Episodic Visual Distortions and Stroke-Like Symptoms in a 56-Year-Old Man With Intravascular Lymphoma

A healthy 56-year-old man presented with vision changes and left upper extremity motor and sensory changes. MRI of the brain without contrast was significant for multifocal areas of restricted diffusion in multiple vascular territories. Neuro-Ophthalmic evaluation revealed an inferonasal visual field defect in the left eye, thickened choroid on optical coherence tomography, and bilateral delayed arteriovenous and choroidal filling on fluorescein angiogram. Repeat MRI demonstrated interval enlargement of many of the same foci of abnormal diffusion-weighted imaging signal. Computed tomography of the abdomen and pelvis revealed 3 distinct lobulated retroperitoneal masses that were biopsied and found to be consistent with diffuse large B-cell lymphoma. Brain biopsy specimens showed intravascular lymphocytes, confirming a diagnosis of intravascular lymphoma (IVL). In this diagnostically challenging case, a link was established between the presence of multiple strokes (some of which showed slow evolution over time) and retinochoroidal hypoperfusion, which provided a critical clue to the ultimate diagnosis of IVL.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD Episodic Visual Distortions and Stroke-Like Symptoms in a 56-Year-Old Man With Intravascular Lymphoma Bart K. Chwalisz, MD, Vivian P. Douglas, MD, DVM, MBA, Konstantinos A. A. Douglas, MD, DVM, MBA, Maria Martinez-Lage, MD, Hilary R. Kelly, MD, Dean M. Cestari, MD Abstract: A healthy 56-year-old man presented with vision changes and left upper extremity motor and sensory changes. MRI of the brain without contrast was significant for multifocal areas of restricted diffusion in multiple vascular territories. Neuro-Ophthalmic evaluation revealed an inferonasal visual field defect in the left eye, thickened choroid on optical coherence tomography, and bilateral delayed arteriovenous and choroidal filling on fluorescein angiogram. Repeat MRI demonstrated interval enlargement of many of the same foci of abnormal diffusion-weighted imaging signal. Computed tomography of the abdomen and pelvis revealed 3 distinct lobulated retroperitoneal masses that were biopsied and found to be consistent with diffuse large B-cell lymphoma. Brain biopsy specimens showed intravascular lymphocytes, confirming a diagnosis of intravascular lymphoma (IVL). In this diagnostically challenging case, a link was established between the presence of multiple strokes (some of which showed slow evolution over time) and retinochoroidal hypoperfusion, which provided a critical clue to the ultimate diagnosis of IVL. Journal of Neuro-Ophthalmology 2020;40:265-270 doi: 10.1097/WNO.0000000000000900 © 2020 by North American Neuro-Ophthalmology Society Division of Neuro-Ophthalmology (BKC, VPD, KAAD, DMC), Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; and Departments of Neurology (BKC), Pathology (MML), and Radiology (HRK), Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Bart K. Chwalisz, MD, Department of Neurology, Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114; E-mail: [e-mail] Chwalisz et al: J Neuro-Ophthalmol 2020; 40: 265-270 Drs. Chwalisz, Douglas VP, Douglas KAA, Cestari: A 56-year-old man with no significant medical history apart from red-green color blindness presented to the emergency department of an outside hospital with a complaint of vision changes, left facial droop, left-hand incoordination, and sensory changes. Four months before presentation, the patient had a first episode of vision change characterized by not being able to see oncoming traffic for several minutes. He subsequently began experiencing episodes of left-sided visual distortions lasting minutes. He reported looking at people and seeing the right side of their face melting "like the faces of the characters in the Indiana Jones movie." He could not specify whether the changes were occurring in the left eye or the left visual field. Over the subsequent weeks, he continued to experience episodes of visual change. In addition, he had episodes of numbness in the left hand, face, and inside of his left cheek. He also developed a tendency to veer to the left when walking. While on a hiking vacation in another state, the patient had a sudden episode of left-hand incoordination making him unable to turn the faucet. The left side of his face drooped. Upon arrival to the emergency department, most of his symptoms had resolved except the left facial drooping. He denied fever, recent infection, skin lesions, weight loss, or confusion. He did recall a similar episode of left-sided weakness a week earlier, for which he did not seek medical attention. The patient was admitted with suspicion of cerebrovascular accident. Transthoracic echocardiogram (TTE) and inpatient telemetry were unrevealing. The patient was diagnosed with multifocal embolic strokes of unknown etiology. He was discharged on aspirin 81 mg and atorvastatin 10 mg daily. 265 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. MRI of the brain without intravenous contrast at initial presentation. Multiple foci of abnormal hyperintense signal were identified on the diffusion weighted images involving the white matter of both frontal lobes, the left parietal lobe, the splenium of the corpus callosum, the left temporal lobe and the left cerebellar hemisphere. Corresponding hypointense signal consistent with restricted diffusion was seen within a few of the right frontal white matter lesions on the corresponding apparent diffusion coefficient maps (not shown). Dr. Kelly: MRI of the brain without contrast demonstrated multifocal areas of diffusion-weighted imaging (DWI) hyperintense signal involving the white matter of both frontal lobes, the left parietal lobe, the splenium of the corpus callosum, the left temporal lobe, and the left cerebellar hemisphere (Fig. 1). There was restricted diffusion within a few of the right frontal white matter lesions on the corresponding apparent diffusion coefficient (ADC) maps, and all lesions demonstrated corresponding T2 FLAIR hyperintense signal (not shown). No flow-limiting stenoses involving the cervical carotid or vertebral arteries were demonstrated on MRA (not shown). Drs. Chwalisz, Douglas VP, Douglas KAA, Cestari: Given the persistence of symptoms of left upper extremity weakness and paresthesias, the patient presented for reevaluation to the emergency department of our hospital. The patient's examination was notable for deficits in visuospatial function, memory, and attention tasks, with a score of 23/30 on the Montreal Cognitive Assessment. He had mild left lower facial weakness, left pronator drift, and left-sided Hoffmann's sign. His strength was full in all 4 extremities. Sensation was intact, with no extinction to double simultaneous stimulation. The neuro-ophthalmic examination revealed visual acuity of 20/20 in the right eye and 20/25 in the left eye. There was no afferent pupillary defect. On Ishihara color vision testing, the patient identified 2/8 (test plate and 1 additional plate) in the right eye and 1/8 (test plate only) in the left eye, consistent with his known history of red-green color blindness. Extraocular motility and ocular alignment were normal. Humphrey visual fields were reliable in both eyes and showed an inferonasal visual field defect in the left eye (Fig. 2A, B). Anterior segment and dilated fundus examination were normal (Fig. 2C, D). Optical coherence tomography scans showed thickening of the choroid (Fig. 3A, B). Fluorescein angiography showed bilateral delayed arteriovenous and choroidal filling with distal pruned capillary bed, leakage, and window defects more prominent in the left eye (Fig. 4A-F). TTE revealed evidence of a patent foramen ovale. Lower extremity duplex ultrasound was negative for deep vein thrombosis. Lumbar puncture showed pink cerebrospinal fluid (CSF) with slight turbidity, 1 white blood cell, 35% neutrophils, 2% eosinophils, 2,195 (tube 1) to 255 (tube 4) red blood cells, total protein 71 mg/dL (range 5-55), glucose 62, 0 oligoclonal bands, immunoglobulin G 7.8 (upper limit of normal: 4.3), and beta-2-microglobulin 1.98 (range 0.7-1.8). A serum and CSF paraneoplastic panel and CSF IgH rearrangement were negative. Dr. Kelly: A repeat MRI of the brain with and without intravenous contrast demonstrated enlargement of many of the foci of abnormal DWI signal (Fig. 5A, B) compared with those seen on the previous outside MRI. Evolving signal characteristics were also noted, with the largest lesions in the right frontal and left parietal white matter demonstrating geographic regions of FIG. 2. Visual fields and fundus photos. A. Left eye. B. Right eye. C. Right eye. D. Left eye. 266 Chwalisz et al: J Neuro-Ophthalmol 2020; 40: 265-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Optical coherence tomography demonstrating choroidal thickening. A. Right eye. B. Left eye. restricted diffusion peripherally, whereas other lesions demonstrated intrinsic T1 hyperintense signal and enhancement. The pattern was overall suggestive of multiple infarcts of varying age, although the persistent restricted diffusion on ADC maps within the right frontal white matter lesions, the pattern of enhancement, and the white matter predominance were all unusual features for multifocal ischemic infarcts. Computed tomography of the abdomen and pelvis with intravenous contrast revealed 3 distinct lobulated retroperitoneal masses that demonstrated soft tissue attenuation with mass effect on the adjacent right kidney (Fig. 5C). A biopsy of the perinephric mass was performed. staining. In situ hybridization for Epstein-Barr virusencoded RNA (EBER) was negative. A diagnostic brain biopsy was also performed. The sections of right frontal lesion specimens showed cerebral cortex with scattered parenchymal small vessels and capillaries plugged with large atypical lymphoid cells, with occasional mitoses (Fig. 6A-C). Immunohistochemical stains were performed and showed that the tumor cells are positive for CD20 and Pax-5, and show extremely high positivity with Ki-67. CD3 shows scattered perivascular and parenchymal mature T-cells (Fig. 7A-D). Dr. Martinez-Lage: Intravascular lymphoma (IVL) associated with systemic large B-cell lymphoma. The core biopsies of the right perinephric mass consist of a dense proliferation of large neoplastic lymphoid cells with moderate cytoplasm, marked nuclear pleomorphism and irregularity, prominent nucleoli, and vesicular chromatin. There is abundant tumor cell necrosis as well as frequent mitotic figures and abundant apoptotic debris associated with the proliferation. Immunohistochemistry stains showed that the neoplastic cells were CD20+ PAX5+ B cells that coexpress BCL6, MUM1, and BCL2. These cells were negative for CD10, CD21, and CD30. Approximately 60% of the cells stained positive for CMYC. The proliferation fraction was approximately 90% on the basis of Ki-67 Final Diagnosis Drs. Chwalisz, Douglas VP, Douglas KAA, Cestari: IVL is a rare subtype of diffuse extranodal large B-cell lymphoma that involves neoplastic proliferation of mononuclear cells within the lumina of medium- to small-sized vessels. It was first reported by Pfleger L and Tappeiner J. in 1959 as "angio-endotheliomatosis proliferans systematisata" (1). Other historical terms for this condition include "proliferating endotheliosis," "malignant angioendotheliomatosis," and "neoplastic endotheliosis" due to the confinement of neoplastic cells FIG. 4. Fluorescein angiography showing bilateral delayed arteriovenous and choroidal filling with distal pruned capillary bed, leakage, and window defects more prominent in the left eye. A. Left eye 18.654 sec. B. Left eye 22.053 sec. C. Left eye 31.853 sec. D. Left eye 59.063 sec. E. Right eye 3:18.433 min. F. Close-up of distal vessels of right eye at 3:18.433 min. Chwalisz et al: J Neuro-Ophthalmol 2020; 40: 265-270 267 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. A and B. Repeat MRI of the brain without and with intravenous contrast demonstrated increase in size of some of the foci of diffusion-weighted imaging hyperintense signal compared to the initial MRI (Fig. 1), as well as evolution of corresponding signal characteristics on the apparent diffusion coefficient maps and T1-weighted noncontrast and postcontrast images (not shown). C. CT of the abdomen and pelvis with intravenous contrast revealed 3 distinct lobulated soft tissue attenuation retroperitoneal masses. within the intraluminal space without involvement of the adjacent tissues, which led to the notion that the malignant cells are derived from the endothelium (2,3). In 1986, it was classified as "intravascular lymphomatosis," and the term angiotropic (intravascular) large-cell lymphoma was proposed based on the immunohistochemical findings (4,5). The World Health Organization has classified IVL as a "Mature B cell" neoplasm due to morphological and phenotypical similarities to the diffuse large B-cell lymphoma (DLBCL) (6). IVL can be primary, when no other systems are involved, or secondary in the setting of systemic lymphoma. IVL is a rare disease with an estimated incidence of less than one person per million worldwide (7). It has been reported only in adult population with median age of 67 years (34-90 years range) without sex predilection. The disease is characterized by its polymorphic clinical presentation as any organ throughout the body can be affected, making diagnosis challenging. Two variants with partially overlapping clinical features have been described; the classic or "Western" variant with high frequency of central nervous system (CNS) and skin involvement (8) and the "Asian variant" that is characterized by a hemophagocytic syndrome (9). In the "Western"-type IVL, bone marrow and reticuloendothelial system involvement are seen less often, suggesting that genetic predisposition or environmental factors have an impact on the development of the clinical manifestations. B symptoms (fever night sweats and weight loss), cutaneous manifestations, (10) and neurologic disturbances have been also reported in the medical literature with neurologic signs and symptoms correlating with the affected area of the nervous system, secondary to compromised tissue perfusion by the tumor cells. Cognitive impairment in the form of subacute encephalopathy or rapidly progressive dementia are found in more than 60% of these patients while paralysis, seizures, stroke-like symptoms, peripheral neuropathy, and myopathy are among other less common neurologic manifestations of IVL (11-13). Ophthalmic involvement has been reported in only a few case reports and includes cranial nerve disturbances, blurry vision, nystagmus, papilledema, cortical blindness, retinal artery occlusion, retinal pigment epithelial change, retinal and choroidal detachment, iridocyclitis with keratic precipitates, and vitreous cell (14). Most visual symptoms are caused by cortical involvement, with only rare reports of involvement of the anterior visual pathway and uveal tract (15). In rare cases, the presence of intravascular tumor cells in ciliary body, retinal, and choroidal blood vessels has been demonstrated pathologically (14). Of particular, neuro-ophthalmic interest, IVL-related optic neuropathy, although rare, has been previously reported (16,17). Dinkin et al recently published the first welldocumented case of bilateral optic neuropathy as a presentation of underlying IVL (18); their case was also remarkable for spontaneous visual improvement before treatment and ultimately prolonged survival after treatment. Because of the rarity of the disease and lack of sensitive diagnostic methods, early diagnosis of IVL is difficult, with FIG. 6. Right frontal lesion specimens. A. Minimally hypercellular brain parenchyma with abnormal atypical cells within vessels. B. The atypical cells have large nuclei with occasional nucleoli and relatively scant cytoplasm and (C) showing mitotic figure. 268 Chwalisz et al: J Neuro-Ophthalmol 2020; 40: 265-270 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 7. The immunophenotype shows that the neoplastic intravascular cells are CD20+ (B-cells), and many of them are actively proliferating (Ki-67). Perivascular reactive T cells are also present. A. CD20-intravascular neoplastic B-cells. B. CD20-intravascular neoplastic B-cells (higher power). C. Ki-67-proliferating cells. D. CD3-reactive T-cells. more than half of cases diagnosed at autopsy. The laboratory findings in patients with IVL are nonspecific but can suggest the diagnosis. Anemia, thrombocytopenia, leucopenia, increased serum lactate dehydrogenase, increased b2-microglobulin, and erythrocyte sedimentation rate are among the most common laboratory abnormalities (8,19). In addition, altered renal, hepatic, and thyroid function tests have been observed in up to 20% of patients (20). It has been suggested that random skin biopsies of macroscopically uninvolved skin are highly specific for IVL but with unclear sensitivity (21); yield could potentially be increased by biopsying angiomas (22). Blind muscle or meningeal biopsy can also be performed. A combination of various tests, such as biopsies of the skin and/or other organs, bone marrow examination, blood test, and imaging studies can be of value in the diagnostic process (23,24). Dr. Kelly: In general, neuroimaging studies are not considered diagnostic and demonstrate nonspecific findings including white matter lesions that can mimic embolic disease or vasculitis. However, MRI with gadolinium and MRA of the head and neck should always be performed on any patient with suspicion of IVL not only to rule out other neurologic diseases but also as part of the staging workup (20). Dr. Martinez-Lage: Small- and medium-sized vessels are more likely to be infiltrated by neoplastic cells (25). Immunophenotypically, the IVL tumor cells express mature B-cell-associated antigens with only rare cases of CD202expression and T and Chwalisz et al: J Neuro-Ophthalmol 2020; 40: 265-270 natural killer cell immunophenotypes (9,26). There is however great variability in the markers that have been described with CD19+, CD20+, CD22+, CD79a+, and CD5+ being the most common (27). Drs. Chwalisz, Douglas VP, Douglas KAA, Cestari: Therapeutic approaches have varied due to the lack of clinical trials and are largely based on the evidence from reported case series and case reports (28). IVL is always considered disseminated disease, warranting systemic therapy. Rituximab has been associated with improved remission rate, event-free survival, and overall survival in a retrospective analysis of the efficacy in 30 IVL patients with the Western variant (29). Systemic treatment with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) (23) and more aggressive therapies including high-dose methotrexate, intrathecal methotrexate, and radiation have been tried in patients with CNS involvement (30). Autologous stem cell transplantation has demonstrated long-term survival rates especially in younger patients in first complete remission, and it should also be considered as part of the treatment plan in patients with IVL (28,31). IVL has a high mortality rate. Prognosis seems to be related to the extent of the disease with lymphoma limited to the skin carrying a favorable prognosis while CNS involvement is associated with a dismal prognosis, although it has improved since addition of rituximab (7,32). Our patient received intercalated high-dose methotrexate and R-CHOP (rituximab, cyclophosphamide, doxorubicin, and prednisone) chemotherapy that was complicated by 269 Copyright © North American Neuro-Ophthalmology Society. 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