HIV-Associated Rapidly Progressive Lymphoma of the Cavernous Sinus

Trainees’ Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD HIV-Associated Rapidly Progressive Lymphoma of the Cavernous Sinus Alexandra Kvernland, MD, Scott N. Grossman, MD, Valeriya Levitan, MD, Doria Gold, MD, Steven L. Galetta, MD CASE 1 A 49-year-old man with newly diagnosed but wellcontrolled HIV on HAART (CD4+ 254, viral load undetectable) presented to the emergency department (ED) with 3 days of right-sided headache, orbital pressure, and acute-onset horizontal binocular diplopia that was worse at distance. Initial examination revealed only an isolated right eye abduction deficit. Laboratory results were notable for elevated inflammatory markers (ESR 82 and CRP 16) and positive serum oligoclonal bands. MRI brain and orbits revealed a T2 hypointense, mildly enhancing, diffusion-restricting lesion in the right cavernous sinus abutting the internal carotid artery (ICA) (Fig. 1A, B). Computed tomography (CT) chest, abdomen, and pelvis revealed a nonspecific right lower lobe nodule. Lumbar puncture with flow cytometry and cytology was unrevealing. The patient received high-dose intravenous steroids, given concern for an inflammatory process without change of symptoms. On rereview of imaging, there was concern for cavernous sinus thrombosis, so therapeutic anticoagulation was also initiated. He was discharged on anticoagulation alone. Two weeks later in neuro-ophthalmology clinic, he noted a change in his binocular horizontal diplopia—now present in all directions of gaze. Examination showed mild right ptosis, 80% adduction, 70% supraduction, 70% abduction, and 40% infraduction of the right eye, and full ocular ductions of the left eye consistent with a new pupilsparing right CN III palsy. Repeat MRI brain and orbits showed interval enlargement of the right cavernous sinus lesion in addition to new skull-based lesions. Repeat cerebrospinal fluid (CSF) flow cytometry revealed a small population of monotypic large B cells. Repeat imaging studies revealed vertebral and omental metastases. CT-guided L2 vertebral biopsy confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) with CD20-positive, BCL-2, c-myc-negative large B cells. He was treated with highdose intrathecal methotrexate and cytarabine. Department of Neurology, New York University Grossman School of Medicine, New York, New York. The authors report no conflicts of interest. Address correspondence to Alexandra Kvernland, MD, NYU Department of Neurology, 222 East 41st Street, 14th Floor, New York, NY 10017; E-mail: [e-mail] e410 CASE 2 A 35-year-old man with a history of congenital transposition of the great arteries status-post repair and pacemaker placement at age 14 years presented with new-onset horizontal binocular diplopia worse when looking to the right followed by right chin numbness consistent with the mental nerve sign (1). In the ED, he had diminished right eye abduction. On social history, he reported being sexually active with inconsistent condom usage. On admission, he complained of a new right frontal headache. MRI was precluded by his pacemaker, but CT with contrast and CT venogram of the head were unrevealing. His initial laboratory workup included HIV antibodies, which returned reactive on Day 2 of admission; HIV viral load was 750,000, CD4+ 643. CSF was notable for protein of 41, glucose of 48, 5 nucleated cells with lymphocytic predominance, and negative cultures including viral cultures. On Day 4 of admission, he developed near-complete ophthalmoplegia and rapidly progressive ptosis of the right eye as well as decreased sensation to light touch in the right V3 distribution. Computed tomography contrast with thin cuts through the cavernous sinuses showed an enhancing 1.9 · 1.0-cm right cavernous sinus mass (Fig. 2A, B). Computed tomography abdomen/ pelvis showed diffuse thickening and mucosal destruction of the terminal ileum with extensive lymphadenopathy. He underwent ultrasound-guided abdominal lymph node biopsy showing atypical CD10 dim+ B cells most compatible with DLBCL. Over days, he developed complete ophthalmoplegia of the right eye with pupillary asymmetry (right eye 4 mm and sluggishly reactive, left eye 3 to 2 mm and briskly reactive). Steroids were considered but held due to concern for tumor lysis syndrome. Intrathecal methotrexate was recommended by oncology. DISCUSSION The most common cause of cavernous sinus syndrome (CSS) is a tumor, including meningioma, schwannoma, hemangioma, congenital cysts, and metastatic disease (2). Kvernland et al: J Neuro-Ophthalmol 2021; 41: e410-e412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 1. MRI brain with and without contrast. Postcontrast T1 coronal (A) and axial (B) sequences depicting a mildly enhancing soft tissue mass within the right cavernous sinus bulging the lateral wall and partially encasing the right cavernous internal carotid artery. In a series of 151 inpatients presenting with CSS described by Keane, tumors were the most frequent cause (30%), followed by trauma (24%) and self-limiting inflammation (23%). Two-thirds of the tumors described were malignant, including nasopharyngeal carcinoma, metastases, and lymphoma (3). Differential diagnosis also includes Tolosa Hunt. Although isolated ocular motor cranial neuropathies can be caused by microvascular ischemia, a multicenter cohort of 109 patients presenting with isolated CN III, IV, or VI palsies revealed that 16.5% were determined to have a nonvascular etiology (3). Both of our patients initially presented with isolated abduction deficits, which rapidly progressed to involve additional ocular motor nerves. Not infrequently, ocular motility deficits may be the initial manifestation of HIV/AIDS, and are broadly classified into 4 main categories including direct infection by HIV, opportunistic infections, neoplastic processes, and vascular processes (4). In a retrospective analysis of cavernous sinus pathology among patients with HIV with mean CD4+ count of 390 cells/mL, Wells et al demonstrated that tuberculosis was the most common etiology (17%) followed by high-grade B-cell lymphoma (13%), meningioma (13%), metastatic carcinoma (13%), and neurosyphilis (7%) (5). Several case reports have described CSS secondary to lymphomatous infiltration as the initial manifestation of HIV, and can initially present as an isolated cranial nerve palsy, similar to our second patient (5,6). Isolated abducens deficits or oculomotor deficits have also been described (7,8). Investigators suggest that in HIV-positive individuals with isolated cranial neuropathy, a diligent and repeated search for lymphoma should be pursued (8). In both of our cases, serial neuroimaging was important to identify additional bony lesions (Patient 1) and abdominal lymphadenopathy (Patient 2) amenable to percutaneous biopsy. In our first patient, diagnosis was delayed as thrombosis was initially felt to be more likely, given the subtle enhancement. MRI appearance can often aid in diagnosis, for example, meningiomas are isointense to hypointense on T1 and T2 images and show avid, homogenous enhancement with dural tail, whereas hemangiomas are T2 hyperintense with characteristic “fill-in” of contrast on dynamic contrast-enhanced T1 MRI. Alternatively, cavernous sinus thrombosis is often hyperintense on T1 and T2 images with only rim enhancement, and carotidcavernous fistulas often show significant flow voids (9). In our second patient with a history of pacemaker placement that precluded MRI, the clinical examination was key to direct CT imaging to the cavernous sinus. The initial CT scan examination failed to confirm a cavernous sinus lesion because thin sections were not used. We suggest that in immunocompromised patients, imaging of the chest and abdomen/pelvis be performed to assess for additional sites of disease, which can be helpful for definitive (histologic) diagnosis. Cavernous sinus syndrome can be a harbinger of rapidly progressive and fatal conditions despite initial isolated ocular motility deficits. A high index of suspicion is needed to prevent diagnostic delay. Although non-Hodgkin lymphoma typically originates in lymphoid tissues, extranodal disease occurs in 10%–30% (10). Intracranial involvement is rare, especially at initial presentation (10). These cases demonstrate that although rare, non-Hodgkin lymphoma presenting initially as CSS is an important diagnostic FIG. 2. Computed tomography brain with and without contrast. Coronal sequences demonstrating a right cavernous sinus enhancing mass forming a convex border with the lateral wall of the cavernous sinus (A, B). Kvernland et al: J Neuro-Ophthalmol 2021; 41: e410-e412 e411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner consideration, especially in immunocompromised patients such as those with newly diagnosed HIV. Given the diagnostic challenges involved, a high index of suspicion and search for extracranial disease amenable to biopsy are imperative because initial intracranial imaging and CSF studies may be low yield. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta; b. Acquisition of data: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta; c. Analysis and interpretation of data: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta. Category 2: a. Drafting the manuscript: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta; b. Revising it for intellectual content: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta. Category 3: a. Final approval of the completed manuscript: A. Kvernland, S. N. Grossman, V. Levitan, D. Gold, and S. L. Galetta. REFERENCES 1. Carbone M, Della Ferrera F, Carbone L, Gatti G, Carrozzo M. Numb chin syndrome as first symptom of diffuse large B-cell lymphoma. Case Rep Dent. 2014;2014:413162. e412 2. Kuybu O, Dossani D. Cavernous Sinus Syndromes. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing, 2020. 3. Tamhankar MA, Biousse V, Ying G-S, Prasad S, Subramanian PS, Lee MS, Eggenberger E, Moss HE, Pineles S, Bennett J, Osborne B, Volpe NJ, Liu GT, Bruce BB, Newman NJ, Galetta SL, Balcer LJ. 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