Pediatric Bartonella henselae neuroretinitis masking co-infections.

PURPOSE: Neuroretinitis (NR) is an inflammatory disorder that presents with painless vision loss due to optic disc edema, peripapillary detachment, and macular lipid exudation. We report the first two documented cases of co-infections of pediatric NR due to Bartonella henselae with HSV and Toxocara cati, respectively. OBSERVATIONS: A 10-year-old female with acute right-sided facial droop, right eye pain, and acute visual loss of the right eye is diagnosed with co-infection of Bartonella and HSV retinitis and is successfully treated with acyclovir, rifampin, and doxycycline. A 13-year-old female with progressive visual loss of the left eye is diagnosed with co-infection of Bartonella and ocular toxocariasis and is successfully treated with doxycycline, rifampin, prednisolone, and albendazole. CONCLUSIONS AND IMPORTANCE: Early recognition and multi-modal treatment is necessary to prevent delayed diagnosis and treat the underlying NR causes for optimal visual recovery.

Introduction

Neuroretinitis (NR) is an inflammatory disorder that presents with painless vision loss due to optic disc edema, peripapillary detachment, and macular lipid exudation., Pathophysiology generally involves an agent or trigger that increases permeability of disc vasculature. The causes of NR are broad and are typically categorized into either infectious, inflammatory, or idiopathic etiologies.

While there are a number of infectious etiologies of NR, cat-scratch disease (CSD) by Bartonella henselae is the most common pathogen, causing more than two-thirds of infectious NR cases. Other potential bacterial causes include Rickettsia ricketsii, Mycobacterium tuberculosis, Salmonella, syphilis, Lyme disease, and leptospirosis. Viral causes include Zika, measles, mumps, rubella, varicella, herpes simplex, herpes zoster, Chikungunya, dengue, influenza A, hepatitis B, Epstein-Barr, and coxsackie B. Parasitic causes include Toxocara species, toxoplasmosis and spirochetes.,

Despite the broad and various etiologies surrounding NR, there are limited case reports regarding the incidence of NR in the setting of a concurrent infection. We report two cases of Bartonella henselae NR that initially masked a co-infection of the another visual threatening pathogen.

Findings

Case 1

A 10-year-old female with no significant past medical history presented to the emergency room with a seven-day history of fever, right-sided facial droop, right eye pain, and acute visual loss in the right eye. Three days prior to presentation, the patient had been prescribed oral valacyclovir and oral prednisone by a local pediatrician for a cranial nerve VII palsy but had continued worsening of symptoms. Pertinent social history included a vaccinated cat living at her primary occupancy. Review of systems was otherwise negative.

On examination, the patient's best correct visual acuity was 20/100 OD and 20/20 OS with a right eye afferent pupillary defect (APD). Intraocular pressure was normal bilaterally. Confrontational visual field testing demonstrated a superior visual field defect in the right eye. Motility testing demonstrated a mild restriction in abduction and pain with extraocular movement of the right eye. Ishihara color plates were 9/11 OD and 11/11 OS. Anterior segment exam was remarkable for 1+ cell and flare in the right eye. Dilated fundus exam was notable for optic nerve edema with a hypopigmented retinal lesion superior to the optic nerve and a macular star lipid exudation surrounding the fovea in the right eye. The anterior segment and dilated fundus exam were unremarkable in the left eye.

T1-weighted magnetic resonance imaging (MRI) of the brain and orbit with contrast revealed enhancement of the right optic nerve extending from the optic nerve head to the intraorbital segment and enhancement of the genu of the right facial nerve, left trigeminal nerve, and left abducens nerve (Fig. 1B–D). MRI imaging of the spine was normal. Preliminary lab results from an outside hospital were significant for positive Bartonella IgG (titers of 1:1024). Given the history of cat contact, ocular exam, laboratory and MRI findings, the preliminary diagnosis was NR and right facial palsy secondary to Bartonella. The patient was started on oral doxycycline and rifampin for presumed infection and was continued on intravenous (IV) methylprednisolone 30 mg/kg for five days given the signs of inflammation.

Fig. 1

(A) Fundus photo of the right eye demonstrates optic disc edema with a superior hypopigmented retinal lesion and a macular star lipid exudation surrounding the fovea. (B) Fundus photo of the left eye with normal optic nerve and fundus. C) OCT of the macula of the right eye demonstrates intra-retinal and sub-retinal fluid extending from the optic nerve. (D–E).

On follow-up three days later, the patient had worsening of both vision and symptoms. Visual acuity had decreased to 20/200 OD with a continued right APD. Anterior segment exam of the right eye demonstrated 2+ cell in the anterior chamber. Dilated fundus exam showed 1–2+ vitritis with a vitreous haze around the superior extramacular hypopigmented lesion as well as significant optic nerve edema and macular exudation (Fig. 1A). Optical coherence tomography (OCT) of the right retina showed sub- and intra-retinal fluid (Fig. 1E) and OCT of the right nerve showed significant optic disc edema.

Serological workup revealed a positive HSV-1 IgG (53.30, reference range <0.91) and positive HSV-1 and -2 IgM antibodies (1.58, reference range <0.89), suggesting a co-infection of Bartonella and active HSV retinitis. The patient was re-admitted for IV acyclovir, doxycycline and rifampin treatment. After completion of IV acyclovir, the patient was discharged and continued oral acyclovir daily for six months as well as oral doxycycline and rifampin for one month. At the one-month follow-up, the patient was noted to have resolution of intraocular inflammation, optic nerve edema, focal retinitis, and facial palsy with vision improving to 20/40 in the right eye.

Case 2

A previously healthy 13-year-old female with no past medical or ocular history presented with three weeks of progressive vision loss in her left eye and headaches. The patient was initially examined at an outside hospital emergency room and was diagnosed with probable cat-scratch disease (CSD) given her recent history of cat contact. She was started on rifampin, doxycycline, and promethazine, which was subsequently discontinued by an outside ophthalmologist after several days of treatment without improvement in vision. The patient was then referred to our service for evaluation. Further clinical history revealed that the patient had not only had recent contact with a stray cat but often kissed and licked the cat regularly. The patient also swam in brackish water one month prior and had limited contact with a dog at home. A review of systems was negative, and she had no history of seasonal or sinus allergies.

On initial presenting exam, her visual acuity was 20/20 OD and hand motion vision OS with a left afferent pupillary defect. Color vision was 11/11 OD and 0/11 OS. She had normal intraocular pressure and extraocular motility in both eyes. Confrontational visual fields were unremarkable in the right eye and were unreliable in the left eye. The anterior segment exam was notably quiet and unremarkable in both eyes. The dilated fundus exam was normal in the right eye and showed a clear view of the left eye with grade +4 optic nerve edema (Fig. 2A). The inflamed and elevated left optic nerve had fine angiomatous vessels and was surrounded by disc/flame hemorrhages, subretinal fluid, and exudation (Fig. 2B). Over a period of weeks, the macula began demonstrating an early macular star exudation (Fig. 2C). In the peripheral retina, there was a large creamy granulomatous lesion with clustered dot-blot hemorrhages and a linear track of exudation extending from the optic nerve toward an inferior peripheral granulomatous lesion (Fig. 2D).

Fig. 2

Initial Presentation Case 2. (A) Low magnification fundus photo montage of the left eye shows left neuroretinitis with inflammatory mass-like size, edema, and disk hemorrhages of the optic nerve, as well as subtle macula exudation. (B) High magnification fundus photos of the inferior peripheral retina of the left eye (5 clock hour) demonstrate an elevated hypopigmented granulomatous-like mass with scattered peripheral retinal hemorrhages on the superior margin. Note subtle change in the retinal pigmentation and distortion of peripheral vessels trajectory (arrows) on the border of the elevated granulomatous mass. (C) High magnification color photo of the left optic nerve with edema, telangiectatic and angiomatous vessels surrounded by disc/flames hemorrhages and focal exudation. (D–E) Optic coherence Tomography (OCT) of the macula show retinal thickening on the thickness map, and central foveal macula scan shows significant thickening of the inner retinal, disruption of Inner and outer segment (IS/OS) junction, thickening of the Henle fiber layer, and focal subtle vitritis. (F) Oct of the Optic nerve noted significant edema on the retina fundus image and respective tomogram. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

MRI of the orbits with contrast was notable for an enhancing lesion in the retina near the fovea with a normal appearing optic nerve and brain. OCT of the macula of the left eye revealed subretinal fluid extended from optic nerve and a blunted and deviated foveal contour.

Laboratory serological studies were positive for Bartonella IgG (1:128) and IgM (1:16) and negative for Toxoplasma IgG and IgM, HSV-1 and HSV-2, syphilis, Lyme antibodies, TPPA, tuberculosis, and HIV. However, the patient had a notable IgE count of 400 UI/ml. Toxocara and Strongyloides were tested given the elevated IgE but were negative. The patient was started on doxycycline, rifampin, and prednisolone for Bartonella. However, given the distinguishing presentation of the optic nerve and retina, the lack of uveitic and systemic signs, and serially elevated IgE levels, an anti-parasitic medication, oral albendazole, was initiated for one month with repeated serology for Bartonella and presumed Toxocara. Bartonella titers increased to 1:512. Toxocara studies remained negative. An additional month of Bartonella treatment was added given the increased titers. At six months, visual acuity improved to 20/400 and dilated exam showed resolution of left optic nerve edema with residual surrounding peripapillary gliosis as well as resolution of the retinal hemorrhages and peripheral exudations (Fig. 3).

Fig. 3

Follow-up for Case 2. (A–B) Low Magnification Fundus montage of the follow-up at 1-month (A) and 3-months (B) while on treatment. Notable improvement in changes in optic nerve edema, retina pigmentation, retinal exudation in the macula, along the inferior arcade, and tracking in a curvilinear manner inferonasally from the optic disc. (C–D) Optic nerve edema at 1-week (C) from presentation noted clear severe edema with circumpapillary granulomatous lesions that improved with treatment on follow-up at 1- month (D) as noted on fundus photo and OCT image of these lesions. (E) By 6 months the optic nerve edema resolved with surrounding peripapillary gliosis and the macular star exudation has been reabsorbed.

Discussion

Bartonella henselae is the most common and well-documented infectious cause of NR., To our knowledge, there has been only one reported case of NR due to herpes simplex virus and five reported cases of ocular larva migrans (OLM) secondary to Toxocara cati. Moreover, the literature of NR due to a co-infection is limited.4, 5, 6 Prior cases of NR with co-infection include Bartonella henselae in conjunction with Borrelia burgdorferi, HIV in conjunction with hepatitis B, and Bartonella henselae in conjunction with DUSN infection. We report two cases of pediatric NR due to Bartonella henselae with HSV and Toxocara cati, respectively. In all reported co-infections, early recognition and dual treatment was necessary to prevent delayed diagnosis and treat the underlying NR causes for optimal visual recovery.7, 8, 9

In the first case, our patient's initial presentation of unilateral facial droop with ipsilateral NR and positive IgG Bartonella serology (titres) was erroneously diagnosed as reactivated CSD infection from either prior exposure or occult infection by the inpatient service. Thus, IV prednisone was chosen for initial treatment. With no anti-viral coverage, her posterior segment inflammation presumptively worsened in the setting of high-dose steroids, and within a few days develop concurrent primary HSV infection. It is worth noting that this patient had 2 days of valacyclovir prior to transfer of care, while not a therapeutic dosage, it may have delayed the HSV diagnosis. While there are two previously reported cases of patients with unilateral facial droop due to presumed CSD NR, one case was subsequently found to have a secondary granulomatous lesion compressing the facial nerve and neither case was tested for HSV serologies.10, 11, 12 Retrospectively, the patient's right facial palsy was likely secondary to an active HSV infection given the clinical history, serologies, and neuroimaging demonstrating right facial nerve enhancement.

In the second case, cat exposure by actively licking the cat for weeks and low IgG and IgM Bartonella henselae titers alone did not explain the ocular findings and elevated IgE levels in this child. Ocular bartonellosis has a broad spectrum of clinical presentations including optic nerve edema, neuroretinitis, intermediate uveitis, vasculitis, retinochorditis and peripheral choroidal granuloma, and systemically can have CNS manifestations of cranial neuropathies and seizures.13, 14, 15 However, in cases with an Bartonella inflammatory mass lesion of the optic nerve, as in our patient, there are usually associated vitreous infiltrates, anterior chamber inflammation, markedly elevated IgG and IgM titers, and flu-like prodrome prior to presentation. These findings were noticeably absent in our patient.

While our patient's severely inflamed optic nerve and peripheral granulomatous retinal lesion findings can be found in sequelae of ocular bartonellosis, the lack of uveitic inflammation and an elevated IgE with no sinus or allergy history was concerning for possible parasitic infection secondary to Toxocara ocular larva migrans (OLM) species. OLM is usually a clinical diagnosis and has three unique presentations: posterior pole granuloma, peripheral granuloma, and endophthalmitis., The nematode larvae can enter the eye through choroidal, retinal, or ciliary circulation, and in peripheral retinal tissue, it can be swaddled with eosinophils with resultant eosinophilia. Toxocara-excretory secretory (TES) antigen and intraocular assay of aqueous or vitreous humor can be used to detect the antibodies, but it may be difficult to obtain specimen in a pediatric patient with a typically formed vitreous. Enzyme-linked immunosorbent assay (ELISA) has become the standard of serologic diagnosis of Toxocara, however, for OLM toxocara the ELISA assay has both poor sensitivity and specificity necessitating a clinical diagnosis. In a histopathology review of 22 cases of tissue confirmed OLM, only 50% had prior serum positive ELISA assays.

Currently, the management of NR is still debated as the condition is typically self-limited, especially in immunocompetent patients. Lack of randomized clinical trials demonstrating the efficacy of antibiotics or steroids makes it even more difficult for experts to reach a consensus., Therefore, we recommend therapy to target the underlying etiology. For NR secondary to CSD, a four-to-six week course of doxycycline and rifampin has been suggested to shorten the duration and systemic symptoms as seen with our patients. Ciprofloxacin or azithromycin may also be beneficial., The treatment of NR secondary to Toxocara includes both anti-helminthic agents and corticosteroids. Prior studies demonstrate a decrease in recurrence when combining both agents. High-dose albendazole is preferred as it can penetrate the blood-retina barrier with the addition of steroids to prevent further inflammation from larvae death.17, 18, 19 Empiric anti-helminthic therapy may also prevent further complications of both tractional and rhegmatogenous retinal detachment.

As treatment courses for NR are dependent on infection sources, a correct diagnosis is crucial for precise pharmacological intervention. Early recognition and diagnosis of NR co-infections are necessary for optimal visual recovery. Consider close monitoring of patients where multiple etiologies are suspected, especially in patients that present with atypical NR, have cranial nerve involvement, or are refractory to initial therapy.

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Axial and coronal T1-weighted MRI of the brain with contrast demonstrates inversion and enhancement of the right optic nerve head extending to the intraorbital segment of the optic nerve. (F) Coronal T1-weighted MRI shows enhancement of the genu of the right facial nerve.

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