Paracentral Acute Middle Maculopathy (PAMM) was first proposed as an independent disease entity by Sarraf et al. in 2013 10). It is a condition in which the inner nuclear layer (INL) is damaged due to acute ischemia of the intermediate capillary plexus (ICP) or deep capillary plexus (DCP) of the retina.
The retina has three layers of capillary plexuses arranged in series: the superficial (SCP), intermediate (ICP), and deep (DCP) capillary plexuses. PAMM results from ischemia of the ICP and DCP and is more common than acute macular neuroretinopathy (AMN). PAMM often occurs in association with other retinal vascular diseases but can also occur independently.
PAMM may appear as an early finding in central retinal artery occlusion (CRAO). PAMM associated with CRAO has been linked to stroke, and prompt referral to a stroke center is recommended 9).
Features of PAMM
Year of discovery: Proposed by Sarraf et al. in 201310).
Affected site: Inner nuclear layer (INL) of the retina. Caused by ICP and DCP ischemia.
Frequency: More common than acute macular neuroretinopathy (AMN).
Visual acuity: Often relatively preserved at 20/20 to 20/30.
Comparison with AMN
Typical subjective symptoms of PAMM are as follows.
Symptoms are characterized by acute onset, and patients notice sudden visual field abnormalities. In the natural course, symptoms often persist.
SD-OCT findings are central to the diagnosis of PAMM. In the acute phase, a hyperreflective band appears in the inner nuclear layer (INL), which progresses to INL atrophy and thinning in the chronic phase.
PAMM lesion patterns are classified into three types based on morphology2).
| Pattern | Morphology | Corresponding vessel |
|---|---|---|
| Arteriolar | Punctate to small lesion | Periarteriolar |
| Globular | Globular lesion | ICP ischemia |
| Fern-like | Fern-like widespread | DCP ischemia |
The fern-like pattern spreads along the DCP and indicates the most extensive ischemia. This pattern is common in severe cases2).
En face OCT allows two-dimensional assessment of the extent and morphology of the lesion. A strong fluorescence finding called Vitreous Chorioretinal Hyperfluorescence (VCH) may be detected on en face OCT. This finding is thought to reflect reactive hyperemia originating from the vitreous and choroid, and is useful for dynamic evaluation of the lesion1).
OCTA can directly visualize blood flow deficits in the capillary networks of the ICP and DCP.
PAMM persists as a paracentral scotoma and interferes with daily activities such as reading and driving. In addition, it may be associated with underlying severe systemic diseases (e.g., CRAO, sickle cell disease), making it important as a trigger for systemic evaluation (see “Causes and Risk Factors” section).
PAMM is associated with various systemic diseases. The main causes and related diseases are listed below.
Association with vascular diseases and systemic conditions:
Juvenile/idiopathic PAMM:
PAMM in young individuals without a clear underlying disease has also been reported. In a study of 5 women with a mean age of 28.6 years, associations with common cold (3 cases), pregnancy (1 case), and oral contraceptive use (2 cases) were suggested, and aspirin 100 mg was administered4).
The diagnosis of PAMM is based on a combination of clinical findings and imaging tests. A systemic workup to identify underlying diseases is also important.
The following table shows the characteristics of major imaging diagnostic methods.
| Examination Method | Main Findings | Features |
|---|---|---|
| SD-OCT | INL hyperreflective band → atrophy | Highest sensitivity, standard test |
| En face OCT | Lesion morphology / VCH | 2D morphological evaluation |
| OCTA | ICP/DCP flow deficit | Vascular visualization |
Since PAMM may be an ocular manifestation of a serious systemic disease, the following workup is performed.
No specific treatment for PAMM has been established. The basis of treatment is identification and management of the underlying disease.
Treatment by Underlying Disease
Hypertension: Initiation or intensification of antihypertensive therapy.
Central retinal vein occlusion/CRAO: Anti-VEGF therapy and referral to a stroke center.
Antiphospholipid syndrome: Anticoagulation therapy and aspirin administration.
Sickle cell disease: Continue hydroxyurea; severe cases require red blood cell exchange transfusion.
Interventions by Case
Idiopathic juvenile PAMM: Aspirin 100 mg has been administered in some cases.
Dengue fever-related: Prednisolone 40 mg/day improved VA (6/12 to 6/9) has been reported.
SCD-related: Best-corrected visual acuity (BCVA) of 20/20 to 20/30 was achieved after red blood cell exchange transfusion (RBCX).
A case of PAMM with central retinal vein occlusion associated with antiphospholipid syndrome: Treatment including aspirin resulted in 20/20 vision after 7 months. VCH changes during the course were confirmed by OCT 1).
In a case of PAMM associated with sickle cell disease (HbSS type) , onset after discontinuation of hydroxyurea has been reported. After red blood cell exchange transfusion (RBCX), best corrected visual acuity of 20/20 to 20/30 was achieved. This suggests the importance of continued management of hydroxyurea for SCD6).
In a case of PAMM associated with dengue fever , prednisolone 40 mg/day was administered during the acute phase with thrombocytopenia, and visual improvement (6/12 to 6/9) was obtained5).
In juvenile idiopathic PAMM (5 women, mean age 28.6 years) , aspirin 100 mg was administered in cases without specific underlying disease. An association with colds, pregnancy, and oral contraceptives was suggested4).
Paracentral scotomas caused by the lesion are often permanent. While visual acuity is often relatively preserved, there is no established evidence that the lesion spontaneously resolves without treatment of the underlying disease. Early identification and treatment of the underlying condition are important.
The mechanism of PAMM onset is understood based on the anatomical characteristics of the retinal capillary plexus and differences in susceptibility to ischemia.
The retinal capillary plexuses (SCP → ICP → DCP) are arranged in series. In this structure, the most peripheral DCP has the lowest perfusion pressure. The concept that a decrease in DCP perfusion pressure causes ischemia in the watershed area has been proposed 7).
From the study of cases where PAMM developed after coronary angiography, an ischemic cascade of ICP and DCP was proposed. It is thought that microemboli or transient blood pressure fluctuations during the procedure cause DCP perfusion failure, leading to inner nuclear layer ischemia 7).
VCH (Vitreous Chorioretinal Hyperfluorescence) detected by en face OCT is thought to reflect reactive hyperemia of the vitreous and choroidal side in response to retinal ischemia. In the case reported by Otero-Marquez et al., VCH findings changed with treatment course and served as an indicator for lesion monitoring 1).
In sickle cell disease, deformed red blood cells occlude retinal capillaries. Hydroxyurea suppresses sickling, so its discontinuation can trigger onset 6). In particular, the DCP is a common site of ischemia in SCD.
Vasospasm and endothelial dysfunction associated with migraine may trigger PAMM 3). Regarding the association with common cold in idiopathic juvenile PAMM, vasculitis and coagulation abnormalities due to viral infection are suspected, but the detailed mechanism remains unclear 4).
VCH may reflect disease activity and treatment response.
Otero-Marquez et al. (2023) reported a case of PAMM associated with central retinal vein occlusion in antiphospholipid syndrome, where en face OCT monitoring of VCH changes over time was useful. After 7 months, visual acuity of 20/20 was achieved and VCH resolution was confirmed 1).
Using VCH as a quantitative evaluation index is a promising direction for future PAMM management.
The classification into three patterns (arteriolar/globular/fern-like) is being investigated for its potential utility in assessing pathology and prognosis.
Jabbehdari & Uwaydat (2023) reported consecutive bilateral PAMM cases and showed that the fern-like pattern reflects extensive ischemia along the DCP. They also revealed that the prevalence of hypertension in PAMM patients reaches 89.9% 2).
Systematic analysis of the relationship between pattern classification, underlying diseases, and prognosis is a future challenge.
The development of new therapeutic drugs for sickle cell disease is expected to have spillover effects on the prevention and treatment of SCD-associated PAMM.
Parikh et al. (2022) reported that in a case of PAMM associated with HbSS-type SCD, red blood cell exchange transfusion (RBCX) contributed to maintaining best-corrected visual acuity of 20/20 to 20/30. They also mentioned the potential for preventing retinal complications through new drug development for SCD 6).
The onset of PAMM in a state of severe immunodeficiency is attracting attention as a new pathological condition in HIV retinopathy.
Kanakis et al. (2023) reported PAMM-like lesions in an HIV patient with a CD4 count of 45, where the SCP, ICP, and DCP were simultaneously impaired, describing them as late PAMM-like lesions in HIV retinopathy8). Follow-up after immune recovery is considered important.
