Paracentral Acute Middle Maculopathy Associated With Bilateral Optic Disc Swelling And Meningitis

Abstract

Background/Purpose

To present a novel case of paracentral acute middle maculopathy (PAMM) associated with bilateral optic disc swelling

Methods

Retrospective case report

Results

A 67-year-old female presented with sudden onset of central vision loss, and subsequent bilateral optic disc edema, retinal vessel attenuation and anterior uveitis. Cerebrospinal fluid analysis showed signs of inflammation. Spectral-domain optical coherence tomography (SD-OCT) demonstrated the pathognomonic hyperreflectivity of the middle retinal layers consistent with PAMM. Swept-source OCT angiography with custom vessel analysis demonstrated a 18.3% decrease in the deep retinal vascular density and 2.4 times increase in absent flow area in the affected eye compared to the fellow eye.

Conclusion

This case demonstrates a novel association between PAMM and bilateral optic disc swelling secondary to central nervous system inflammation and possible infection. While SD-OCT is valuable in detecting PAMM, OCT angiography with vessel analysis can provide additional insight on the disease mechanism.

Introduction

Paracentral acute middle maculopathy (PAMM) is characterized by hyperreflective bands affecting the inner plexiform player (IPL), inner nuclear layer (INL) and outer plexiform layer (OPL) on spectral-domain optical coherence tomography (SD-OCT). It was first described by Sarraf and colleagues in 2013 as a variant of acute macular neuropathy (AMN) with a possible vascular etiology affecting intermediate and deep retinal capillaries^{1, 2}. Subsequent studies revealed the ischemic nature of PAMM, which was a sign found in various retinal vascular diseases including nonproliferative diabetic retinopathy, central retinal vein occlusion, and retinal artery occlusion^{3, 4}. Interestingly, PAMM can also occur in otherwise healthy patients with an antecedent upper respiratory tract infection^{1, 5}, implying a substantial role of inflammation/infection in its pathogenesis. In this report, we present a case of PAMM in a patient with bilateral optic disc swelling secondary to a possible viral infection of the central nervous system (CNS).

Case Report

A 67-year-old Caucasian female presented with painless central vision loss in the right eye. She had a history of sinus infection and pneumonia a few weeks before her presentation, which subsided after levofloxacin treatment. She denied symptoms of temporal tenderness or jaw claudication. Her review of systems and past ocular history were otherwise non-contributory.

At presentation, she reported a subjective central scotoma in her right eye. Her best-corrected visual acuity was 20/500 with eccentric gaze in the right eye and 20/15 in the left. A subtle relative afferent pupillary defect was present in the right eye. Intraocular pressures were within normal limits. Slit-lamp exam showed quiet anterior chambers bilaterally. Fundus examination was unremarkable except for a slightly pale macula on the right. Near-infrared (NIR) reflectance imaging of the right eye revealed a subtle, dark gray patchy change affecting the fovea (Figure 1A). The foveal SD-OCT image revealed a typical PAMM lesion with a hyperreflective, plaque-like band at the interface of the OPL and INL extending into the INL (Figure 1B). The light signal was attenuated deep to the PAMM lesion on OCT (Figure 1B). The outer retinal structures were otherwise intact. The NIR and OCT images of the left eye were within normal limits (Figure 1C). The patient was referred for complete neurologic workup. Initial tests included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complete blood count, metabolic panel and hypercoagulability panel were normal. CT angiography of the head and neck was notable for a beaded appearance of bilateral cervical internal carotid arteries, suggestive of fibromuscular dysplasia. Since there was a single micro-embolic signal picked up on the transcranial Doppler emboli monitoring, she was started on aspirin and atorvastatin.

Figure 1.

(A) Near infrared (NIR) image of the right eye at presentation. Black arrow: dark grey patchy foveal lesion. (B) Spectral-domain optical coherence tomography (OCT) image of the right and left eye through the fovea at the level indicated by the green line in NIR image. Both initial and 4-week follow-up images are shown. Between the white arrows: hyperreflective band at the inner nuclear layer (INL) spanning from the inner plexiform layer (IPL) to the outer plexiform layer (OPL). Asterisks: shadow effect below the retinal lesion. (C) NIR and OCT images of the left eye. (D) Middle retina segmentation containing the IPL, INL and OPL. Thickness was measured and compared on Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany. Scale bar = 200 μm

Upon follow-up 5 days later, she developed a vague sensation of pain with right eye movement and headache. Her visual acuity was E 3’200 in the right eye and 20/20 in the left, although she described “blurry vision” in her left eye. Slit lamp examination revealed 1+ anterior chamber cells in the left eye. Funduscopy revealed bilateral moderate optic disc edema with attenuated vessels (Figure 2A and B). Fluorescein angiography was normal except for hyper-fluorescence of the optic nerves and mild peripapillary small vessel leakage (figure 2C). Humphrey automated visual field analysis illustrated dense central scotoma in the right eye and general reduction in the left eye (Figure 2D). Repeat brain MRI showed bilateral optic nerve and perineural fat enhancement (right greater than left), while head CT and CT venogram were all negative (Supplementary Figure S1). Lumber puncture demonstrated a normal opening pressure (17 mmHg) with normal glucose, elevated protein (69 mg/dL), pleocytosis (32 nucleated cells, 68% polymorphic neutrophil, 31% lymphocytes) in the cerebral spinal fluid (CSF). However, CSF culture showed no bacterial or fungal growth, and absence of bartonella. PCR was negative for HSV, CMV, VZV and EBV. Flow cytometry and cell cytology demonstrated no abnormal/malignant cells. Serology for Lyme disease, syphilis, tuberculosis (QuantiFERON Gold), toxoplasmosis, CMV and HIV were also negative. Repeat inflammatory markers (ESR, CRP) were again normal. Autoimmune panel (antinuclear antibodies, anti-double stranded DNA antibodies, extractable nuclear antigen panel, anti-proteinase 3 and anti-myeloperoxidase antibodies) and serum aquaporin 4 antibodies were negative. While awaiting the above results, empiric IV treatment with 1 gm of methylprednisolone and 900mg acyclovir (q8hr) was initiated for 3 days. She was discharged on oral prednisone taper and valacyclovir 500mg TID.

Figure 2.

(A) Color fundus photos of both eyes. Note the subtle pale lesion of right macula and bilateral optic disc swelling. Boxed areas were enlarged in panel (B). (C) Fluorescein angiography revealed leakage from the optic discs without other obvious leakage or filling defects. (D) 24-2 Humphrey visual field with SITA-Standard strategy of both eyes demonstrating central depression in the right eye, and non-specific changes in the left eye.

The patient returned to clinic 3 weeks later, vision was improved to 20/100 (eccentric gaze, Supplementary Figure S2) in the right eye and 20/20 in the left eye without visual symptoms. On examination, the anterior chambers were quiet, and there was resolution of optic disc swelling (Supplementary Figure S3). There was still bilateral retinal vessel attenuation and pale right macula compared to the left. The previously hyperreflective middle retinal layers on OCT now demonstrated significant INL thinning with attenuated IPL and OPL (Figure 1B and D). OCT angiography was now available (methodology in Supplementary Material). The en face projection revealed diffuse white patchy changes in the middle retina corresponding to the hyperreflective PAMM in the right eye (Figure 3A). While there was no demonstrable difference in the superficial retinal plexus of both eyes upon visual inspection, an enlarged deep foveal avascular zone with abnormal deep retinal capillary vasculature was observed in the right eye compared to the left eye (Figure 3A and B, Table 1). A 18.3% reduction of vessel density (2) was seen in the deep capillary plexus of the right eye. There was an increased area of absent flow signal in both the superficial and deep retinal capillary plexi in the right eye compared to the left (Table 1). Detailed quantitative parameters developed by our group⁶ confirmed that most vascular abnormalities were limited to the deep capillary plexus of the right eye. These included reduced vessel area density and vessel perimeter index (both accounting for vessel length and diameter, with greater influence from larger vessels in the latter), reduced vessel skeleton density (reflecting reduced perfusion at the capillary level), and reduced vessel complexity index (reflecting less complicated vascular morphology due to reduced perfusion) (Table 1). Despite a hyperreflective inner retina, no signal attenuation on OCTA was appreciated. This was due to both the 1050nm light source and the microangiography algorithm used in our swept-source OCTA unit⁶.

Figure 3.

6mm×6mm optical coherence tomography (OCT) angiography images of both eyes acquired by swept source OCTA instrument (PLEX^® Elite 9000) provided by Carl Zeiss Meditec Inc., Dublin, CA). (A) Structural en face images of deep retinal structure demonstrate the hyperreflective middle retinal lesion in the right eye. The superficial capillary plexus was normal in both eyes, while the deep capillary plexus demonstrated vessel attenuation in the right eye more than left. Higher magnification of the boxed areas in (A) are shown in (B) with corresponding color frames.

Table 1.

Quantification of Vascular Changes Based on Optical Coherence Tomography Angiography Images in Both Eyes^*

	Superficial Plexus		Deep Plexus
	OD	OS	OD	OS
Vascular Density (mm−1) †	24.8	24.9	20.1	24.6
Flow Impairment Area (mm2)	2.88	1.55	3.84	2.21
Vessel Perimeter Index	0.33	0.34	0.28	0.33
Vessel Area Density	0.39	0.40	0.34	0.37
Vessel Skeleton Density	0.15	0.15	0.12	0.14
Vessel Complexity Index	2.46×1010	2.47×1010	2.03×1010	2.52×1010

^*The quantification protocol was described in the supplementary material and method

^†Vascular density was measured using the method published before⁶

Discussion

Initially described as a subtype of AMN by Sarraf and associates in 2013, PAMM was considered a disease associated with risk factors such as caffeine, blood loss, viral infection, and toxemia of pregnancy¹. Subsequent reports of PAMM in various disease settings have favored the shift from a distinct retinal disease to a clinical finding on retinal imaging related to conditions with compromised deep retinal capillary plexus perfusion^2–4. This is consistent with the current case report, which describes the association of PAMM with bilateral optic disc swelling from CNS inflammation and possible infection.

Features of PAMM noted in this study include the normal appearing macula on funduscopy, parafoveal dark gray patchy lesions on NIR imaging, and hyperreflectivity of the INL and OPL on SD-OCT. In light of the ischemic nature of PAMM, it is plausible that the inflammatory factor causing bilateral papillitis could also lead to occlusion of the intermediate and deep retinal capillary plexi. This is supported by the observation of paripapillary vessel attenuation and decreased vessel density in the parafoveal area on OCT angiography. Indeed, PAMM lesions have previously been noted in cases of both local and systemic inflammation such as birdshot chorioretinopathy⁷, postviral Purtscher-like retinopathy⁵, retinal vasculitis due to Behcet’s disease⁸ and post-H1N1 vaccination⁴. Moreover, the internal carotid fibromuscular dysplasia found on CT angiography can predispose to retinal vessel occlusion⁹. However, to what extent this may contribute to the occurrence of PAMM has not been examined.

Recent studies have utilized OCT angiography in cases of PAMM. The percent reduction of the deep capillary vascular density in this case is consistent with a previous case series study² suggesting the reproducibility of the analyzing procedure. Further, using proprietary software⁶, we quantified flow impairment area, which was enlarged in PAMM at both retinal capillary plexi. Detailed quantitative parameters demonstrated reduced vascular density, capillary perfusion, vessel complexity, and vessel diameter in the deep capillary plexus in the eye with PAMM. These values will be useful in follow-up to monitor ongoing vascular remodeling⁶. Future studies with our analytic protocol will shed light on the diagnostic value of OCT angiography in PAMM cases.

The complicated clinical presentation in this case prompted a broad differential diagnosis, which included infectious, inflammatory, vascular/vasogenic, hypercoagulable, toxic/medication-induced, and idiopathic causes. Systemic workup for infectious and hypercoagulable were negative. Inflammatory causes were considered, particularly due to associated sinus and lung disease. However, her autoimmune panel was negative (see Case Report), as was her systemic review of systems for anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, and Behçet's disease.

The finding of bilateral of optic disc swelling can result from a wide variety of causes. Aside from infectious and inflammatory papillitis, bilateral optic disc swelling can also be secondary to increased intracranial pressure, malignant hypertension, medications (i.e. tetracycline), toxic-metabolic disorders, and nutritional defects (i.e. B12 deficiency). Careful exclusion of the above-mentioned causes in conjunction with the abnormal CSF findings and a history of antecedent respiratory tract infection support the diagnosis of bilateral papillitis either due to an idiopathic inflammatory process responsive to corticosteroids, or a viral process responsive to acyclovir yet undetected by CSF PCR studies. Giant cell arteritis (GCA) can also present as sudden onset of vision loss and pallid swelling of the optic nerve from severe ischemia. However, our patient, in addition to lacking typical constitutional symptoms, had normal ESR and CRP measurements, which exclude 99.2% of GCA patients¹⁰.

To our knowledge this is the first case describing PAMM in association with bilateral optic disc edema and evidence of intraocular and CSF inflammation, possibly secondary to infection. The pathogenesis may be due to a combination of ocular inflammation and preexisting vascular abnormalities causing occlusion of the deep retinal capillary around the fovea. OCT angiography with vasculature analysis is valuable for both the diagnosis and mechanistic study of PAMM.

Supplementary Material

Supplemental Data File _.doc_ .tif_ pdf_ etc.__1

Supplemental Digital Content 1: Supplementary Methods.docx

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Supplemental Digital Content 2: Supplementary Figures.pdf

Summary Statement.

A patient developed bilateral papillitis and meningitis 5 days after her sudden onset of central vision loss. Optical coherence tomography of the affected eye showed evidence of paracentral acute middle maculopathy. Inflammation was resolved after steroid and antiviral treatment while deep retinal ischemia persisted.