Superior ophthalmic vein and cavernous sinus thrombosis associated with COVID-19: a case report / Trombose de veia oftálmica superior e seio cavernoso associada à COVID-19: relato de caso

ABSTRACT Cavernous sinus and superior ophthalmic vein thrombosis is a rare clinical condition, and little described in the literature. The clinical presentation is nonspecific and highly variable, and symptoms may include red eye, ophthalmoplegia, coma, and death. The main etiology results from infection of the paranasal sinuses. The final diagnosis must be made through imaging tests such as magnetic resonance imaging. We describe a case of cavernous sinus and superior ophthalmic vein thrombosis after COVID-19 infection in a 64-year-old patient with persistent ocular hyperemia and pain on eye movement. Ophthalmological examination showed preserved visual acuity, conjunctival hyperemia, dilation of episcleral vessels and retinal vascular tortuosity in the right eye. Magnetic resonance imaging confirmed the diagnosis. The association with the COVID-19 was raised, excluding other infectious causes. Enoxaparin and Warfarin were started with significant improvement in the ocular clinical presentation and maintenance of initial visual acuity after 12 months of follow-up.

RESUMO A trombose de seio cavernoso e veia oftálmica superior é uma condição clínica rara e pouco descrita na literatura. A apresentação clínica é inespecífica e altamente variável. Os sintomas podem incluir olho vermelho, oftalmoplegia, coma e morte. A etiologia principal resulta da infecção dos seios paranasais. O diagnóstico final deve ser efetuado por meio de exames de imagem, como ressonância magnética. Descrevemos um caso de trombose de seio cavernoso e veia oftálmica superior após COVID-19 em paciente de 64 anos e com quadro de hiperemia ocular persistente e dor à movimentação ocular. Ao exame oftalmológico, observou-se acuidade visual preservada, hiperemia conjuntival, dilatação de vasos episclerais e tortuosidade vascular retiniana em olho direito. A ressonância confirmou o diagnóstico. A associação com a COVID-19 foi levantada, excluindo-se demais causas infecciosas. Prescrevemos enoxaparina e varfarina, com melhora do quadro clínico ocular e manutenção da acuidade visual inicial após 12 meses de acompanhamento.

Retinal microvascular morphology versus COVID-19: What to anticipate?

BACKGROUND: To investigate retinal microvascular morphological changes in previously COVID-19 infected patients using optical coherence tomography angiography (OCTA), and compare the findings to age- and gender-matched healthy subjects. METHODS: In this cross-sectional study, OCTA findings (6.0 × 6.0 mm scan size and scan quality index ≥7/10) from previously COVID-19 infected patients (group 1, 32 patients, 64 eyes) with ≥1 month of complete recovery were compared to healthy subjects (group 2, 33 subjects, 66 eyes) with no history of COVID-19 infection. A positive real-time reverse transcription-polymerase chain reaction test on a naso-pharyngeal swab sample confirmed the diagnosis. The AngioVueAnalytics, RTVue-XR 2017.1.0.155 software measured and recorded OCTA parameters. RESULTS: Group 1 had significantly lower superficial capillary plexus vessel densities in all foveal regions than group 2 (P<0.05). Foveal deep capillary plexus vessel density in group 1 was also significantly lower than in group 2 (P=0.009); however, no significant differences were found in other regions (P>0.05). All foveal avascular zone (FAZ) parameters were higher in group 1 than in group 2, with significant differences in FAZ area (P=0.019) and foveal vessel density 300 µm area around FAZ (P=0.035), but not FAZ perimeter (P=0.054). The outer retina and choriocapillaris flows were significantly lower in group 1 than in group 2 (P<0.05). CONCLUSIONS: Prior COVID-19 infection seems to be associated with significant changes in retinal microvascular density, as well as FAZ and flow parameters, which may be attributed to different pathogenic mechanisms that lead to SARS-CoV-2 infection, such as thrombotic microangiopathy and angiotensin-converting enzyme 2 disruption.

Paracentral acute middle maculopathy in Susac syndrome after dual exposure to SARS-CoV-2 antigen.

We report a case of Susac syndrome after SARS-CoV-2 infection and subsequent vaccination that presented with meningitis and retinal microembolisation in the form of paracentral acute middle maculopathy (PAMM). After presenting with headache, fever and myalgia followed by scotomata, a woman in her 50s was hospitalised for meningitis; she had had mild COVID-19 infection 2 months prior to admission, having received the first vaccine dose 1 month prior to the neurological manifestation. Eye fundus examination and optical coherence tomography were suggestive of PAMM. D-dimer levels and erythrocyte sedimentation rate were elevated. Before infectious investigation results were available, she was started on empirical antibiotic and antiviral treatment. Having ruled out infectious causes, she was started on high-dose prednisolone. After 1 month, there was partial resolution of retinal lesions. This case highlights that exposure to SARS-CoV-2 antigen may be related to this rare syndrome; treatment with steroids may improve central and retinal impairment.

Ocular Pathology and Occasionally Detectable Intraocular Severe Acute Respiratory Syndrome Coronavirus-2 RNA in Five Fatal Coronavirus Disease-19 Cases.

INTRODUCTION: In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic broke out. The virus rapidly spread globally, resulting in a major world public-health crisis. The major disease manifestation occurs in the respiratory tract. However, further studies documented other systemic involvement. This study investigates histopathologic eye changes in postmortem material of coronavirus disease 2019 (COVID-19) patients. METHODS: Sections of formalin-fixed, paraffin-embedded eyes from 5 patients (10 eyes) who died of COVID-19 at the University Hospital in Basel were included. Gross examination and histological evaluation were performed by 3 independent ophthalmopathologists. Immunohistochemical staining was performed using antibodies against fibrin, cleaved caspase 3, and ACE-2. Five enucleated eyes of patients not infected with SARS-CoV-2 served as control group. All cases have been studied for presence of SARS-CoV-2 RNA by means of reverse transcription PCR and RNA in situ hybridization (ISH). The choroidal vessels of one case were analyzed with electron microscope. RESULTS: Ophthalmopathologically, 8 eyes from 4 patients displayed swollen endothelial cells in congested choroidal vessels. No further evidence of specific eye involvement of SARS-CoV-2 was found in any of the patients. In the 8 eyes with evidence of changes due to SARS-CoV-2, immunohistochemical staining demonstrated fibrin microthrombi, apoptotic changes of endothelial and inflammatory cells. In control eyes, ACE-2 was detectable in the conjunctiva, cornea, retina, and choroidea and displayed significantly lower amounts of stained cells as in COVID-19 eyes. SARS-CoV-2 RNA was detectable in both bulbi of 2/5 patients, yet ISH failed to visualize viruses. Electron microscopy showed no significant results due to the artifacts. DISCUSSION/CONCLUSION: As already described in other organs of COVID-19 patients, the ophthalmological examination revealed-microthrombi, that is, hypercoagulation and vasculopathy most probably due to endothelial damage. A possible viral spread to the endothelial cells via ACE-2 provides one pathophysiological explanation. The expression of ACE-2 receptors in the conjunctiva hints toward its susceptibility to infection. To what extend eyes, function is disrupted by SARS-CoV-2 is subject to further studies, especially in the clinic.

Retinal vessels modifications in acute and post-COVID-19.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 primarily affecting the respiratory system which can damage vessels walls virtually in any body district. Changes affecting retinal vessels are a good marker for systemic vascular alterations. This study investigated retinal vessels during the acute phase of COVID-19 and after patients recovery. Fifty-nine eyes from 32 COVID-19 patients and 80 eyes from 53 unexposed subjects were included. Mean arteries diameter (MAD) and mean veins diameter (MVD) were assessed through semi-automatic analysis on fundus color photos at baseline and 6 months later in patients and subjects unexposed to the virus. At baseline MAD and MVD were significantly higher in COVID-19 patients compared to unexposed subjects (p < 0.0001). Both MAD and MVD significantly decreased in COVID-19 patients at follow-up (from 97.5 ± 10.9 to 92.2 ± 11.4 µm, p < 0.0001 and from 133.1 ± 19.3 to 124.6 ± 16.1 µm, p < 0.0001, respectively). Despite this reduction vessels diameter remained significantly higher in severe COVID-19 patients compared to unexposed subjects. Transient retinal vessels dilation could serve a biomarker for systemic inflammation while long-lasting alterations seen in severe COVID-19 likely reflect irreversible structural damage to the vessels walls and should be further investigated for their possible effects on tissues perfusion and function.

Expression of the SARS-CoV-2 Receptor ACE2 in Human Retina and Diabetes-Implications for Retinopathy.

Purpose: To investigate the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 in human retina. Methods: Human post-mortem eyes from 13 non-diabetic control cases and 11 diabetic retinopathy cases were analyzed for the expression of ACE2. To compare the vascular ACE2 expression between different organs that involve in diabetes, the expression of ACE2 was investigated in renal specimens from nondiabetic and diabetic nephropathy patients. Expression of TMPRSS2, a cell-surface protease that facilitates SARS-CoV-2 entry, was also investigated in human nondiabetic retinas. Primary human retinal endothelial cells (HRECs) and primary human retinal pericytes (HRPCs) were further used to confirm the vascular ACE2 expression in human retina. Results: We found that ACE2 was expressed in multiple nonvascular neuroretinal cells, including the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments in both nondiabetic and diabetic retinopathy specimens. Strikingly, we observed significantly more ACE2 positive vessels in the diabetic retinopathy specimens. By contrast, in another end-stage organ affected by diabetes, the kidney, ACE2 in nondiabetic and diabetic nephropathy showed apical expression of ACE2 tubular epithelial cells, but no endothelial expression in glomerular or peritubular capillaries. Western blot analysis of protein lysates from HRECs and HRPCs confirmed expression of ACE2. TMPRSS2 expression was present in multiple retinal neuronal cells, vascular and perivascular cells, and Müller glia. Conclusions: Together, these results indicate that retina expresses ACE2 and TMPRSS2. Moreover, there are increased vascular ACE2 expression in diabetic retinopathy retinas.

Symptomatic Retinal Microangiopathy in a Patient with Coronavirus Disease 2019 (COVID-19): Single Case Report.

Purpose: Coronavirus Disease 2019 (COVID-19) can cause conjunctivitis in up to 31.6% of patients. Additionally, retinal findings compatible with retinal microvascular ischemia have also been associated with coronavirus disease in asymptomatic patients. We describe a case of bilateral retinal changes compatible with microangiopathy occurring during the late phase of COVID-19.Case report: A 50-year-old man with bilateral pneumonia and positive polymerase chain reaction for SARS-CoV-2 developed an arcuate visual field defect in his left eye. Funduscopy revealed multiple, bilateral cotton-wool spots without haemorraghes. OCT-angiography revealed multifocal areas of retinal microvascular ischemia in the superficial plexus, the largest of which corresponded to the arcuate scotoma observed in the automated perimetry.Conclusion: Visual field defects due to retinal microangiopathy can occur during the late phase of COVID-19. Vascular changes observed in the retina may mimic what may be happening in other, less-accessible organs.

Simultaneous Bilateral Central Retinal Artery Occlusion following COVID-19 Infection.

Purpose: Coronavirus-19 disease (COVID-19) has been associated with a high risk of thrombotic complications. Here, we report the case of a patient who developed simultaneous bilateral retinal artery occlusion following COVID-19 infection.Case Report: A 42-year-old male with no systemic co-morbidities presented with sudden, painless loss of vision in both eyes. Fundoscopy showed retinal edema and cherry-red spots in both eyes. Fluorescein angiography showed reperfusion, absence of choroidal ischemia, and Optical Coherence Tomography showed thickened inner retinal layers suggestive of retinal edema and the outer retinal layers appeared intact. Blood investigations for vasculitis, coagulation profile, lipids, and homocysteine level were within normal limits.Conclusion: COVID-19 patients may develop a systemic coagulopathy and acquired thrombophilia characterized by a tendency for venous, arterial, and microvascular thrombosis. This hypercoagulable state is believed to be a hyperinflammatory response; physicians and ophthalmologists, alike, should be aware of these possible long-term sequelae.

Vascular Damage May Mimic Retinitis and Optic Neuritis in COVID-19.

Ophthalmologic nvolvement in SARS-CoV-infected patients is variegated. One of the ophthalmologic pathologies is optic neuritis. Optic neuritis in SARS-CoV-infected patients may precede the classical pulmonary manifestations of COVID-19 and can be unilateral or bilateral. Optic neuritis has been repeatedly reported in COVID-19 patients and may occur with or without affection of other cranial nerves. Since cerebro-spinal fluid parameters can be abnormal in COVID-19 associated optic neuritis, these patients require a spinal tap. Before diagnosing SARS-CoV-2 associated optic neuritis various differentials need to be excluded. Since SARS-CoV-2 causes endothelial damage complicated by thrombus formation and thromboembolism, ophthalmologic vascular complication due to an infection with SARS-CoV-2 such as anterior ischemic optic neuropathy (AION), central retinal artery occlusion (CRAO), and retinal vein occlusion need to be excluded. CRAO may result from arterial hypertension, myocarditis, heart failure, Takotsubo syndrome, atrial fibrillation, or atrial flutter, frequent cardiac complications of COVID-19. Since CRAO can be accompanied by ischemic stroke, patients with SARS-CoV-2 associated optic neuritis need to undergo a cerebral MRI.

Optical coherence tomography angiography findings in patients with COVID-19.

OBJECTIVE: To examine the changes in choriocapillaris and retina caused by coronavirus disease 2019 (COVID-19) by comparing optical coherence tomography angiography (OCTA) findings of COVID-19 patients and healthy controls. METHODS: The study and control groups consisted of 54 eyes of 27 participants, each. Patients and controls underwent OCTA examination. Foveal zone vessel density and parafoveal zone vessel density (for 4 quadrants: nasal, temporal, superior, inferior) were calculated for both superficial and deep capillary plexuses. Additionally, choriocapillaris flow and foveal avascular zone areas were calculated. RESULTS: For the parafoveal area in the study group, vessel density was significantly lower in the superior and nasal quadrants of the superficial capillary plexus and in all quadrants of the deep capillary plexus compared with controls (p < 0.05 for all). The study group had significantly higher choriocapillaris flow area values compared with controls (p = 0.042). CONCLUSION: Reduced vessel density of the retinal capillary plexus was detected in COVID-19 patients who may be at risk for retinal vascular complications.

Retinal Vessel Diameter Changes in COVID-19 Infected Patients.

Purpose: To evaluate the longitudinal changes in retinal vessel diameters in patients with coronavirus disease 2019 (COVID-19).Methods: This study included 25 patients with COVID-19 (Group 1) and 25 healthy subjects (Group 2). The diameters of peripapillary temporal and nasal retinal arteries and veins were measured at baseline and at 4 months after remission.Results: The baseline diameters of the inferior temporal vein and the artery were increased in group 1 compared to controls (p = .007 and p = .041, respectively). There was also an increase in the diameters of the inferior and superior nasal veins and arteries in group 1 at baseline (p = .001, p = .019, p = .037, and p = .008, respectively). Retinal vessel diameters decreased after remission in all quadrants in comparison to baseline measurements (all p < .05).Conclusion: Increased retinal vessel diameters were measured in COVID-19 patients during the disease. Measurement of retinal vessel diameters may be a noninvasive method of estimating the vascular risk.

Retinal changes in COVID-19 hospitalized cases.

The main objective of this study was to evaluate the retinas of severely or critically ill COVID-19 patients during their hospital stay, at varying time points after symptoms onset. This was a case series observed during May 2020 in two referral centers for COVID-19 treatment in Rio de Janeiro, Brazil. 47 eyes from 25 hospitalized patients with severe or critical confirmed illness were evaluated. A handheld retinal camera was used to acquire bilateral fundus images at several time points after symptoms onset. Electronic health records were retrospectively analyzed and clinical data collected. Severe and critical diseases were noticed in 52% (13/25) and 48% (12/25) of enrolled patients, respectively. Retinal changes were present in 12% (3/25) of patients: a 35 year-old male demonstrated bilateral nerve fiber layer infarcts and microhemorrhages in the papillomacular bundle, but required mechanical ventilation and developed severe anemia and systemic hypotension, acute kidney injury and neurologic symptoms during the course of the disease (critical illness); a 56 year-old male, who required full enoxaparin anticoagulation due to particularly elevated D-dimer (>5.0 mcg/mL), demonstrated unilateral and isolated flame-shaped hemorrhages; and a 49 year-old hypertensive male showed bilateral and discrete retinal dot and blot microhemorrhages. The other 22 patients evaluated did not demonstrate convincing retinal changes upon examination. There was no correlation between disease severity and admission serum levels of CRP, D-dimer and ferritin. This was the first study to show that vascular retinal changes may be present in not insignificant numbers of severe or critical COVID-19 inpatients. These retinal changes, only seen after morbid developments, were likely secondary to clinical intercurrences or comorbidities instead of a direct damage by SARS-CoV-2, and may be important and easily accessible outcome measures of therapeutic interventions and sentinels of neurologic and systemic diseases during COVID-19 pandemic.