dystrophies (e.g., Stargardt disease, macular telangiectasia type 2) with which it is sometimes confused due to imaging overlap.

5. Environmental Information

Environmental/infectious/lifestyle factors (overlapping with Section 2 risk factors, detailed here with supporting evidence):

• Infectious agents: Influenza-like illness (classic historical association); SARS-CoV-2 (multiple case series, including an 11-patient/20-eye series with mean age 33.8 ± 12.6 years, female-predominant, mean interval 2.8 ± 2.5 days from positive PCR to ocular symptom onset); dengue virus (serotype 1 documented; described as a major manifestation of "dengue maculopathy" with scotomas persisting ≥6 months despite corticosteroid pulse therapy)
• Vaccination: COVID-19 mRNA (Moderna) and adenoviral vector (Oxford-AstraZeneca) vaccines — reported as temporally associated triggers in case reports, though causality is not established (temporal association vs. causation)
• Lifestyle factors: Oral contraceptive use, excessive caffeine intake
• Pharmacologic/iatrogenic exposures: IV epinephrine, ephedrine, IV contrast administration
• Physiologic stressors: Systemic shock, hypovolemia, hypotension, pregnancy, trauma (including Purtscher retinopathy-associated cases)

No occupational, toxin, or pollution exposures were identified in the literature searched.

Sources: - COVID-19 Related AMN: A Case Series — PMC - Case report: dengue fever associated AMN — PMC - AMN in Dengue Fever: Short-term Prospectively Followed Up Case Series — JAMA Ophthalmology - Bilateral AMN after Oxford-AstraZeneca COVID-19 vaccine — PMC

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): 1. Trigger event (viral illness, vasoactive drug, hypovolemia/shock, vaccination, trauma) → 2. Microvascular compromise of a watershed, low-flow vascular bed — historically attributed to the deep capillary plexus (DCP) of the retina, but more recent OCT-angiography evidence implicates the inner choroid/choriocapillaris as the primary site of perfusion deficit → 3. Ischemia of the outer retina at the level of the outer plexiform layer (OPL) and outer nuclear layer (ONL), with secondary involvement of the photoreceptor ellipsoid zone (IS/OS junction) → 4. Photoreceptor and Müller cell injury, manifesting as hyperreflective bands on structural OCT and hyporeflective lesions on near-infrared reflectance/en face OCT → 5. Clinical manifestation: paracentral scotoma corresponding topographically to the area of capillary/choriocapillaris non-perfusion.

Molecular pathways: No specific signaling cascade (Wnt, MAPK, mTOR, PI3K-AKT) has been implicated; the mechanism is vascular/ischemic rather than a defined biochemical pathway defect.

Cellular processes: Ischemia-driven photoreceptor outer segment disruption; no confirmed apoptosis/autophagy pathway studies in human tissue (no histopathology available given lack of biopsy/autopsy specimens — this is a clinical-imaging diagnosis).

Imaging-based mechanistic evidence: - OCT angiography (Nemiroff et al., 2018, PMID: 29561336) demonstrated flow voids in the deep capillary plexus corresponding to AMN lesions, supporting DCP ischemia as (at least one) mechanism. - More recent work (2024, PMC11271325) found choriocapillaris vessel area density reduced by 27% and choroidal vessel area density reduced by 41% relative to adjacent control tissue, supporting an alternative/additional choroidal perfusion deficit hypothesis. - En face OCT analysis indicates the pathognomonic infrared hyporeflectivity is caused by photoreceptor-level alterations rather than inner retinal layer changes (PMC7885468). - Structural OCT shows hyperreflectivity in the outer plexiform and outer nuclear layers nasal to the fovea, with disruption of the ellipsoid zone.

Debate/uncertainty: There is active debate in the literature (as of 2024 sources) whether the DCP or the choriocapillaris/inner choroid is the primary site of vascular insult — this remains an area of ongoing research rather than settled mechanism.

Suggested GO terms: GO:0001525 (angiogenesis, as a related/contrasting process), GO:0006915 (apoptotic process, hypothesized downstream of ischemia), GO:0034599 (cellular response to oxidative stress). Suggested CL terms: CL:0000573 (retinal cone cell), CL:0000604 (retinal rod cell), CL:0000751 (rod bipolar cell — deep capillary plexus territory), CL:0000636 (Müller cell).

Sources: - OCT Angiography of AMN reveals deep capillary ischemia — PubMed (PMID 29561336) - OCTA suggests choriocapillaris perfusion deficit as etiology of AMN — PMC - Multimodal imaging for paracentral acute maculopathy; diagnostic role of en face OCT — PMC

7. Anatomical Structures Affected

Organ level: Eye — specifically the posterior segment/retina (macula). Systemically, AMN is a manifestation/complication of an inciting systemic illness rather than causing secondary organ damage itself.

Tissue/cell level: - Outer plexiform layer (OPL) and outer nuclear layer (ONL) — primary site of hyperreflective change - Photoreceptor inner/outer segments (ellipsoid zone) — site of disruption - Deep capillary plexus (DCP) — implicated vascular bed - Choriocapillaris / inner choroid — alternative/additional implicated vascular bed - Cell types: photoreceptors (rods and cones), Müller cells (secondary involvement)

Subcellular level: Photoreceptor outer segment disc membranes (structural disruption); no specific organelle-level (mitochondrial, ER) pathology has been documented in humans due to absence of histopathologic specimens.

Localization (UBERON): Macula lutea (UBERON:0002583), retina (UBERON:0000966), specifically the parafoveal/paracentral retina (lesions characteristically spare or point toward, but do not center on, the fovea). Fovea itself (UBERON:0004791) is typically relatively spared, correlating with preserved central acuity.

Lateralization: Bilateral in ~54% of cases; unilateral in the remainder. No consistent left/right predominance reported.

Sources: - Acute macular neuroretinopathy: A comprehensive review — PubMed

8. Temporal Development

Onset: Acute — typically in young adulthood (median age ~26 years per Bhavsar et al. review; mean 29.5 years; COVID-associated series mean 33.8 ± 12.6 years). Onset pattern is acute, frequently 1–7 days after a systemic trigger (fever, vaccination, dengue/COVID infection).

Progression: - Acute phase (days to weeks): hyperreflective OPL/ONL band, IR hyporeflectivity, visible fundus lesion (reddish-brown/petaloid), scotoma onset - Subacute/evolution phase (weeks to months): lesion fading, evolution of ellipsoid zone disruption, gradual improvement in acuity - Chronic/residual phase: outer retinal thinning/atrophy at lesion site may persist; scotomas often persist indefinitely even after visual acuity substantially recovers

Disease course pattern: Predominantly monophasic/self-limited with a single acute event and gradual partial-to-good recovery; recurrence is uncommon but has been reported. Not typically relapsing-remitting or chronically progressive in the way of a neurodegenerative disease.

Duration: Self-limited acute event; residual scotomas may be permanent/lifelong even though the acute inflammatory/ischemic phase resolves.

Remission patterns: Spontaneous — no treatment has been shown to alter the natural course; recovery is attributed to natural resolution of the ischemic insult rather than intervention.

Critical periods: No defined window of therapeutic opportunity has been established, consistent with lack of proven treatment.

Sources: - Acute macular neuroretinopathy: A comprehensive review — PubMed - The characteristics of AMN following COVID-19 infection — PMC

9. Inheritance and Population

Epidemiology: AMN is rare; precise population-level prevalence/incidence figures are not established via national registries. One retrospective single-center study found AMN-coded visits rose from 0.66 per 100,000 visits (2019) to 8.97 per 100,000 visits (2020), coincident with the COVID-19 pandemic — suggesting substantial under-ascertainment in typical (non-pandemic) years and an environmentally-modulated incidence.

Inheritance pattern: None — AMN is not a genetic/heritable disease. No penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier frequency data apply.

Population demographics: - Sex ratio: Strongly female-predominant — 84% female in the Bhavsar review (156 eyes/101 cases); male:female ratio 0.57:1 in the COVID-19-associated series (i.e., ~64% female) - Race/ethnicity: Preferentially affects young, non-Latino white women, per case-series data (selection bias in published literature is a caveat) - Age distribution: Predominantly reproductive-age young adults — median age 26 years, mean 29.5 years across pooled cases; COVID-associated cohort mean 33.8 ± 12.6 years - Geographic distribution: Most published cases originate from the United States (per Bhavsar review), though this likely reflects publication/reporting bias rather than true geographic clustering; dengue-associated cases reported from Taiwan and other dengue-endemic regions.

Sources: - Acute macular neuroretinopathy: A comprehensive review — PubMed - The characteristics of AMN following COVID-19 infection — PMC

10. Diagnostics

Clinical/imaging tests (diagnosis is primarily clinical-imaging based; no lab biomarker or biopsy is diagnostic):

• Fundoscopy: Reddish-brown, wedge-shaped/petaloid macular lesions with apices pointing toward the fovea; may be subtle, hypopigmented/grayish-white, or entirely absent on exam ("occult AMN," diagnosed by imaging alone) (PMC5762149)
• Structural OCT (spectral-domain): Hyperreflective band at the OPL/ONL junction acutely, evolving to outer nuclear layer thinning and ellipsoid zone disruption chronically — the primary diagnostic modality
• Near-infrared reflectance (IR) imaging: Characteristic hyporeflective lesion, often more sensitive than color fundus photography for detecting subtle or occult lesions
• En face OCT: Localizes the hyporeflective signal to the photoreceptor layer rather than inner retina
• OCT angiography (OCTA): Flow voids/reduced vessel density in the deep capillary plexus; more recent data show reduced choriocapillaris (−27%) and choroidal (−41%) vessel area density
• Fluorescein angiography (FA): Typically unremarkable or shows only subtle late staining — FA is relatively insensitive in AMN, an important distinguishing feature from other vascular retinopathies
• Visual field testing: Confirms paracentral scotoma corresponding to lesion location
• Multifocal ERG: Reduced amplitude corresponding to lesion area (reported in some case series)

Genetic testing: Not applicable/not indicated — AMN is not a genetic disorder, so gene panels, WES/WGS, CMA, karyotyping, FISH, and mitochondrial DNA testing have no established diagnostic role.

Omics-based diagnostics: None established; AMN is not currently diagnosed via transcriptomic, proteomic, metabolomic, or epigenomic assays.

Clinical diagnostic criteria: No formal society-endorsed diagnostic criteria (e.g., DSM/ICD operational criteria) exist beyond the characteristic clinical + multimodal imaging picture (fundoscopic lesion morphology + OCT hyperreflective band + IR hyporeflectivity + corresponding scotoma).

Differential diagnosis: - Paracentral acute middle maculopathy (PAMM) — key differential/spectrum-overlap condition; PAMM lesions are more superficial (inner nuclear layer/DCP level) versus AMN's outer retinal (OPL/ONL) involvement; PAMM patients tend to be older (>50 years), more often male, with vasculopathic risk factors, versus AMN's younger (often <30 years), female-predominant demographic - Acute idiopathic maculopathy - White dot syndromes (multiple evanescent white dot syndrome, MEWDS) - Macular telangiectasia type 2 - Central serous chorioretinopathy - Solar/photic retinopathy - Occult macular dystrophy

Screening: No population-based or genetic screening applies (acquired, non-heritable condition).

Sources: - Occult Acute Macular Neuroretinopathy — PMC - Paracentral acute middle maculopathy and acute macular neuroretinopathy — PubMed - PAMM — EyeWiki - Multimodal imaging for paracentral acute maculopathy — PMC

11. Outcome/Prognosis

Survival/mortality: Not applicable — AMN is a non-life-threatening, vision-specific condition with no associated mortality.

Morbidity/function: - Visual acuity outcomes are generally good — acuity is "often only mildly affected" since foveal center is typically spared - Paracentral scotomas frequently persist indefinitely, even when Snellen acuity recovers to near-normal, representing the main residual morbidity - No validated disease-specific quality-of-life instrument was identified in the literature searched

Disease course/complications: Self-limited in the majority; recurrence is uncommon. Outer retinal atrophy at the lesion site can be seen on long-term OCT follow-up even after subjective symptom resolution ("despite local retinal atrophy, subjective complaints disappear completely" in some patients) — indicating a dissociation between structural and functional/subjective recovery.

Recovery potential: Variable — some patients experience a fully self-limiting course with essentially complete retinal/functional recovery; others have persistent, permanent reduction in visual acuity and/or scotomas. No treatment has been shown to alter this natural trajectory.

Prognostic factors: No validated prognostic biomarkers or models identified; lesion size/location (foveal-sparing vs. foveal-involving) is the most intuitively relevant clinical factor described in case reports, though not formally validated.

Sources: - Acute macular neuroretinopathy — Retina Specialist - Acute macular neuroretinopathy: A comprehensive review — PubMed

12. Treatment

Pharmacotherapy: No proven, causative, or standardized treatment exists. The mainstay of management is observation. Isolated case reports describe use of systemic corticosteroids with subjective/anatomical improvement in scotomas, but this is not supported by controlled evidence and is not a standard-of-care recommendation. Corticosteroid pulse therapy has also been tried in dengue-associated AMN without preventing persistent visual disturbance.

Pharmacogenomics: Not applicable — no established pharmacogenomic considerations for AMN treatment.

Advanced therapeutics (gene therapy, cell therapy, RNA-based therapies, targeted therapies, immunotherapy): None applicable or under investigation for AMN specifically.

Surgical/interventional treatment: None indicated; AMN is not a surgical disease.

Supportive care: Reassurance, monitoring for resolution, low-vision support if permanent scotomas cause functional impairment (e.g., for reading).

Experimental treatments/clinical trials: No AMN-specific registered clinical trials were identified in the sources reviewed.

Treatment outcomes: Because no treatment has demonstrated efficacy over observation, "response rates" are not meaningfully defined; most published corticosteroid use reflects anecdotal, uncontrolled experience.

Treatment strategy: The de facto clinical pathway is: (1) confirm diagnosis via multimodal imaging (OCT, IR, OCTA), (2) rule out/treat any identifiable underlying systemic trigger (e.g., manage the associated viral illness, discontinue oral contraceptives if implicated, address hypotension/shock), and (3) observe with serial OCT/visual field follow-up.

Suggested MAXO terms: MAXO term for "watchful waiting"/clinical observation would apply; no MAXO term for a specific pharmacologic or procedural intervention is well-supported given the absence of an evidence-based treatment.

Sources: - Acute macular neuroretinopathy — Retina Specialist - AMN in Dengue Fever — JAMA Ophthalmology

13. Prevention

Primary prevention: No specific primary prevention strategy exists, since AMN is an unpredictable, idiosyncratic response to diverse systemic triggers (infection, vaccination, vasoactive drugs, hypotension). General avoidance/caution regarding known associated triggers (e.g., judicious use of vasoactive sympathomimetics, avoiding hypovolemia) has been suggested anecdotally but is not a validated prevention protocol.

Secondary prevention: Early recognition via multimodal imaging in at-risk patients (e.g., those presenting with paracentral scotoma after febrile illness) allows prompt diagnosis, though this does not alter the natural disease course.

Immunization: Not applicable in a preventive sense — vaccination is itself a reported (rare) trigger rather than a preventive measure for AMN.

Screening/genetic screening: Not applicable — non-heritable condition.

Behavioral interventions: Possible modifiable risk factor avoidance (e.g., reducing excessive caffeine intake, considering alternatives to oral contraceptives in a patient with a prior AMN episode) has been informally suggested in case discussions but lacks trial-level evidence.

Counseling: Genetic counseling is not applicable. Patients may benefit from counseling regarding the generally favorable but variable visual prognosis and the possibility of persistent scotomas.

Public health/prophylaxis: No public health intervention or prophylactic medication regimen has been established.

14. Other Species / Natural Disease

Not established. No literature was identified describing naturally occurring AMN in non-human species, veterinary case reports, or OMIA entries. AMN appears to be a human-specific clinical entity as currently described in the literature (searches for veterinary/animal natural disease returned no relevant AMN-specific results, only unrelated age-related macular degeneration animal model literature).

15. Model Organisms

No dedicated animal or in vitro model of AMN was identified in the literature searched (MGI, ZFIN, RGD, and general model-organism searches did not surface AMN-specific models). This is consistent with AMN's status as an acquired, imaging-defined clinical syndrome without a known genetic driver to model, and with the practical difficulty of modeling transient, spontaneously-resolving deep capillary plexus/choriocapillaris ischemia. Related ischemic retinal models (e.g., rodent retinal vein occlusion or middle cerebral/retinal artery occlusion models used to study deep capillary plexus ischemia and PAMM) may be indirectly relevant analogs but were not confirmed as validated AMN models in the sources reviewed. This section should be flagged as a research gap in the disease knowledge base.

Summary of Key Data Gaps for Knowledge Base Curation

1. No genetic/molecular section applies — flag explicitly as N/A rather than leaving blank, to distinguish from an incomplete curation.
2. No animal models or veterinary natural disease identified — flag as N/A/research gap.
3. MONDO ID requires direct confirmation from the current MONDO release (not independently verified in this search).
4. ICD-10-CM code shows some inconsistency across sources (H35.89 vs. H35.3) — recommend verifying against current CMS/WHO coding guidance.
5. Mechanism (DCP vs. choriocapillaris as primary ischemic site) is an active, unresolved scientific debate — should be represented as competing hypotheses rather than a single settled mechanism.

Key primary references (PMIDs): - Bhavsar KV et al. Acute macular neuroretinopathy: A comprehensive review of the literature. Surv Ophthalmol. 2016;61(5):538-565. PMID: 26973287 - Nemiroff J et al. Optical coherence tomography angiography of acute macular neuroretinopathy reveals deep capillary ischemia. PMID: 29561336 - Fawzi AA et al. Acute macular neuroretinopathy: long-term insights revealed by multimodal imaging. Retina. 2012;32(8):1500-1513. - Rahimy E et al. Paracentral acute middle maculopathy and acute macular neuroretinopathy. PMID: 24220881

Sources: - Orphanet: Acute macular neuroretinopathy - Acute macular neuroretinopathy: A comprehensive review of the literature - PubMed - OCT Angiography of AMN reveals deep capillary ischemia - PubMed - OCTA suggests choriocapillaris perfusion deficit - PMC - Multimodal imaging for paracentral acute maculopathy — PMC - The characteristics of AMN following COVID-19 infection — PMC - COVID-19 Related AMN: A Case Series — PMC - Bilateral AMN after Oxford-AstraZeneca COVID-19 vaccine — PMC - Case report: dengue fever associated AMN — PMC - AMN in Dengue Fever — JAMA Ophthalmology - Occult Acute Macular Neuroretinopathy — PMC - PAMM and AMN — PubMed - Paracentral Acute Middle Maculopathy — EyeWiki - Acute macular neuroretinopathy — Retina Specialist - NORD/MONDO: acute macular neuroretinopathy - ICD10Data H35.89