Methicillin-Resistant Staphylococcus aureus Sepsis and Orbital Cellulitis Leading to a Combined Central Retinal Artery and Vein Occlusion: A Case Report

Abstract

Combined central retinal artery and vein occlusion (CCRAVO) is a rare entity characterized by features of tortuous retinal veins, retinal hemorrhage, optic disk edema and pallor, macula edema, cherry-red spot, and cotton-wool spots. The occurrence of CCRAVO in the adult population is often in the setting of systemic disease; while CCRAVO in the pediatric population is frequently associated with infection of the sinuses, preseptal cellulitis, or orbital cellulitis. It has been hypothesized that CCRAVO can result from methicillin-resistant Staphylococcus aureus (MRSA) sepsis-induced coagulation disturbances, orbital cellulitis, and even orbital compartment syndrome; however, there are insufficient reports of this complication. This case report sheds light on one such case with irreversible vision loss as a sequela.

Introduction

The retina is the innermost layer of the eye that frequently is affected by vision-impairing vascular diseases. ¹ Combined central retinal artery and vein occlusion (CCRAVO) is a rare disorder that demonstrates features of both central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) within the affected eye. Some of the more common features include a cherry-red spot and retinal whitening, as well as dilated, tortuous veins, and retinal hemorrhages. ² Owing to the rarity of CCRAVO, its exact incidence is unclear. Nonetheless, there have been multiple reported cases of CCRAVO that reflect its occurrence in the setting of hypercoagulable states like systemic lupus erythematosus,^3-9 antiphospholipid syndrome,^5,10,11 homocysteinemia,^12-14 Churg-Strauss syndrome, ¹⁵ Factor V Leiden mutations,^16,17 Behçet’s disease, ¹⁸ Factor VIII mutations, ¹⁹ Protein C deficiency,^20,21 lymphomas or leukemias,^22,23 orbital cellulitis,^24,25 pregnancy, ²⁵ trauma,^26,27 and most recently with COVID-19 vaccinations.^1,28 These hypercoagulable states are common causes of CCRAVO in younger-aged populations. ¹² On the contrary, older-aged populations tend to develop CCRAVO secondary to pre-existing conditions such as hypertension, hyperlipidemia, atherosclerotic cardiovascular disease, and diabetes mellitus.^12,16,19,20

One of the more formidable risk factors for developing CCRAVO is community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) sepsis due to its alteration of the coagulation cascade inducing a hypercoagulable state.^29,30 In fact, MRSA is reported to be the most common cause of community and hospital-acquired bacteremia with an incidence rate of 38.2 to 45.7 per 100,000 people each year. ³¹ Risk factors for community-acquired bacteremia include indwelling prosthetic devices, intravenous (IV) drug use, osteomyelitis, and cellulitis. Intravenous drug users often have S aureus nasal colonization and are more susceptible to CA-MRSA bacteremia. ³² With CA-MRSA sepsis inducing a hypercoagulable state, it is intuitive for patients to be at an increased risk for developing CCRAVO as a sequela to sepsis. As CCRAVO is a sight-threatening disease, it requires careful investigation and management to reduce the likelihood of patients developing permanent vision loss. Here we describe a rare case of CCRAVO that developed in a patient with severe orbital cellulitis and septic shock secondary to CA-MRSA.

Case Report

A 51-year-old homeless Caucasian male with a history of posttraumatic stress disorder, major depressive disorder, anxiety, bipolar disorder, hypothyroidism, and extensive history of IV drug use was transferred to our hospital for the management of right upper and lower extremity abscesses, right facial swelling, purulent nasal drainage, fever with chills, and nausea for a duration of 3 weeks. The patient initially attempted to drain an abscess on his right lower extremity using an unsterile needle, which eventually developed into multiple abscesses on both his right-upper and right-lower extremities. The abscesses also involved his face with continuous purulent drainage, prompting his decision to seek medical care. Per documentation from an outside facility, the patient had an intact vision and normal extraocular movements with no history of headache, eye pain, facial numbness, difficulty breathing, dysphagia, vomiting, or cough. There was no pertinent surgical or family history. Social history was significant for alcohol abuse, tobacco, illicit IV drug use (heroin and amphetamine), and noncompliance with medications.

Vitals on admission showed a temperature of 37.7 °C, a pulse of 117 beats per minute, a respiratory rate of 22 cycles per minute, and blood pressure of 156/86 mm Hg with a saturation of 94% on room air. Succinct examination revealed facial erythema and swelling, purulent drainage from the nares with necrotic tissue over the nose and abscesses with purulent drainage over the right upper and lower extremities. The patient was also noted to have severe pain, conjunctival chemosis and injection with reduced vision, and limited extraocular movements in the right eye. The intraocular pressure and visual acuity could not be assessed at this time as the patient refused the exam. Emergent bedside right lateral canthotomy with cantholysis was performed due to concern for right periorbital cellulitis and orbital compartment syndrome. The patient was promptly started on acetazolamide 250 mg IV every 6 hours for 4 doses, brimonidine 0.15% ophthalmic solution twice a day, and timolol 0.5% eye drops twice a day to help reduce intraocular pressure.

Pertinent laboratory workup showed leukocytosis of 43.3 × 103/UL with an absolute neutrophil count of 39.36 × 103/UL and bands of 6.47 × 103/UL; anemia with hemoglobin and hematocrit of 9.0 g/dL and 26.7%; platelet count of 507 × 103/UL; an unremarkable comprehensive metabolic panel, lactic acid of 3 mmol/L, erythrocyte sedimentation rate of 21 mm/hr, and C-reactive protein was >18 mg/dL. The urine drug screen was positive for opioids and amphetamines, the hepatitis panel was reactive for hepatitis C, and a hemoglobin A1c of 6.1% was noted. Computed tomography (CT) scan of the face and orbits (Figure 1) showed marked fat stranding, soft-tissue thickening, and edema of the periorbital nasal bridge and right nasal bone. No preseptal orbital abscess or foreign body was displayed.

Figure 1.

CT scan of the patient’s face showing intraconal fat stranding in the right eye (arrows) in the (A) horizontal plane and (B) coronal plane.

The patient underwent urgent incision, drainage, and debridement of the abscesses and was started on broad-spectrum IV antibiotic coverage with clindamycin 900 mg every 6 hours and piperacillin-tazobactam 4.5 g every 6 hours. This regimen was eventually changed to IV vancomycin after blood and wound cultures grew methicillin-resistant Staphylococcus aureus (MRSA). On day 3 of admission, the patient developed a markedly elevated white blood cell count of 70.4 × 103/UL and a significant drop in hemoglobin to 6.4g/dL despite appropriate antibiotic coverage. He developed septic and hemorrhagic shock with a blood pressure of 61/36 mm Hg. The patient was intubated and stabilized with blood transfusions and pressor support. An endoscopy was performed and revealed a bleeding gastric ulcer that was clipped.

One week after the patient was extubated, he reported right-sided vision loss. A comprehensive eye exam was performed, which revealed an intraocular pressure of 15 mm Hg, a round, reactive pupil with a relative afferent pupillary defect, negative for retropulsion, and a full range of extraocular movements with mild pain on abduction secondary to the lateral canthotomy. Visual fields by confrontation showed a central and peripheral scotoma, and a visual acuity of 20/light perception vision was noted. Direct ophthalmoscopy displayed lateral canthal hyperemia, mild purulent discharge, trace temporal conjunctiva injection with normal epithelium, endothelium, stroma, tear film, corneal sensation, and an intact blink reflex. The anterior chamber had normal depth without cells or flare; the iris was normal with no rubeosis, and the lens was normal. No lymphadenopathy was appreciated in the preauricular group of lymph nodes. Indirect ophthalmoscopy showed a clear vitreous with no cells, blurred margins of the optic nerve head, mild attenuation of exiting vessels, and a cup-to-disk ratio of 0.1. Fundoscopy further revealed attenuated arteries with a cartwheel appearance, focal arterial sheathing, large artery yellow plaques, aneurysmal dilation-beading of vessels in the far periphery at 11 and 1 O’clock, respectively; inferior arcade-peripapillary vein flame hemorrhage, and superior arcade paramacular flame hemorrhage with few scattered Roth spots. Diffuse retinal whitening, cherry-red spot, and multiple dot-blot hemorrhages were seen predominantly in the superior lattice. Evidently, the findings were consistent with both central retinal artery and vein occlusion (Figure 2). The left eye exam was grossly normal.

Figure 2.

Color fundus photo of the right eye from handheld 20 diopters lens. (A) 20 D lens provides an Indirect view of the fundus, with a “flipped and reverse” image; therefore, the optic nerve (asterix) is to the right and the flame hemorrhage (check) is in the inferior arcade of the retina. Typical characteristics of central retinal artery occlusion are seen including cherry-red spot (M), retinal edema denoted by the overall white surrounding the macula (MI), flame hemorrhages, and optic nerve pallor. Also note the incomplete blood column or box-caring of the vessels (arrow). (B) Supero-temporal view of fundus showing additional findings of retinal vein occlusion, including macular edema, vein tortuosity, aneurysmal dilation-beading (arrow), and vein flame hemorrhage. Courtesy of C. Prospero Ponce, MD.

Given the unilateral loss of vision, a magnetic resonance imaging (MRI) scan of the brain and a carotid artery Doppler analysis were performed to rule out concurrent stroke—both of which were negative. The MRI reflected the bulging of the optic disc and thickening of the right optic nerve as seen in Figure 3. An echocardiogram was performed to rule out intracardial shunts. The patient was also worked up for hypercoagulable states and autoimmune disorders due to the exceptionally rare finding of CCRAVO. The patient had a normal activated prothrombin time (aPTT) and was negative for anti-thrombin III antigen, protein C, protein S, activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation, hyperhomocysteinemia, leukocyte alkaline phosphatase deficiency, antinuclear antibody (ANA), rheumatoid factor (RF), lupus anticoagulant, and anti-cardiolipin. No monoclonal proteins were detected on serum protein electrophoresis. The infectious workup was negative for treponemal serology and HIV.

Figure 3.

Magnetic resonance imaging of the brain showing bulging of the optic disk and thickening of the right optic nerve (arrow).

During the hospital course, the patient was also noted to have multiple episodes of desaturation on room air to 70% to 80% saturation. Computed tomography of the thorax revealed ill-defined ground-glass opacities, interstitial thickening, and a thick-walled cystic lesion. Fungal infection, tuberculosis, and septic emboli secondary to MRSA sepsis were considered differentials. Work-up for the same was negative for tuberculosis by QuantiFERON Gold and sputum culture, coccidioides, and aspergillus. Hence, respiratory failure was attributed to septic emboli which improved significantly with treatment.

The patient received a 6-week course of inpatient IV vancomycin, aggressive wound care, and supportive treatment which led to the resolution of his symptoms. He was referred to a long-term acute care facility for appropriate wound care, de-addiction, and management of multiple psychiatric comorbidities. An outpatient ophthalmology referral was provided to monitor for the development of neovascular glaucoma or retinal vascularization bleeding. At discharge, the wounds had improved, no further gastrointestinal bleed was noted, and the patient was saturating >90% on room air, however, he had an irreversible vision loss in his right eye.

Discussion

Our patient experienced a complicated hospital course with multiple risk factors for the development of MRSA sepsis and orbital cellulitis. He was homeless, an IV drug user, and had an active source of inadequately managed cellulitis with abscesses in his right-upper and right-lower extremity. In the absence of any trauma to the eye and a normal eye exam during the first medical encounter, seeding of MRSA from the bacteremia likely led to the development of orbital cellulitis and eventually orbital compartment syndrome over the course of 4 days in our patient’s eye. On presentation to our facility, the patient exhibited signs of orbital compartment syndrome that included severe tenderness, limited extraocular movements, and mild proptosis—all of which were promptly managed by medical and surgical intraocular pressure-reducing strategies. Other findings that are typically associated with orbital compartment syndrome, such as a relative afferent pupillary defect, elevated intraocular pressure, optic disk edema, retinal edema, and retinal artery pulsations, could not be detected due to intense pain and the patient’s altered mental state. Common causes of orbital compartment syndrome include orbital abscess, orbital emphysema, orbital cellulitis, inflammation, tumors, orbital hemorrhage from trauma, surgery, or injections, dependent edema, or prolonged fluid resuscitation after burns. ³³ Our patient had orbital cellulitis and inflammation as predisposing risk factors to the development of orbital compartment syndrome. It has been reported that prolonged elevated pressures in the eye can lead to permanent vision loss. ³³ Given the altered mentation and delayed presentation to our hospital, it is unclear as to how long the patient had experienced compromise to the orbital structures prior to undergoing the lateral canthotomy and cantholysis and treatment with acetazolamide and brimonidine eye drops at our emergency department.

With CCRAVO being an uncommon vaso-occlusive disease associated with many systemic conditions, the pathomechanism is largely multifactorial. For example, orbital compartment syndrome causes an increased direct pressure leading to compressive optic neuropathy, limited blood flow, stagnation due to restricted movements of the eye, and the inflammation of nutrient vessels. This elevated pressure in the globe can lead to reduced arterial inflow and CRAO, which eventually leads to venous under-filling, stagnation thrombosis, venous occlusion or CRVO, and finally CCRAVO. ⁵ Other contributing factors for the development of CCRAVO in our patient include skin necrosis, heroin, and IV drug use, MRSA cellulitis and bacteremia, thrombocytosis, leukocytosis, elevated C-reactive protein, hepatitis C infection, and curling ulcer. ¹² In addition, acute sepsis can also lead to uncontrolled activation of the coagulation cascade inducing the formation of microthrombi and increased risk of thromboembolism. Since the patient had no intra-cardiac shunt, it is unlikely that an embolic event led to CCRAVO; however, thrombosis secondary to a sepsis-related hypercoagulable state could still be a possibility.^29,30

Combined central retinal artery and vein occlusion is predominantly a clinical diagnosis that demonstrates features of both CRAO and CRVO and should be suspected when a patient develops acute vision loss in one eye with retinal whitening. Notable features include tortuous and enlarged veins, retinal hemorrhage, cherry-red spot, attenuated retinal arteries, delayed filling of the arteries with dye, and extended arteriovenous transit time in fluorescein angiography—all of which support the diagnosis of CCRAVO.^16,34,35 Our patient demonstrated many of these findings on fundoscopy as seen in Figure 2.

The management of combined vascular occlusions is controversial due to the rarity of this condition. The treatment modality needs to be individualized and hence, emergent ophthalmology consultation is required to guide therapy, especially in the acute setting. Several therapies have been studied which include hyperbaric oxygen,^16,36 fibrinolytic therapy (early < 72 hrs), ²⁰ triamcinolone for macular edema, ²⁰ bevacizumab to reduce macular edema and neovascularization, ²⁰ intravitreal dexamethasone implant, ³⁷ pan-retinal photocoagulation, ¹¹ acetazolamide, timolol, and atropine. ¹¹ Unfortunately, even with prompt treatment, CCRAVO tends to have a poor visual prognosis. ⁴ Interestingly, some studies report partial or near-complete recovery,^{5,12,13,37,38} whereas other studies report permanent vision loss.^{4,5,9-12,17,39} Recovery is believed to depend on the severity of the disease, early diagnosis, and prompt treatment, and if the patient was on long-term anticoagulation for other underlying conditions. ⁵ Fundus fluorescein angiography (FFA) is important in follow-up to identify early vascularization.

A few cases of orbital cellulitis leading to CCRAVO have been reported. However, MRSA sepsis progressing to orbital cellulitis followed by CCRAVO is exceedingly rare. To the best of our knowledge, this case report is the first to identify this association. With growing evidence of combined vascular occlusion, further study is needed to determine the best therapeutic approach in these conditions.

Conclusion

Concomitant retinal arterial and vein vascular occlusions are unusual and should be carefully investigated for hypercoagulable states, embolism, and local ocular conditions. Orbital cellulitis can be a leading cause with an overall poor prognosis; therefore, early suspicion and prompt diagnosis with appropriate treatment are essential to limit the complications of this sight-threatening disorder.