November 03, 2021
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Woman presents with bilateral pain, blurry vision, floaters and photophobia

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A 39-year-old woman was referred to the uveitis clinic at the New England Eye Center for a few weeks’ history of bilateral pain, blurry vision, floaters and photophobia.

She was diagnosed with ocular sarcoid 3 years prior but was reportedly quiescent until recently, for which she was started on prednisolone acetate 1% twice daily with intermittent compliance.

Allison V. Coombs
Allison V. Coombs
Nisha S. Dhawlikar
Nisha S. Dhawlikar

Her medical history was significant for ADHD and a history of intravenous drug use 9 years ago. Her medication list included trazodone, Ritalin (methylphenidate, Novartis) and Suboxone (buprenorphine and naloxone, Indivior). Review of systems was positive for fatigue, joint pain and hip pain. She denied a history of cold sores or shingles, recent illness, exposure to pets at home, tick bites, recent travel, shortness of breath, skin lesions, gastrointestinal issues, focal neurologic symptoms, diabetes and family history of autoimmune disease.

Examination

Upon initial examination, best corrected visual acuity was 20/40 in the right eye and 20/25 in the left eye. IOP was normal in both eyes, and pupillary and external exams were unremarkable. Anterior segment exam was notable for a raised yellow conjunctival lesion with adjacent hemorrhage along the limbus in the right eye. Both corneas were otherwise clear, with normal irises without transillumination defects or heterochromia. There was no anterior chamber cell before dilation, but 2+ pigmented cells were noted after dilation.

Posterior segment exam revealed 2+ anterior vitreous cell and trace vitreous haze in both eyes. The optic discs appeared healthy. Examination of the right macula revealed retinal pigment epithelium mottling, but it was otherwise flat without retinal lesions. The vasculature was unremarkable in both eyes, and there was a chronic-appearing small chorioretinal scar in the superonasal periphery in the left eye. The patient was started on difluprednate 0.05% four times a day in both eyes.

At 1-month follow-up, visual acuity decreased to 20/60 in the right eye and 20/30 in the left eye. The yellow conjunctival lesion in the right eye had resolved, and there were 0.5+ anterior chamber cells in both eyes. The exam was otherwise stable. Given the persistent inflammation, the patient was started on oral prednisone 50 mg daily, and the difluprednate was decreased to twice daily in both eyes.

Two weeks later, the patient reported she stopped the oral prednisone due to intolerable side effects. Visual acuity had decreased to 20/200 in the right eye and 20/40 in the left eye. The anterior chamber cells had resolved, but she had persistent 2+ vitreous cells in both eyes. The fundus exam was remarkable for a new white lesion in the nasal macula of the right eye as well as subtle smaller white lesions in the periphery with a few small blot hemorrhages. There were similar white retinal lesions in the macula of the left eye superotemporally and inferotemporally, with scattered hemorrhages outside the arcades, one with a central white spot (Figure 1).

Fundus photos of the right and left eyes showing white retinal lesions
Figure 1. Fundus photos of the right and left eyes. There is a white retinal lesion in the nasal macula of the right eye and smaller pinpoint lesions in the superior periphery. Similar small white retinal lesions are noted in the macula of the left eye in addition to the superonasal chorioretinal scar. There are small hemorrhages noted in the periphery of both eyes, including a Roth spot in the superior periphery of the left eye.

Source: Erin Lanzo, MD, Lana Rifkin, MD, and Michelle C. Liang, MD

What is your diagnosis?

See answer below.

Bilateral pain, blurry vision

This patient had bilateral panuveitis with anterior vitreous cells, vitreous haze and retinal lesions with hemorrhages. The differential diagnosis necessitates consideration of inflammatory, infectious and neoplastic etiologies.

Inflammatory conditions that may present with these findings include sarcoidosis, Behçet’s disease, multifocal choroiditis and, less likely, Vogt-Koyanagi-Harada disease, sympathetic ophthalmia, acute posterior multifocal placoid pigment epitheliopathy, birdshot choroiditis and serpiginous choroiditis.

Patients should be tested for infectious etiologies to rule out systemic diseases such as syphilis, toxoplasmosis, tuberculosis, Bartonella and HIV. Herpetic disease (herpes simplex virus, varicella zoster virus and cytomegalovirus) can also cause panuveitis. Finally, endogenous endophthalmitis must be considered in a patient with predisposing risk factors.

When inflammatory and infectious workups yield negative results, investigation for neoplastic masquerade syndromes such as leukemia and lymphoma should be pursued.

This patient also had scattered retinal hemorrhages, one with a central whitening, in the left eye. Underlying systemic causes for Roth spots include bacterial endocarditis, leukemia, myeloma, anemia, anoxia or carbon monoxide poisoning, preeclampsia, hypertension, diabetic retinopathy and HIV retinopathy.

Additional workup

Our patient underwent testing for syphilis, toxoplasmosis, HIV, Lyme and Bartonella, all of which were negative. She had elevated ACE and lysozyme levels, leading to the prior diagnosis of suspected ocular sarcoid.

OCT was obtained to further evaluate the macular findings. In the right eye, a hyperreflective intraretinal lesion was noted nasal and superotemporal to the fovea with some vitreous cell visible (Figure 2). A small inner retinal hyperreflective lesion was also noted in the left eye (Figure 3).

Macular OCT shows parafoveal hyperreflective lesions
Figure 2. Macular OCT shows parafoveal hyperreflective lesions in the right eye. Vitreous cells can also be visualized.
OCT imaging of the left eye shows a small nasal hyperreflective inner retinal lesion
Figure 3. OCT imaging of the left eye shows a small nasal hyperreflective inner retinal lesion.

Fluorescein angiogram of the right eye demonstrated blocking from vitreous opacities and hypofluorescence in the macula with late leakage of the optic disc. Imaging of the left eye revealed blocking in the area of retinal hemorrhages and similar late leakage of the disc. In addition to the superonasal scar, there were punctate hyperfluorescent spots within the macula and periphery (Figures 4a to 4e).

Early, middle and late angiograms of the right eye demonstrate hyperfluorescence of the disc
Figure 4. Early, middle and late angiograms of the right eye demonstrate hyperfluorescence of the disc with patchy macular hyper- and hypofluorescence and blocking from vitreous opacities (a to c). Middle and late phase angiograms of the left eye show punctate hyperfluorescent spots in the macula and periphery, disc leakage and hyperfluorescence of the superonasal scar (d to e).

Examination of the patient’s hands revealed small, irregular, nontender hemorrhagic macules consistent with Janeway lesions (Figure 5).

Janeway lesions on the right palm
Figure 5. Janeway lesions on the right palm.

These findings raised concern for endogenous endophthalmitis secondary to suspected infectious endocarditis in the setting of intravenous drug use.

The patient underwent tap and injection of intravitreal voriconazole and vancomycin in the right eye for suspected endogenous endophthalmitis. Due to a reported cephalosporin allergy, she did not receive intravitreal ceftazidime. She was started on prednisolone acetate 1% twice daily and ofloxacin four times daily in both eyes.

Blood cultures grew Streptococcus viridans in three of four bottles, sensitive to ceftriaxone. Complete blood count showed an elevated white blood cell count, and HIV testing was negative. The patient was started on IV vancomycin and ceftriaxone and admitted to the medicine service for further workup of bacteremia.

Discussion

Endogenous endophthalmitis is rare and occurs in 0.4% to 0.5% of bacteremia or fungemia cases. It accounts for 2% to 8% of endophthalmitis cases overall. The most common organisms implicated vary by region, although fungal infection (Candida albicans and Aspergillus) is more common than bacterial. In the United States and Europe, gram-positive bacteria are more prevalent, with S. viridans accounting for 71% of streptococcal species infection. In East Asia, gram-negative bacteria, specifically Klebsiella, represent the majority of cases. Infective endocarditis is the most common risk factor.

The most common ocular symptom is decreased vision. Patients may also report pain, photophobia and floaters. On exam, there is often anterior chamber inflammation with or without hypopyon, vitreous cell and haze, and absence of a red reflex. The hallmark finding is vitreous involvement. Other findings may include eyelid edema, conjunctival injection and circumcorneal congestion. Fungal lesions often appear as fluffy white retinal lesions (Candida) or yellow-white lesions (Aspergillus). Infections may also present with a subretinal or choroidal abscess, and MRSA has been associated with retinal detachment. The right eye is more commonly affected than the left, most likely owing to the more direct route from the right carotid artery, and bilateral cases, as in our patient, account for 12% of cases overall.

Pathophysiology involves hematogenous spread of the infecting organism through the posterior segment vasculature or, in cases of central nervous system infection, from the optic nerve. Septic emboli can act as a nidus for dissemination into surrounding ocular tissue.

To make the diagnosis, several ancillary tests may be helpful in addition to laboratory workup. B-scan ultrasound may show vitreous exudates and choroidal or retinal abscess. OCT may reveal vitreous cells and retinal lesions. Culture and PCR of the vitreous fluid are essential, although they yield varying results. Vitreous culture via aspiration yields positive growth in 44% of cases, while diagnostic vitrectomy has a 92% culture yield. Aqueous sample may be necessary if vitreous fluid cannot be obtained. Blood cultures should be obtained if systemic infection is suspected.

Regarding management, intravitreal injection of antibiotics in combination with systemic antibiotics is the mainstay of treatment. If there is no improvement within 48 hours of antibiotic administration, surgery may be warranted.

The blood-retinal barrier may affect the penetration of commonly used systemic antibiotics, although the inflammatory response can disrupt this barrier, leading to enhanced penetration of systemic antibiotics into ocular tissue. Various studies in animal models demonstrate penetration of antibiotics in normal and inflamed eyes.

Pertinent to the case discussed here, ceftriaxone effectively crosses the blood-ocular barrier, and culture data supported its usage. The patient had reported a previous reaction to cephalosporins, and thus, intravitreal ceftazidime was withheld in the clinic. In collaboration with infectious disease colleagues, it was decided that the nature of the reaction was likely nonallergic, and intravenous ceftriaxone would be the most appropriate medication to administer under monitored care.

One retrospective study of patients with endophthalmitis from 2005 to 2019 details 483 cases, 47 of which were patients with documented allergy to beta-lactams, cephalosporin or vancomycin. Forty-six of the 47 received intravitreal vancomycin, and 36 of the 47 received intravitreal ceftazidime. Of the 36 who received ceftazidime, 28 had a documented penicillin allergy, and five had a cephalosporin allergy. None of the patients experienced an allergic reaction. In a hospital setting where patients are closely monitored, it may be appropriate to administer intravitreal antibiotics despite documented allergy.

The mortality for patients with endogenous endophthalmitis is significant. A study out of West Virginia followed patients from 2009 to 2019 and found a rate of 12.4% 1-year mortality in cases of endogenous endophthalmitis. Bacterial causes typically have a worse prognosis than fungal causes.

As such, it is essential to consider this diagnosis in the right setting in order to facilitate prompt diagnosis and initiation of systemic treatment.

Case resolution

Four days after intravitreal injection and initiation of intravenous antibiotics, our patient’s visual acuity improved to 20/70 in the right eye and 20/20 in the left eye. The anterior chamber was quiet, and trace anterior vitreous cell was noted. She was continued on topical and systemic medications. At 7-day follow-up, her visual acuity was 20/30 in the right eye and 20/20 in the left eye, and her retinal lesions showed interval consolidation (Figures 6 and 7).

Color fundus photos show interval improvement in foveal lesions
Figure 6. Color fundus photos of the right and left eyes show interval improvement in foveal lesions.
Magnified photo of the macula shows consolidation of nasal foveal lesion
Figure 7. Magnified photo of the macula in the right eye shows consolidation of the nasal foveal lesion.

As part of her systemic workup, the patient underwent an echocardiogram that revealed mitral and tricuspid valve vegetations (Figure 8). MRI of the brain demonstrated abnormal leptomeningeal ring enhancement with underlying cerebritis of the left posteroinferior frontal lobe, suggestive of meningitis. The contiguous ring enhancement with central restricted effusion raised concern as well for focal abscess (Figure 9). Additional foci of abnormal T2/FLAIR signal within the supratentorial white matter were noted, reflecting possible sequelae of emboli vs. chronic microangiopathy (Figure 9).

Mitral and tricuspid valve vegetations
Figure 8. Mitral and tricuspid valve vegetations.
MRI of the brain shows abnormal leptomeningeal ring enhancement
Figure 9. MRI of the brain shows abnormal leptomeningeal ring enhancement with underlying cerebritis of the left posteroinferior frontal lobe. Additional foci of abnormal T2/FLAIR signal within the supratentorial white matter are noted, reflecting possible sequelae of emboli vs. chronic microangiopathy.

During her hospital stay, the patient underwent mitral and tricuspid valve replacement, as well as a superior mesenteric artery thrombectomy for a mesenteric artery thrombus causing mesenteric ischemia. She was followed by the neurology and neurosurgery teams for the intracranial findings, who advised against surgical intervention. The addiction medicine team was consulted to engage the patient regarding her relapsed use of intravenous drugs. With successful multidisciplinary management, she was later discharged in stable condition.