Unilateral Frosted Branch Angiitis Following COVID-19 Disease: Case Report and Literature Review
Article ID: 2024-0010-CR
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Article ID: 2024-0010-CR
Frosted branch angiitis (FBA) is a rare and aggressive form of retinal vasculitis that can cause vision loss. This condition is typically idiopathic and can be associated with various infections or malignancies. Recently, FBA has been linked to COVID-19 in some reports. This report describes a rare association between COVID-19 and FBA and presents characteristic findings from multimodal imaging. We describe the case of a 30-year-old man, otherwise healthy, who experienced acute vision loss in his left eye 1 week after testing positive for COVID-19. His initial visual acuity was 20/20 in the right eye and counting fingers at 2 feet in the left eye. A fundus examination disclosed extensive vascular sheathing affecting the arteries and veins, accompanied by widespread intraretinal, preretinal, and subretinal hemorrhages indicative of FBA. Fundus fluorescein angiography revealed notably delayed filling in both arterial and venous systems. Optical coherence tomography of the left eye displayed inner retinal layer hyperreflectivity, suggesting ischemia coupled with substantial subretinal fluid. The systemic evaluation of the patient was unremarkable. The treatment included systemic corticosteroids, azathioprine, intravitreal bevacizumab, and panretinal photocoagulation. After 6 months of treatment, the left eye examination showed resolution of vascular sheathing, retinal hemorrhages, and subretinal fluid, although the final visual acuity in the left eye remained unchanged. In conclusion, FBA may manifest in otherwise healthy and immunocompetent individuals following SARS-CoV-2 infection.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped RNA virus, was first identified and reported in December 2019 as the causative agent of the respiratory illness termed Corona Virus Disease 2019 (COVID-19). The World Health Organization declared this disease a pandemic in March 2020 when several measures, including lockdown, were taken to control the disease spread.1 The virus gains entry to the human cell through the angiotensin-converting enzyme 2 (ACE-2) receptors, which are abundant in the vascular endothelium of highly vascularized tissues like the lungs, kidneys, brain, and ocular structures like the retina and choroid.2 COVID-19-associated systemic vasculitis stems from endotheliitis caused by either direct viral invasion or immune-related inflammation leading to microvascular dysfunction and tissue ischemia.3
Retinal changes associated with COVID-19 disease are thought to be part of the associated systemic enodtheliitis.4 Frosted branch angiitis (FBA) is a special form of retinal vasculitis characterized by severe retinal vessel sheathing that resembles frosted tree branches. Although typically idiopathic, FBA has been linked to viral infections, autoimmune diseases, and malignancies in various reports.5
To date, there are only three case reports of FBA in association with COVID-19.6–8 In this report, we present an additional case of unilateral FBA associated with COVID-19 in an otherwise immunocompetent and healthy individual.
A 30-year-old man, otherwise healthy, presented to the emergency department with progressive vision loss in his left eye that had worsened over the previous week. His past medical and ocular history was unremarkable. One week before his ocular complaint, the patient was diagnosed with COVID-19 disease, which was confirmed by polymerase chain reaction (PCR) testing. His disease consisted of mild upper respiratory symptoms with a cough and runny nose associated with low-grade fever. He underwent home quarantine and was managed conservatively with oral paracetamol and without the need for hospitalization. Upon examination, his best-corrected visual acuity (BCVA) was 20/20 in the right eye and counting fingers at 2 feet (CF; approximately 20/2000) in the left eye. A slit lamp examination revealed a clear cornea with a quiet anterior chamber and a clear lens in both eyes. A dilated fundus examination of the right eye was within normal limits, whereas the left eye exhibited clear vitreous alongside extensive vascular sheathing affecting the arteries and veins, accompanied by widespread intraretinal, preretinal, and subretinal hemorrhages (Fig. 1A). Fundus fluorescein angiography, conducted 3 weeks after presentation, displayed notably delayed filling in the arterial and venous systems and hypofluorescent areas situated at the preretinal, intraretinal, and subretinal levels indicative of blockages by hemorrhages. In addition, peripheral hypofluorescent areas, more prominent nasally, representing zones of capillary dropout, were also observed (Fig. 1B,C). Spectral-domain optical coherence tomography (SD-OCT) of the left eye demonstrated hyperreflectivity of the inner retinal layers, indicative of ischemia and subretinal fluid (Fig. 1D).
(A) Ultra-widefield fundus photograph of the left eye showing extensive vascular sheathing involving the arteries and veins with intraretinal, preretinal, and subretinal hemorrhages consistent with frosted branch angiitis. (B,C) Three weeks later, ultra-widefield fundus fluorescein angiography demonstrated delayed filling of the arterial and venous systems, with hypofluorescent areas at the preretinal, intraretinal, and subretinal levels indicating hemorrhage-induced blockage. Late diffuse vascular leakage was also observed. (D) Spectral-domain optical coherence tomography of the left eye displayed hyperreflectivity of the inner retinal layers representing ischemia and subretinal hypo-reflective space, indicating neuro-sensory detachment/subretinal fluid.
Based on the constellation of findings, a diagnosis of FBA was made, and our differential diagnoses included neoplastic causes like leukemia and lymphoma, infectious causes like cytomegalovirus, tuberculosis, or syphilis, autoimmune causes like Behçet’s disease, multiple sclerosis, and systemic lupus erythematosus, or an idiopathic occurrence associated with the recent viral disease episode. To work up the patient for these differential diagnoses, he underwent a wide range of investigations, including laboratory tests, radiological assessments, and consultations with other services.
The results of routine laboratory examination, including complete blood count, liver function test, renal function test, erythrocyte sedimentation rate, and C-reactive protein, were within normal limits. An extensive systemic examination was conducted for potential infectious or inflammatory causes, including human immunodeficiency virus serology, QuantiFERON-TB Gold, purified protein derivative skin test, chest radiography, syphilis serology, anti-nuclear antibodies, anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, myeloperoxidase antibodies, serine proteinase 3 antibodies, and complement levels (C3, C4). The results of all these tests were negative. Magnetic resonance imaging, incorporating angiography and venography of the brain, showed no abnormalities. The internal medicine and rheumatology teams thoroughly assessed the patient and found no systemic involvement. A diagnosis of unilateral frosted branch angiitis following COVID-19 was established.
The patient underwent treatment with intravenous methylprednisolone (1 g/day) for 3 days, followed by a gradually tapering dose of oral prednisolone, starting at 1 mg/kg (80 mg), and oral azathioprine 100 mg. In addition, two doses of intravitreal bevacizumab (administered 4 weeks apart) were given to address subretinal fluid and prevent neovascular glaucoma development. Eight weeks after presentation, pan-retinal photocoagulation was performed once retinal hemorrhages had resolved (Fig. 2A,B). Six months post-treatment, the left eye examination indicated a quiet eye with laser scars, mild residual vitreous hemorrhage, resolved vascular sheathing, and retinal hemorrhages (Fig. 2C). Left SD-OCT revealed resolved subretinal fluid along with significant atrophy of inner and outer retinal layers (Fig. 2D). The final BCVA of his left eye remained unchanged (CF). Informed consent was obtained from the patient for the anonymous use and publication of data and images.
(A) Ultra-widefield fundus photograph and (B) spectral-domain optical coherence tomography of the left eye 2 weeks after treatment with systemic corticosteroids, azathioprine, and intravitreal bevacizumab showing significant improvement in vascular sheathing and macular edema. (C) Ultra-widefield fundus photograph and (D) spectral-domain optical coherence tomography of the left eye after 6 months, showing resolution of vascular sheathing and the previously documented hemorrhages, with panretinal photocoagulation scars, as well as the resolution of macular edema with significant thinning of the inner and outer retinal layers.
Frosted branch angiitis was initially described in Japan in 1976 as intense and striking retinal vascular sheathing resembling the frosted branches of a tree.9 Later, Kleiner10 categorized patients with such retinal features into three groups based on the underlying cause. The first group included FBA patients with lymphoma and leukemia, where vascular sheathing was caused by the infiltration of malignant cells into the vascular wall. The second group involved FBA associated with intraocular infections such as cytomegalovirus, herpes simplex virus, rubella, syphilis, tuberculosis, or systemic autoimmune diseases like Bechet’s disease, multiple sclerosis, and systemic lupus erythematosus. The third group compromised acute idiopathic FBA in otherwise young and healthy individuals. Given that our patient was otherwise healthy, and the extensive workup did not reveal a specific cause of his ocular findings, he was diagnosed with idiopathic FBA, which is consistent with Kleiner’s third group.
The idiopathic FBA is hypothesized to be related to hypersensitivity reaction with immune complex deposition and is usually preceded by a prodromal viral illness, as Walker et al.5 reported its occurrence in 33% of patients. Given the temporal relation, we proposed that COVID-19 could have been the triggering factor for our patient’s ocular disease. However, this relation is only a hypothesis, and a confirmed association cannot be proven.
It has been proposed that SARS-CoV-2 enters the retinal endothelium via ACE2 receptors, leading to endothelial disruption, complement activation, and inflammation.11,12 The presence of the virus was confirmed through retinal biopsy, where it was detected in the retinal tissues of 3 out of 14 (21%) COVID-19 patients.13
Various posterior segment manifestations have been described in association with COVID-19. The most common non-vision-threatening findings include retinal hemorrhages and cotton wool spots,12,14 whereas central retinal vein occlusion with macular edema has been the most frequently observed vision-threatening manifestation.12,15 Other reported associations include central retinal artery occlusion, paracentral acute middle maculopathy, and acute macular neuroretinopathy.12
The occurrence of retinal vasculitis in conjunction with COVID-19 has been documented in some reports.16,17,18,19 However, to date, there are only three reports of retinal vasculitis in the form of FBA associated with COVID-19.6,7,8 Similar to our case, FBA was documented in an otherwise healthy 10-year-old girl a few weeks following SARS-CoV-2 infection; she was managed initially with intravenous corticosteroids and plasmapheresis and kept on maintenance therapy of oral prednisone therapy and infliximab infusion.6 Another report documented the occurrence of unilateral FBA in association with COVID-19 in a patient with stable mixed connective tissue disease; she was managed initially with a high dose of intravenous steroids and antiviral therapy and later administered tapering oral prednisolone and mycophenolate mofetil.7 In another case report, a patient with known acquired immunodeficiency syndrome presented with unilateral FBA and coexisting cytomegalovirus and SARS-CoV-2 infections; he was managed with intravenous ganciclovir for 2 weeks.8
The occurrence of retinal vasculitis in association with COVID-19 was reported in a healthy 37-year-old patient whose visual acuity improved after receiving three doses of intravenous methylprednisolone.16 Asymptomatic retinal vasculitis was reported in an 11-year-old child with COVID-19 who presented to the dermatology department with chilblains.17 Another report described the development of retinal vasculitis in a patient with exacerbation of mixed connective tissue disease following COVID-19; however, it is unclear whether this finding was related to the exacerbation of the original disease or solely linked to the SARS-CoV-2 infection.18 In a recently published case series exploring the spectrum of chorioretinal vasculopathy associated with COVID-19,19 two of the reported cases were bilateral occlusive retinal vasculitis associated with COVID-19; one of the patients had a medical history of sickle cell trait and the other a history of hypothyroidism. The report also described the case of a 33-year-old previously healthy patient who presented with a Purtscher-like retinopathy along with periphlebitis with a picture of encephalitis associated with COVID-19.19
Viral infections are associated with the development of autoimmune disorders in susceptible individuals. The development or the exacerbation of autoimmune diseases has been reported with COVID-19.20,21,22 Multiple theories have been proposed to explain this phenomenon, including molecular mimicry, cellular damage by cytokines, persistent viral antigen caused by ineffective clearance, or the development of neutrophil extracellular traps.23
Systemic steroids were the mainstay of treatment primarily reported in the literature for cases of idiopathic FBA.5 Our patient was treated with systemic steroids, along with azathioprine because of the severity of the presentation and to prevent possible future recurrences. Intravitreal antivascular endothelial growth factor injections and pan-retinal photocoagulation were performed to address the macular edema and retinal ischemia. However, our patient had a final visual acuity of CF along with thinning retinal layers on OCT, explained by the presenting macular ischemia.
In conclusion, we report a case of FBA in an otherwise healthy patient after contracting COVID-19. Acute FBA can be preceded by viral infections, including COVID-19. It is essential that clinicians be aware of this possibility, especially in this era with the emergence of new SARS-CoV-2 variants.
This study received no external funding.
The authors have declared that no conflict of interest exists.
