Acute retinal ischaemia associated with paracentral acute middle maculopathy detected on multimodal imaging: a premonitory sign of severe carotid occlusive disease

Abstract

A man in his 60s presented with a subacute paracentral scotoma and preserved visual acuity in the left eye. He was found to have a very subtle area of deep retinal whitening at the macula and multiple retinal cholesterol emboli. Optical coherence tomography (OCT) with En face imaging revealed globular paracentral acute middle maculopathy (PAMM). A diagnosis of PAMM associated with branch artery occlusion was made and the patient was immediately transferred to the nearest stroke centre. Investigations revealed severe carotid occlusive disease for which the patient underwent carotid endarterectomy. Paracentral scotomas in patients with little clinical findings on fundus examination should raise the suspicion for PAMM, which is easily identifiable on OCT. Eye care professionals must recognise PAMM as a possible sign of acute retinal arterial ischaemia—an ocular and systemic emergency that requires immediate referral to specialised stroke centres.

Background

Paracentral acute middle maculopathy (PAMM) is a well-described optical coherence tomography (OCT) finding consisting of hyper-reflective band-like lesions involving the inner nuclear layer (INL) in patients with retinal capillary ischaemia. Regions of vascular instability, like the watershed zones of the outer plexiform layer (OPL) and INL, are particularly susceptible.¹ PAMM can present as either an isolated phenomenon or a complication of a retinal vasculopathy or a systemic condition.² Usually, fundus examination reveals very subtle retinal lesions that can be easily overlooked. Using En face OCT, clinicians can identify three distinct PAMM patterns: arteriolar, globular and fern-like.³ Globular PAMM is associated with branch retinal arterial occlusions (BRAOs) and can be the only sign (along with the other patterns of PAMM) of acute retinal arterial ischaemia, which is a systemic emergency that requires immediate referral to specialised stroke centres.⁴

Case presentation

A man in his 60s with no ocular history presented with a subacute change in vision in the left eye. His symptoms had begun a week prior with a large central red spot that slowly diminished over days, leaving a residual paracentral scotoma. He was known for coronary artery disease, for which he had undergone a coronary artery bypass graft a year prior. He was diabetic and had new york heart association (NYHA) class III congestive heart failure as well as atrial fibrillation. His medications included: atorvastatin for dyslipidaemia; furosemide, spironolactone, sacubitril/valsartan and bisoprolol for heart failure; dapagliflozin for diabetes; apixaban and low-dose aspirin as combined anticoagulation and antiplatelet therapy.

Uncorrected visual acuity was 20/20-1 in the left eye, and intraocular pressure was 15 mm Hg. Anterior segment examination was normal apart from 1+ nuclear sclerosis bilaterally. Gonioscopy revealed wide-open angles (Shaffer grade 4) in both eyes. Fundus examination of the left eye showed multiple small yellowish and reflective cholesterol emboli in the retinal arterioles of the macula and along the inferior vascular arcade (figure 1A). There was a very subtle area of deep retinal whitening at the macula, inferior and distal to a small retinal arteriole containing a cholesterol embolus (figure 1B). Spectral-domain OCT obtained through the lesion showed PAMM (figure 2A, B). The corresponding mid-retina En face OCT revealed an ovoid focal area of hyper-reflectivity (figure 2C). This subtype of the disease is referred to as globular PAMM. The patient was diagnosed with PAMM associated with incomplete BRAO. Given the visible retinal emboli and the absence of any suggestive systemic symptoms, we elected not to obtain laboratory testing for giant cell arteritis (GCA). Instead, the patient was immediately transferred to a stroke centre for further medical management.

Figure 1.

Colour fundus photograph of the left eye (A) showing multiple small yellowish and reflective cholesterol emboli in the retinal arterioles of the macula and along the inferior vascular arcade (white arrows). Magnified image of the macula (B) revealing a subtle area of deep retinal whitening inferior and distal to a small retinal arteriole containing a cholesterol embolus (white box).

Figure 2.

Spectral-domain OCT of the macula of the left eye at the time of diagnosis. The horizontal (A) and vertical (B) B-scans demonstrate a hyper-reflective plaque-like lesion extending from the inner plexiform to the outer plexiform layers, consistent with PAMM. A hyper-reflective dot is seen superior to the PAMM lesion at the level of the ganglion cell layer, likely corresponding to the cholesterol embolus. The En face visualisation through the mid-retina (C) shows a focal ovoid area of hyper-reflectivity corresponding to ‘globular’ PAMM. OCT, optical coherence tomography; PAMM, paracentral acute middle maculopathy.

Investigations

At the stroke centre, non-contrast CT of the brain was obtained and came back normal without signs of acute ischaemic or haemorrhagic stroke. Brain MRI with diffusion-weighted imaging (DWI) sequences, which are very sensitive in the detection of small and early brain infarcts, did not reveal signs of acute ischaemia. Incidentally, there was evidence of chronic cortical microbleeds reflecting cerebral amyloid angiopathy which is likely related to the patient’s longstanding hypertension and anticoagulant medication use. The patient was hospitalised pending further investigations into the source of embolism. CT angiography revealed a hypodense ulcerated plaque of the left carotid bulb with 70% stenosis of the internal carotid artery, which was the likely source of retinal embolism. Cardiac echocardiography was unremarkable.

Differential diagnosis

The main differential diagnosis of PAMM is acute macular neuroretinopathy (AMN).⁵ While PAMM was initially described as a variant of AMN, the two are now considered distinct entities. AMN typically presents with intraretinal reddish-brown wedge-shaped lesions around the fovea in young healthy women.⁵ OCT findings differ in that the hyper-reflectivity is deep to the OPL in AMN while it is superficial in PAMM. AMN can also affect the outer retina with disruption of the ellipsoid/ interdigitation zone, which is not seen in PAMM and not seen in our case.⁵

The differential diagnosis for the aetiology of PAMM is broad and includes local retinal vascular diseases like arterial and venous occlusions, diabetic retinopathy and retinal vasculitis, and extrinsic factors like migraines, medications and viral infections.¹ In our case, multiple retinal cholesterol emboli were seen in the retinal arterioles and adjacent to the area of PAMM, providing a clear explanation for the downstream ischaemia and prompting a diagnosis of incomplete BRAO. Our patient also had no signs of diabetic retinopathy or uveitis and no relevant extrinsic factors were obtained on history.

Among the potential aetiologies for retinal arterial occlusions (RAOs), atherosclerotic disease of the ipsilateral carotid artery remains the most common cause of embolism.⁶ Our patient not only had high-grade stenosis of the ipsilateral internal carotid artery but also had an ulcerated plaque, making carotid disease the likely source of embolism.⁶ A cardiogenic embolic source from our patient’s known atrial fibrillation was considered less likely given his use of anticoagulation and since retinal ischaemia is caused more often by carotid atherosclerosis than by atrial fibrillation.⁷

Retinal ischaemia associated with inflammatory aetiologies like GCA is important to exclude in RAOs, especially in patients over the age of 50 years who do not have visible retinal emboli. Since our patient had multiple retinal emboli, we elected not to test for GCA. Also, our patient had an incomplete BRAO which is not typically associated with GCA since the latter is a disease of medium-sized and large arteries and not of the arterioles.⁸

Treatment

To reduce the risk of ischaemic stroke, carotid revascularisation was proposed. The patient underwent successful left carotid endarterectomy (CEA) within 2 weeks of the initial presentation.

Outcome and follow-up

The patient was seen in follow-up regularly up to 5 months after hospital discharge. His vision remained normal with improvement in the previously reported paracentral scotoma. At 5 months, follow-up fundus examination highlighted the disappearance of the previously identified cholesterol emboli (figure 3A), and OCT showed regression of the PAMM lesions with resolution of the hyper-reflective lesions, subsequent atrophy of the INL and attenuation of the OPL (figure 3B, C).

Figure 3.

Colour fundus photograph of the left eye at follow-up (A) demonstrates the disappearance of the previously described cholesterol emboli. The area of deep retinal whitening also disappeared. Horizontal (B) and vertical (C) spectral-domain optical coherence tomography of the macula at follow-up shows the resolution of the hyper-reflective lesions, atrophy of the inner nuclear layer (between the white arrows) and attenuation of the outer plexiform layer (between the orange arrows).

Discussion

As demonstrated in our case, multimodal imaging and in particular En face OCT is useful to identify PAMM and its subtypes.³ Our patient had mild visual symptoms and preserved visual acuity which, combined with his subtle fundus findings, could easily have been overlooked in a busy ophthalmology clinic. However, the OCT findings were very telling. The horizontal and vertical sections revealed characteristic lesions of PAMM, and En face imaging identified the globular subtype. Also, the latter images clearly delineated the area of ischaemia providing an explanation to the patient’s scotoma and normal visual acuity from lack of foveal involvement.

Isolated PAMM can be the first sign of the ischaemic cascade in acute arterial retinal ischaemia, which, when completed, results in clinically visible RAO.⁹ In this cascade, PAMM begins as a fern-like configuration at the level of the deep capillary plexus (DCP) closer to the perivenular pole and progresses laterally to involve the entire INL, producing a globular pattern. In severe forms of ischaemia, anterior extension might occur, leading to ischaemia of the inner retinal layers and subsequent clinical RAOs.^{3 10} Thus, when a patient presents with PAMM and minimal fundus changes, incomplete RAO must be considered in the differential diagnosis. In our particular case, multiple reflective cholesterol emboli were found in the retinal arterioles and adjacent to the area of PAMM—providing a clear explanation for the downstream ischaemia. In RAO, ischaemia to the DCP and subsequent PAMM is due to primary hypoperfusion from diminished arterial inflow pressure.¹⁰

The risk of cardiovascular events after isolated PAMM remains unclear.¹¹ However, given that PAMM can be the first and only sign of incomplete RAO (even in the absence of any visible emboli), it is prudent to manage those cases similarly to clinical RAOs.¹² RAOs are best classified as minor strokes and must be managed according to established guidelines.^{4 12} It is currently recommended that ophthalmologists refer patients to the nearest specialised stroke centre for prompt assessment without attempting to perform any further testing by themselves.⁴ In our case, we referred our patient to the nearest stroke centre for immediate investigations as part of the standard ‘stroke protocol’. We had high suspicion for the presence of an ipsilateral atherosclerotic carotid lesions given the multiplicity of the cholesterol emboli. Our patient had no acute cerebral ischaemia on MRI but was hospitalised pending further investigations. The likely source of retinal embolism was identified on CT angiography that showed ipsilateral severe carotid stenosis with an ulcerated plaque. CEA was performed to reduce the risk of future ischaemic stroke.

In patients older than 50 years, the rationale for referring patients to the nearest stroke centre is first to identify patients at high risk of stroke who need to be hospitalised and urgently treated, and second to identify the source of embolism.⁴ In patients who have no visible retinal embolus, it is imperative to exclude GCA as the aetiology of the RAO even in the absence of systemic symptoms like headache and jaw claudication (occult GCA).¹³ Urgent brain imaging (ideally MRI with DWI sequences) is recommended to detect asymptomatic cerebral infarctions which are found in up to one-third of patients with BRAO.¹⁴ Identifying patients with silent cerebral infarcts is important because they are at higher risk of stroke, particularly early after the onset of the RAO. Then, a systemic evaluation for carotid occlusive and thromboembolic disease must be performed and should include: imaging of the cervicocephalic vessels like carotid ultrasound as well as echocardiography and prolonged cardiac monitoring.⁴

In patients with central or paracentral scotomas and little clinical findings on fundus examination, the diagnosis of PAMM should be considered. Obtaining a macular OCT is crucial to make the correct diagnosis. En face OCT can be useful to detect the subtypes of PAMM which are associated to different pathophysiological mechanisms.¹⁵ In the appropriate clinical context, ophthalmologists must be aware that PAMM can be the only sign of RAO and must immediately refer those patients to the nearest stroke centre for immediate stroke risk stratification and risk factor management.

Learning points.

• Paracentral scotomas in patients with little clinical findings on fundus examination should raise the suspicion for paracentral acute middle maculopathy (PAMM), which is easily recognisable on optical coherence tomography (OCT).

• Globular PAMM (as seen on En face OCT) is associated with distal ischaemic events in small terminal retinal arterioles and capillaries, and should raise the suspicion for microembolic events.

• PAMM can be the first (and only) sign of acute retinal arterial ischaemia—an emergency requiring immediate referral to a specialised stroke centre for adequate work-up and management.

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