Optic Perineuritis Associated With Cryptococcal Meningitis Presenting With a "Hot Orbit" in a Patient With Chronic Lymphocytic Leukemia

A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was significant for type II diabetes mellitus and chronic lymphocytic leukemia, stable on no therapy since diagnosis 8 years prior. The initial examination was significant for diffuse restriction of left ocular motility, marked lid edema, and mild dyschromatopsia. Computed tomography demonstrated asymmetric left periorbital soft tissue swelling and intraconal fat stranding with an irregular left optic nerve sheath complex and clear paranasal sinuses. He was hospitalized for orbital cellulitis and treated empirically with broad-spectrum intravenous antibiotics, but his visual acuity declined over the ensuing 2 days. Subsequent MRI demonstrated left-greater-than-right circumferential optic nerve sheath enhancement, and leptomeningeal enhancement. An orbital biopsy demonstrated monoclonal B-cell lymphocyte aggregation, whereas a lumbar puncture was positive for Cryptococcus antigen with subsequent demonstration of abundant Cryptococcus by Papanicolaou stain. The final diagnosis was optic perineuritis secondary to cryptococcal meningitis presenting with orbital inflammation. Although his clinical course was complicated by immune reconstitution inflammatory syndrome, symptoms and signs of optic neuropathy ultimately resolved after 1 month of intensive antifungal therapy.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Optic Perineuritis Associated With Cryptococcal Meningitis Presenting With a “Hot Orbit” in a Patient With Chronic Lymphocytic Leukemia Daniel L. Liebman, MD, MBA, Emily K. Tam, MD, MPH, Marie Y. Lithgow, MD, Joseph E. Kane, OD, Nancy J. Fischbein, MD, Daniel R. Lefebvre, MD, Bart K. Chwalisz, MD, Eric D. Gaier, MD, PhD Abstract: A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was significant for type II diabetes mellitus and chronic lymphocytic leukemia, stable on no therapy since diagnosis 8 years prior. The initial examination was significant for diffuse restriction of left ocular motility, marked lid edema, and mild dyschromatopsia. Computed tomography demonstrated asymmetric left periorbital soft tissue swelling and intraconal fat stranding with an irregular left optic nerve sheath complex and clear paranasal sinuses. He was hospitalized for orbital cellulitis and treated empirically with broad-spectrum intravenous antibiotics, but his visual acuity declined over the ensuing 2 days. Subsequent MRI demonstrated left-greater-than-right circumferential optic nerve sheath enhancement, and leptomeningeal enhancement. An orbital biopsy demonstrated monoclonal B-cell lymphocyte aggregation, whereas a lumbar puncture was positive for Cryptococcus antigen with subsequent demonstration of abundant Cryptococcus by Papanicolaou stain. The final diagnosis was optic perineuritis secondary to cryptococcal meningitis presenting with orbital inflammaDepartment of Ophthalmology (DLL, BKC, EDG), Mass Eye and Ear, Boston, Massachusetts; Department of Ophthalmology (EKT), Boston Medical Center, Boston, Massachusetts; Department of Pathology (MYL), Boston VA Medical Center, Boston, Massachusetts; Department of Optometry (JEK), Boston VA Medical Center, Boston, Massachusetts; Department of Radiology (NJF), Stanford University Medical Center, Stanford, California; Department of Ophthalmology (DRL), Boston VA Medical Center, Boston, Massachusetts; Division of Ophthalmic Plastic and Reconstructive Surgery (DRL), Massachusetts Eye and Ear, Boston, Massachusetts; Division of Neuro-Immunology (BKC), Massachusetts General Hospital, Boston, Massachusetts; Department of Ophthalmology (EDG), Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; and Picower Institute for Learning and Memory (EDG), Massachusetts Institute of Technology, Cambridge, Massachusetts. EDG: 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] 272 tion. Although his clinical course was complicated by immune reconstitution inflammatory syndrome, symptoms and signs of optic neuropathy ultimately resolved after 1 month of intensive antifungal therapy. Journal of Neuro-Ophthalmology 2022;42:272–277 doi: 10.1097/WNO.0000000000001538 © 2022 by North American Neuro-Ophthalmology Society Drs. Liebman, Tam, Kane, Lefebvre, Chwalisz, Gaier: A 75-year-old man presented with left-sided retroorbital pain, left eyelid swelling, tearing, and pain with ocular movement. His medical history included type II diabetes mellitus and chronic lymphocytic leukemia (CLL), the latter of which was stable without treatment since the initial diagnosis 8 years prior. The patient had reported 2 months of abdominal pain, 20-pound weight loss, and fatigue. CBC demonstrated a leukocytosis of 39.9 ·109 cells/L with 86% lymphocyte predominance, a clear change from 18.2 ·109 cells/L drawn 3 months prior. Days later, he developed a throbbing frontal headache with a pressurelike quality and nasal congestion with clear drainage, for which he was remotely prescribed oral amoxicillin– clavulanate 875–125 mg to treat presumptive sinusitis. Three days later, he reported interval worsening of left retroorbital pain, 1 day of new left upper eyelid swelling, pain with eye movement, and intermittent binocular diplopia. Same-day Oculoplastics consultation revealed best-corrected visual acuities of 20/20 in the right eye and 20/25 in the left eye, no relative afferent pupillary defect (rAPD), and subtle dyschromatopsia by Ishihara in the left eye. A “hot orbit” was noted, with marked left upper and lower eyelid edema and 2+ Liebman et al: J Neuro-Ophthalmol 2022; 42: 272-277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study conjunctival injection. There was no intraocular inflammation, and the optic discs appeared normal. Emergent computed tomography (CT) of the orbits was performed. Dr. Fischbein: Selected initial CT images (Fig. 1) demonstrated diffuse irregular circumferential soft tissue thickening associated with the left optic nerve sheath complex. There was also asymmetric postseptal intraconal stranding in the left orbit, and mild proptosis. There was no organized fluid collection suggestive of an abscess. No abnormalities of the bone or intracranial compartment were identified, and no rightsided abnormality was noted. These findings were felt by the reading radiologist to be concerning for orbital cellulitis, albeit in the context of clear sinuses and intact orbital walls. Drs. Liebman, Tam, Kane, Lefebvre, Chwalisz, Gaier: Radiographic data and clinical appearance supported an initial clinical impression of orbital cellulitis, although the lack of acute constitutional symptoms, paranasal sinus disease, and/or antecedent dental or craniofacial surgery highlighted the absence of a defined underlying cause. Although the most common cause by far of orbital cellulitis is spread of infection from adjacent paranasal sinusitis, orbital cellulitis can occur as a result of hematogenous seeding from a distant source within the body (1). Given the patient’s history of CLL and the CT-evident involvement of the left optic nerve–sheath complex, the patient was admitted to the inpatient medicine service and treated with intravenous vancomycin 1g q12h and ceftriaxone 1g q12h. Blood cultures x 2 were obtained at admission and ultimately demonstrated no growth. Complete blood count testing was notable for 39.7 ·109 white cells/L (84.7% lymphocytes); erythrocyte sedimentation rate, c-reactive protein, platelets, and thyroid stimulating hormone were normal. The following day, a new rAPD of the left eye was apparent and dyschromatopsia by Ishihara color plate testing was more readily apparent. Visual acuity declined to 20/40 in the left eye. Exophthalmometry (Hertels) demonstrated 2 mm of net proptosis in the left eye. Dilated funduscopy demonstrated new diffuse optic disc edema and peripapillary retinal folds (Fig. 2). Automated perimetry demonstrated profound global visual field depression in the left eye with modest depression also noted in the right eye. These changes prompted further evaluation by gadolinium-enhanced MRI of the brain and orbits. Dr. Fischbein: Orbital MRI demonstrated enlargement and swelling of the left optic nerve, and diffuse irregular thickening and enhancement of the left optic nerve sheath (Fig. 3). The right optic nerve sheath was mildly thickened and abnormally enhancing. Irregular stranding of the intraconal fat was present on the left, and there was slight asymmetrical enlargement of the extraocular muscles greater on the left. Intracranially, there was abnormal enhancement surrounding the bilateral olfactory apparatus and more diffuse leptomeningeal enhancement. Drs. Liebman, Tam, Kane, Lefebvre, Chwalisz, Gaier: Evidence of pathology involving both optic nerves and the leptomeninges triggered suspicion for infiltrative disease stemming from the patient’s history of CLL. However, given that perineuritis carries a broad differential additionally inclusive of a range of infectious and inflammatory processes, a broad workup was pursued. Serologic testing for syphilis, tuberculosis, sarcoidosis, antineutrophil cytoplasmic antibody, Epstein–Barr virus, cytomegalovirus, Lyme disease, beta d-glycan, Aspergillus, herpes simplex, HIV, Toxoplasma, and COVID-19 were negative or within normal limits. A left anterior orbital fat biopsy was obtained; a concurrent temporal artery biopsy was also FIG. 1. Initial head CT showing left orbital intraconal stranding and enlargement of the left optic nerve-optic sheath complex on axial and coronal images (red arrows). There is also mild left proptosis and slight asymmetrical enlargement of the left extraocular muscles. The right orbit is grossly unremarkable. No abnormality of the cavernous sinuses or intracranial compartment is noted on CT. Liebman et al: J Neuro-Ophthalmol 2022; 42: 272-277 273 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Fundus photography from hospital day one demonstrating left optic disc edema and peripapillary retinal folds. obtained while the patient was in the operating room, because giant cell arteritis is a potential (albeit rare) cause of optic perineuritis. Subsequently, a lumbar puncture was obtained. Dr. Lithgow: There was no evidence of granulomatous inflammation or fibrosis in the temporal artery. The orbital fat biopsy demonstrated aggregation of lymphocytes (Fig. 4A). Flow cytometry of orbital tissue revealed the presence of a monoclonal lambda-restricted B-cell population (Fig. 4B,C). Lumbar puncture was notable for an opening pressure of 15 cm H20, and cerebrospinal fluid analysis was positive for cryptococcus antigen with a 1:2560 titer. Abundant cryptococcal elements were subsequently visualized on CSF cytology (Papanicolaou stain) (Fig. 5). Cerebrospinal fluid flow cytometry demonstrated a similar lambda-restricted B-cell population as noted from the orbital biopsy. Final Diagnosis Optic perineuritis and meningitis secondary to cryptococcal infection with orbital aggregation of lymphoma cells. Drs. Liebman, Tam, Kane, Lefebvre, Chwalisz, Gaier: Edmunds and Lawford (1883) first described optic perineuritis (OPN) in a histopathologic examination of an optic nerve with inflammatory infiltrates loosely organized around the nerve sheath (2). Once believed to be a variant of optic neuritis, OPN is now generally recognized as a distinct entity wherein the primary inflammatory focus is the optic nerve sheath rather than the axonal portion of the nerve. OPN frequently presents a diagnostic challenge and is often initially misdiagnosed as anterior optic neuritis because of overlaps in hallmark symptoms and funduscopic findings. OPN typically presents with decreased vision and pain with eye movement. Examination findings typically include optic disc edema, rAPD, and dyschromatopsia (3). Afferent dysfunction may manifest subacutely and less prominently in OPN compared with optic neuritis. As demonstrated in this case, OPN can nevertheless occasionally progress rapidly and be accompanied by orbital inflammatory manifestations including ophthalmoplegia, ptosis, and exophthalmos (4). Distinguishing OPN and optic neuritis is clinical and largely supported (but not dictated) by radiographic evidence. FIG. 3. T1 postgadolinium fat-suppressed (A) coronal and (B) axial brain MRI images demonstrating left greater than right optic nerve sheath thickening and enhancement (red arrows), with additional left intraconal fat stranding. There is also enhancement surrounding the bilateral olfactory bulbs and diffuse leptomeningeal enhancement overlying the brain surface. 274 Liebman et al: J Neuro-Ophthalmol 2022; 42: 272-277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 4. Orbital fat biopsy. A. ·10 magnification B. Cytospin of orbital biopsy flow cytometry sample demonstrating the presence of lymphocytes C. Flow cytometry of orbital biopsy demonstrating monoclonal lambda-restricted B cells. Dr. Fischbein: Advances in neuroimaging—particularly high-resolution, thin-section, gadolinium-enhanced, fat-suppressed MRI with a dedicated orbit protocol—have enabled radiographic classification of OPN as an inflammatory disorder primarily affecting the optic nerve sheath (5). Dedicated orbital MRI with coronal, axial, and sagittal sequences constitutes the most specific diagnostic imaging modality for this condition and typically demonstrates a characteristic pattern of circumferential enhancement around the optic nerve. Other conditions, including infiltrative processes such as sarcoidosis or neoplastic processes such as optic nerve sheath meningioma, leukemia/lymphoma, or metastases, can produce a similar radiographic appearance (4,6,7). There can be concomitant edema and/or enhancement of the axonal portion of the optic nerve, extraocular muscles, sclera, and orbital fat (8). Although CT imaging shows changes that are less specific for OPN because of the limited ability of CT to distinguish the optic nerve from the optic nerve sheath, CT can highlight changes of more generalized orbital inflammation or findings such as calcifications or bony erosion that may help to distinguish OPN from other causes such as meningioma and lymphoma. Ultimately, clinical context FIG. 5. CSF cytology (Papanicolaou stain of ThinPrep, 600x) demonstrating abundant cryptococcus. Liebman et al: J Neuro-Ophthalmol 2022; 42: 272-277 is required to distinguish OPN from other potential causes of perioptic nerve thickening and enhancement. Dr. Lithgow: OPN is characterized by an inflammatory response primarily involving the optic nerve sheath. Although a biopsy is not typically necessary or sought for diagnostic confirmation, prior case series have demonstrated fibrosis and marked thickening of the optic nerve sheath with varying degrees of lymphocytic infiltration (6,8). The presence of necrobiotic granulomas and vasculitic changes have been reported (9). In their initial report, Edmunds and Lawford described 2 forms: an “exudative” form (a localized nonsuppurative pachymeningitis) and a “purulent” form (leptomeningitis extending to involve the perineural subarachnoid space) (4). Although this classification is no longer used, it merits emphasis that the optic nerve sheath is an extension of the meninges, and thus OPN should be considered a subcategory of meningitis. Drs. Liebman, Tam, Kane, Lefebvre, Chwalisz, Gaier: OPN most commonly arises as an isolated/idiopathic syndrome. Unlike optic neuritis, OPN does not confer an increased risk of current or future demyelinating disease (4,8). OPN has however been documented as a secondary manifestation of a range of infectious and inflammatory etiologies, including ANCA vasculitides (10), sarcoidosis (11), syphilis (12,13), Crohn Disease (14), Behcet Disease (15), IgG4-related disease (16,17), antimyelin oligodendrocyte glycoprotein (MOG)-related disease (18), and tuberculosis (19,20). As a harbinger condition, OPN has been reported as the presenting feature of giant cell arteritis (21), and, relevant to this case, it has also been rarely documented as an initial central nervous system manifestation of both acute (22) and chronic lymphocytic leukemia (23). Thus, a new diagnosis of OPN necessitates consideration of a broad differential and execution of a comprehensive diagnostic workup. 275 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 6. Progression of Humphrey Visual Field 24-2 testing at initial presentation, 1 month follow-up, and 1 year followup. It must be emphasized that OPN is not itself a primary neuropathy, but rather a focal inflammation of the optic nerve sheath that intersects with both meningeal processes and other forms of orbital inflammatory disease such as periscleritis, orbital myositis, dacryoadenitis, and nonspecific orbital inflammation. This may account for the fact that primary/idiopathic OPN is highly responsive to corticosteroid therapy. Furthermore, idiopathic OPN typically tends not to self-resolve without corticosteroid therapy, whereas demyelinating optic neuritis typically does. Given that corticosteroids are the first line of treatment for idiopathic OPN, it is imperative that infectious etiologies be considered, especially in immunesuppressed patients. Our patient’s case also illustrates that OPN can present with an inflammatory clinical picture sufficient to masquerade as orbital cellulitis. Lack of sinus pathology on CT or history of antecedent maxillofacial surgery quickly prompted consideration of alternative diagnoses, although the need for dedicated neuroimaging and confirmation of OPN only emerged after the subsequent development of 276 visual dysfunction. It has been speculated that the mechanism for optic nerve dysfunction in OPN may be ischemic because of compression of arterioles that penetrate the inflamed nerve sheath (8,24); the time course of this patient’s sequential ophthalmic manifestations is consistent with this hypothesis. Up to 50% of cryptococcal meningitis patients suffer from a degree of vision loss, although most frequently because of papilledema or infiltrative/inflammatory optic neuropathy (25). The surprising subsequent discovery in this case of underlying cryptococcal meningitis highlights the importance of maintaining a broad differential and workup for OPN, even when a causative etiology may seemingly be evident at the onset (e.g., CLL). Neuroophthalmologists are frequently presented with diagnostic dilemmas that require consideration of infectious, inflammatory, and infiltrative etiologies; another important facet of this case is that it demonstrates that these categories of disease are not mutually exclusive. Complex interactions can exist among malignant hematologic milieu, infectious triggers, and inflammatory responses (26). It is possible that this patient’s unusual presentation regarding his OPN and his cryptococcal meningitis reflects both the suppressive and deranging effects CLL can exert on the natural immune system, and a possible predisposition to atypical fungal infection because of immune compromise and his preexisting diabetes mellitus. Our patient was initiated on intravenous amphotericin and flucytosine. Shortly thereafter, he required a four-day critical care admission after developing new fever, shortness of breath, and altered mental status attributed to immune reconstitution inflammatory syndrome. Visual and orbital symptoms gradually improved, and he was ultimately discharged on oral fluconazole. His neuro-oncology team determined that a transformation had not occurred, and that he did not warrant additional treatment for CLL beyond that which was targeted at his infection. The presence of monoclonal cells in the CSF and orbital tissue was thus felt to most likely represent circulatory leakage as opposed to leptomeningeal spread of his cancer. At 1 month follow-up, his symptoms of headache and orbital pain had abated, and his visual acuity was 20/30 in the left eye without an rAPD or disc edema with marked improvement in automatic perimetric responses (Fig. 6). At 1 year followup, his visual acuity was 20/20 in both eyes, with stable automated perimetric performance. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. L. Liebman, D. R. Lefebvre, B. K. Chwalisz, and E. D. Gaier; b. Acquisition of data: D. L. Liebman, E. K. Tam, M. Y. Lithgow, J. E. Kane, and D. R. Lefebvre; c. Analysis and interpretation of data: D. L. Liebman, E. K. Tam, M. Y. Lithgow, J. E. Kane, N. J. Fischbein, D. R. Lefebvre, B. K. Chwalisz, and E. D. Gaier. Category 2: a. Drafting the manuscript: D. L. Liebman; b. Revising it for intellectual content: D. L. Liebman, E. K. Tam, M. Y. Lithgow, J. E. Kane, N. J. Fischbein, D. R. Lefebvre, B. K. Chwalisz, Liebman et al: J Neuro-Ophthalmol 2022; 42: 272-277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study and E. D. Gaier. Category 3: a. Final approval of the completed manuscript: D. L. Liebman, E. K. Tam, M. Y. 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