Microvasculopathy in Lyme-Associated Papillitis Revealed by Optical Coherence Tomographic Angiography

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Microvasculopathy in Lyme-Associated Papillitis Revealed by Optical Coherence Tomographic Angiography Marisa G. Tieger, MD, John B. Miller, MD, Eric D. Gaier, MD, PhD Case Report L yme disease is a tick-borne illness caused by the Borrelia burgdorferi spirochete and transmitted by the Ixodes tick (1). Lyme disease can manifest in the posterior pole, commonly in the form of papillitis (1). Diagnosis of Lyme papillitis requires a thorough workup to eliminate other infectious and autoimmune etiologies of papillitis in addition to positive serologic and/or cerebrospinal fluid (CSF) markers (2). Previous reports of optic nerve involvement in Lyme disease have been attributed to increased intracranial pressure or inflammatory papillitis (3). More rare neurologic manifestations of Lyme disease include cerebral and retinal vasculitis in addition to stroke (1,4). We report a case of Lyme papillitis with peripapillary capillary attenuation evident on optical coherence tomographic angiography (OCT-A) that may suggest ischemic injury imparted by Lyme infection at the optic nerve head as a contributor to visual loss. A 63-year-old man living in rural New England with a history of idiopathic thrombocytopenic purpura on monthly rituximab infusions and oral prednisone (10 mg daily), systemic hypertension, hyperlipidemia, and alcoholic cirrhosis presented with 2 weeks of cloudy vision in his left eye. He reported myalgias, jaw claudication, and scalp tenderness. Visual acuities were 20/20 in the right eye and 20/30-1 in the left eye. A relative afferent pupillary defect was present in the left eye. Automated visual fields revealed an inferior arcuate defect in the left eye (Fig. 1A, B-insets). Right greater than left optic disc edema and peripapillary flame hemorrhages were appreciated funduscopically (Fig. Department of Ophthalmology (MGT, JBM, EDG), Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Harvard Medical School (MGT, JBM, EDG), Boston, Massachusetts; Department of Ophthalmology (EDG), Boston Children’s Hospital, Boston, Massachusetts; and Department of Brain and Cognitive Sciences (EDG), Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts. Supported by E. D. Gaier: NIH K08 EY030164. The authors report no conflicts of interest. Address correspondence to Eric D. Gaier, MD, PhD, Department of Ophthalmology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115; E-mail: [e-mail] e338 1A, B). Fluorescein angiography (FA) revealed filling defects in the left optic nerve head most prominent superiorly and aneurysmal dilatation inferiorly; later images for the right eye showed diffuse aneurysmal dilation and papillary leakage (Fig. 1C, D). OCT-A showed expansion of the papillary capillary network for the more edematous right optic disc and decreased OCT-A signal in the left peripapillary region most prominent superiorly (Fig. 1E, F). OCT of the macula showed normal anatomy in the right eye and superotemporal perifoveal thinning of the ganglion cell complex with subtle focal superficial microvascular attenuation on OCT-A in that area of the left eye (Fig. 1G, H). Gadolinium-enhanced MRI of the brain and orbits demonstrated elevated T2 signal without enhancement in the left optic nerve and a normal right optic nerve. Laboratory workup revealed an elevated white blood cell count (12.36 K/mL, 92% neutrophils), normocytic anemia (hgb 10.6 g/dL), elevated platelets (402 K/mL), elevated sedimentation rate and C-reactive protein (97 mm/h and 65.2 mg/L), and negative syphilis serology. The patient was treated for presumed giant cell arteritis with IV methylprednisolone 1 g daily for 3 days, followed by an oral prednisone taper from 80 to 60 mg daily. A temporal artery biopsy (2.8 cm 2 days after presentation) was negative. The acuity in his left eye declined to the hand motions level with persistently elevated inflammatory markers. He was readmitted and given IV methylprednisolone again for 3 days, followed by oral prednisolone at 100 mg tapering to 80 mg daily. A second temporal artery biopsy 11 days after initial presentation (1 cm) was negative. Despite continued treatment with high-dose corticosteroid and addition of tocilizumab, the patient continued to gradually lose vision in both eyes. Further workup revealed positive anti-Lyme IgG (8, 23, 39, 58, and 66 kDa bands), IgM (23 and 41 kDa bands) antibodies in the blood, and separate samples obtained at the time of lumbar puncture revealed antibodies in CSF (IgG: 2.6 relative to background; IgA: .5.0 relative to background) and blood including IgA (2.3 relative to background). A CSF:serum IgA ratio of 2.2 was consistent with intrathecal synthesis (5). After a 28-day course of IV ceftriaxone, his visual acuity Tieger et al: J Neuro-Ophthalmol 2022; 42: e338-e340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence improved to 2/200 in the left eye and remained stable in the right eye at 20/30 for follow-up over 2 years. Lyme papillitis often poses a diagnostic challenge. Diagnostic criteria for Lyme-associated optic neuropathy include definitive proof of active Lyme infection by way of culture or histologic evidence of B. burgdorferi in the CSF or optic nerve (2). Strong evidence implicating Lyme as causative in this case include exclusion of other causes of inflammatory/infectious optic neuropathy, exposure to an endemic area, myalgias, positive serum titers, CSF pleocytosis, and intrathecal Lyme antibodies with a CSF:serum ratio supportive of intrathecal synthesis (2). As such, the patient reported in this article met the criteria for strong evidence supporting the diagnosis of Lyme papillitis. Further support is lent by his worsening with corticosteroid and tocilizumab treatment and his improvement and stability after antibiotic treatment. OCT-A allows for detailed imaging of the retinal and papillary microvasculature and has been used in the evaluation of various causes of optic disc edema, including anterior ischemic optic neuropathy, papilledema, and optic neuritis (6–8). Previous reports have identified dilation of the peripapillary capillary network in the acute phase of nonarteritic anterior ischemic optic neuropathy and arteritic anterior ischemic optic neuropathy (7,8). In addition, focal attenuations in the superficial peripapillary capillary network have been reported in the setting of giant cell arteritis (7). In the case presented in this article, there was significantly more capillary attenuation in the left optic disc compared with the right optic disc that corresponded with visual function at the time of presentation and final outcome. Importantly, the focal area of capillary attenuation in the left superior optic disc seen on FA and OCT-A corresponded to the superior perifoveal thinning of the ganglion cell complex and subtle superficial microvascular attenuation on macular OCT/OCT-A (Fig. 1D, F, H). These defects correspond to and likely account for the inferior altitudinal defect on visual field testing. The attenuation of OCT-A signal at the left optic nerve head is unlikely FIG. 1. Ocular imaging including optical coherence tomographic angiography (OCT-A) on presentation of bilateral Lymeassociated optic neuropathy. A–B. Fundus photography of the right (A) and left (B) eyes demonstrating right . left optic disc edema with peripapillary flame hemorrhages. Insets show automated perimetry (Automated 24-2 SITA) results for each eye, respectively. C–D. Fluorescein angiography showing diffuse papillary leakage with aneurysmal dilation in the right eye (C) and a superior perfusion defect (yellow arrow) and inferior aneurysmal dilatation in the left optic disc (D). Insets show the time postinfusion (minutes:seconds). F–H. OCT-A images with corresponding B-scan images through the center of the optic disc or fovea depicting segmentation (Avanti, Optovue, Fremont, CA). E–F. Papillary and peripapillary OCT-A images with retinal segmentation (upper and lower boundaries depicted by red lines) showing diffuse expansion of the papillary and peripapillary capillary network for the right eye (E) and attenuation of the papillary and peripapillary network most prominent superiorly (yellow arrow) in the left eye (F). G–H. Macular OCT-A images with superficial segmentation (upper boundary depicted by red and lower boundary depicted by green lines) showing normal microvasculature in the right eye (G) and focal capillary attenuation in the superotemporal macula (yellow arrows) in the left eye (H). Insets show ganglion cell complex heat maps (composite retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer relative to normative controls) showing normal results in the right eye and thinning superotemporal to the fovea in the left eye, respectively. Tieger et al: J Neuro-Ophthalmol 2022; 42: e338-e340 e339 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence to represent an imaging artifact because one would expect segmentation error or obscuration by edema to be greater in the more edematous right optic nerve, which actually showed expansion of the peripapillary capillary network. Thus, the OCT-A findings in this case reliably demonstrate microvascular defects in the optic nerve head associated with visual loss secondary to Lyme papillitis, and these changes better reflected the functional status of the optic nerve than the fundus appearance. The pathophysiology of Lyme papillitis remains elusive; it remains unclear whether tissue damage occurs secondary to an immune-mediated process or infiltration and destruction by B. burgdoferi (3). In this case, the peripapillary capillary attenuation in the optic disc that was less edematous may represent vascular compromise related to that observed in Lyme-associated cerebral vasculitis (4) or retinitis (1). Lyme-associated cerebral vasculitis occurs secondary to perivascular and vascular lymphocytic infiltration induced by B. burgdoferi, resulting in thickening of small, medium, and large arteries, and consequential narrowing and occlusion (4). It stands to reason that a similar process may occur at the optic nerve head, for which B. burgdoferi has a clear predilection. This unique case highlights the utility of OCT-A to identify microvasculature changes in the papillary network in an infectious cause of papillitis. The OCT-A findings described in this article should not be considered specific for this condition, but may signify a potential vaso-occlusive/ ischemic component of optic nerve injury, by contrast to other proposed mechanisms (3). Further study is needed, perhaps using more advanced ocular imaging technology, to confirm these findings in Lyme papillitis. In addition, the peripapillary capillary attenuation visualized during the acute phase corresponded with visual function on presentation and after treatment, suggesting that OCT-A may serve e340 as a better prognostic indicator than the clinical examination in Lyme papillitis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. B. Miller and E. D. Gaier; b. Acquisition of data: J. B. Miller and E. D. Gaier; c. Analysis and interpretation of data: MGT, J. B. Miller and E. D. Gaier. Category 2: a. Drafting the manuscript: M. G. Tieger; b. Revising it for intellectual content: M. G. Tieger, J. B. Miller, and E. D. Gaier. Category 3: a. Final approval of the completed manuscript: M. G. Tieger, J. B. Miller, and E. D. Gaier. REFERENCES 1. Raja H, Starr MR, Bakri SJ. Ocular manifestations of tick-borne diseases. Surv Ophthalmol. 2016;61:726–744. 2. Sibony P, Halperin J, Coyle PK, Patel K. Reactive Lyme serology in optic neuritis. J Neuroophthalmol. 2005;25:71–82. 3. Rothermel H, Hedges TR III, Steere AC. Optic neuropathy in children with Lyme disease. Pediatrics. 2001;108:477–481. 4. Zajkowska J, Garkowski A, Moniuszko A, Czupryna P, Ptaszynska-Sarosiek I, Tarasow E, Ustymowicz A, qebkowski W, Pancewicz S. Vasculitis and stroke due to Lyme neuroborreliosis —a review. Infect Dis (Lond). 2015;47:1–6. 5. Theel ES, Aguero-Rosenfeld ME, Pritt B, Adem PV, Wormser GP. Limitations and confusing aspects of diagnostic testing for neurologic Lyme disease in the United States. J Clin Microbiol. 2019;57:e01406–e01418. 6. Fard MA, Jalili J, Sahraiyan A, Khojasteh H, Hejazi M, Ritch R, Subramanian PS. Optical coherence tomography angiography in optic disc swelling. Am J Ophthalmol. 2018;191:116–123. 7. Gaier ED, Gilbert AL, Cestari DM, Miller JB. Optical coherence tomographic angiography identifies peripapillary microvascular dilation and focal non-perfusion in giant cell arteritis. Br J Ophthalmol. 2018;102:1141–1146. 8. Gaier ED, Wang M, Gilbert AL, Rizzo JF III, Cestari DM, Miller JB. Quantitative analysis of optical coherence tomographic angiography (OCT-A) in patients with non-arteritic anterior ischemic optic neuropathy (NAION) corresponds to visual function. PLoS One. 2018;13:e0199793. Tieger et al: J Neuro-Ophthalmol 2022; 42: e338-e340 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.