Leukemic and Lymphomatous Optic Neuropathy: A Case Series

Optic neuropathy in the context of leukemia and lymphoma raises concern for central nervous system involvement or relapse and warrants prompt evaluation and treatment. To date, a gold standard for the diagnosis and management of leukemic optic neuropathy has yet to be established.

Trainees’ Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD Leukemic and Lymphomatous Optic Neuropathy: A Case Series Victoria Lee, PhD, Asim V. Farooq, MD, Hassan A. Shah, MD Background: Optic neuropathy in the context of leukemia and lymphoma raises concern for central nervous system involvement or relapse and warrants prompt evaluation and treatment. To date, a gold standard for the diagnosis and management of leukemic optic neuropathy has yet to be established. Methods: Case series and review of the literature. Two illustrative cases were selected to discuss their treatment course and outcome. Results: We report 7 cases of patients with leukemia or lymphoma presenting with optic nerve infiltration. All patients received steroid therapy for presumed infiltrative optic neuropathy, and 4 patients underwent radiation therapy. Along with systemic chemotherapy, all patients received intrathecal chemotherapy except one. Three patients received chimeric antigen receptor T-cell therapy. Conclusions: Leukemic and lymphomatous optic neuropathy is difficult to diagnose and treat, and there is no gold standard for diagnosis or treatment in the current literature. We help clarify how this disease should be approached in a multidisciplinary fashion and on an individual basis to correctly diagnose and treat the vision loss, while considering the patient’s long-term prognosis based on their systemic disease. Journal of Neuro-Ophthalmology 2021;41:e796–e802 doi: 10.1097/WNO.0000000000001365 © 2021 by North American Neuro-Ophthalmology Society O ptic neuropathy in the context of leukemia and lymphoma can be attributed to infectious, inflammatory, infiltrative, ischemic, or toxic-metabolic etioloPritzker School of Medicine (VL), University of Chicago, Chicago, Illinois; and Department of Ophthalmology and Visual Science (AVF, HAS), University of Chicago, Chicago, Illinois. Internal funding support. The authors report no conflicts of interest. This study was approved by the Institutional Review Board of the University of Chicago. Address correspondence to Hassan A. Shah, MD, University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2114 Chicago, IL 60637; E-mail: [e-mail] e796 gies (1). Because the optic nerve is a direct extension of the central nervous system (CNS), the finding of optic nerve dysfunction in patients with leukemia or lymphoma raises concern for CNS involvement or relapse, thus warranting prompt evaluation and treatment (2–8). Even in the setting of prompt management, leukemic optic neuropathy carries a poor visual prognosis and many patients ultimately progress to optic atrophy and death (9). There is no consensus on how to definitively diagnose leukemic or lymphomatous optic neuropathy because there may or may not be positive findings on MRI (17), and obtaining an optic nerve biopsy is difficult and may cause harm. Treatment is often started in the setting of decreased vision, optic nerve swelling, and the finding of malignant cells on lumbar puncture (19,20). Furthermore, there is no established protocol for the timing or modality of treatment. Infiltrative optic neuropathy is often treated with intrathecal (IT) chemotherapy, steroids, and/or radiation (19,25–27). It is also not clear whether earlier treatment changes the visual prognosis or whether there is a role for prophylactic treatment for the optic nerves in the setting of CNS disease. Because it is difficult to perform large studies on a condition that is a rare presentation of leukemia or lymphoma (1,9,16), it is important to study the details of individual cases so that ophthalmologists and other physicians involved in the care of these patients can make the best decisions possible. We report 7 cases of patients with leukemia or lymphoma presenting with optic nerve infiltration and present 2 illustrative cases. RESULTS Of 7 patients with presumed infiltrative optic neuropathy, 4 patients had acute lymphoblastic leukemia, 1 patient had diffuse large B-cell lymphoma, 1patient had T-lymphoblastic lymphoma, and 1 patient had mycosis Lee et al: J Neuro-Ophthalmol 2021; 41: e796-e802 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner fungoides complicated by large-cell transformation. Three patients had abnormal optic nerve findings on MRI, and 4 patients had blasts in the cerebrospinal fluid (CSF). No patients underwent an optic nerve biopsy. With the exception of 1 case, all patients received IT injections of chemotherapeutic agents and 3 patients received chimeric antigen receptor T-Cell (CAR T-cell) therapy. All patients received steroids for presumed infiltrative optic neuropathy, and 4 patients underwent radiation therapy (RT) of the brain or orbit. Patients had either 0 or 1 CNS relapse before optic nerve involvement. Using the logarithm of the minimum angle of resolution chart, the mean visual acuity was 1.481 in eyes with optic neuropathy at onset and the final mean visual acuity was 1.652 after treatment. Five of 7 patients were deceased within 3 years of developing optic neuropathy. Further details are provided in Table 1. CASE REPORTS Case 1 A 13-year-old adolescent boy reported blurry vision in both eyes, more pronounced on the right. He had a history of pre–B-cell acute lymphoblastic leukemia. Three months previously, he developed CNS relapse and was started on reinduction chemotherapy with vincristine, dexamethasone, daunorubicin, and triple IT chemotherapy (methotrexate, hydrocortisone, and cytarabine). He was without evidence of residual disease until 4 days before his visual symptoms, when he developed a second CNS relapse and was restarted on triple IT chemotherapy. On examination, his visual acuity was 20/125 in the right eye and 20/50 in the left eye. Color vision was absent in the right eye and normal in the left eye. He had a right relative afferent pupillary defect (RAPD) and full visual fields bilaterally. His optic nerves were completely obscured by large areas of gliosis and hemorrhages bilaterally, which were suspicious for leukemic infiltration. MRI of the orbits and brain demonstrated bilateral thickening and enhancement of the optic nerve heads, with subtle enhancement of the intraorbital optic nerves. Lumbar puncture revealed 7 pleomorphic white blood cells but was negative for blasts. His visual function remained stable until 6 weeks later, when he reported acute vision decline in his right eye. The visual acuity examination at that time showed only light perception in the right eye and 20/50 in the left eye. There was a right RAPD and now diminished color vision as well as visual field loss in the left eye. The patient received intravenous (IV) dexamethasone and 3day orbital RT, followed by IV vincristine, oral (PO) 6mercaptopurine, and a dexamethasone taper. He received CD19-targeting CAR T-cell therapy (Kymriah; Novartis, Basel, Switzerland) 1 month later. Lee et al: J Neuro-Ophthalmol 2021; 41: e796-e802 Although there was significant improvement in the patient’s left eye after radiation, he developed complete loss of vision in his right eye 9 days after receiving CAR–T-cell therapy. Visual acuity examination showed no light perception in the right eye and 20/40 in the left eye. There was a right RAPD and an improvement to normal color vision and full visual fields in the left eye. MRI of the brain and orbits showed retinal or vitreous detachments of the right globe, which were presumed to be due to either leukemic infiltrates or inflammatory response by CAR-T cells. Lumbar puncture showed no evidence of blasts. Fundus examination revealed retinal neovascularization with diffuse-organized exudation in the right eye and widespread vasculitis in the left eye. Given the degree of exudation in the right eye, there was high suspicion that this was an inflammatory response driven by the CAR–T-cell destruction of leukemic cells rather than leukemic infiltration alone. At this point, it was concluded that RT would be unlikely to stop—and could worsen—the exudation. Furthermore, although local steroid injection could improve the exudation and decrease subretinal fluid, there was concern that steroids may interfere with the CAR–T-cell response against the malignancy. A decision was made to proceed with the intravitreal injection of bevacizumab to address the retinal neovascularization and alleviate some of the exudation. RT and local and systemic steroids were deferred. One month later, the visual acuity in the right eye improved to hand motion with a right RAPD. The visual acuity in the left eye was 20/40 with full visual fields. Fundus examination revealed resolution of the exudative detachment in the right eye, and the retina was attached. There remained significant exudate. The patient continues to be followed, and his visual acuity has remained relatively stable. Case 6 A 17-year-old adolescent girl presented with right facial palsy along with left eye irritation and blurry vision. She has a history of T-lymphoblastic lymphoma with one prior relapse and was in presumed remission when her visual symptoms developed. On examination, her visual acuity was 20/20 in the right eye and 20/800 in the left eye. Color vision was normal in the right eye and not assessable in the left eye. She had a left RAPD and full visual fields bilaterally. Fundus examination revealed bilateral infiltrative optic neuropathy with flame hemorrhages, more pronounced in the left eye. Lumbar puncture was positive for blasts, consistent with CNS relapse, but MRI of the brain showed no evidence of abnormal enhancement. Despite a normal MRI, the findings on examination and CSF analysis were strongly concerning for tumor infiltration of the optic nerves or discs. The patient was treated with IV and PO dexamethasone, triple IT chemotherapy (methotrexate, hydrocortisone, and cytarabine), IV vincristine, and PO nilotinib. e797 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Case Age/Sex Number Date of of Diagnosis Diagnosis Relapse Date of Relapse VA at Prior Onset OD CNS Date of CNS Date of Eye and OS Relapse Diagnosis Involvement (logMAR) Lee et al: J Neuro-Ophthalmol 2021; 41: e796-e802 1 13/M Pre–B-ALL August 2019 2 November 1 2019 and February 2020 2 10/M Pre–B-ALL May 2010 3 May 2013, 0 May 2015, and August 2016 3 78/M B-ALL December 3 1984 1986, April 0 2016, and December 2017 4 64/F B-ALL March 2017 5 71/M Diffuse largeDecember 2 B-cell 2018 lymphoma 0 — May 2019 and October 2020 1 1 November 2019 March 2020 MRI Findings Treatment Final VA Systemic Treatment of Optic OD and OS CSF Findings at Onset Neuropathy (logMAR) Mortality 20/125 Thickening of Pleomorphic VIC (IV), MTX (IT), DEX (IV), and 20/ optic nerve WBC and ARA-C (IT), HCT orbital 50 heads, mild negative (IT), 6-MP (PO), RT, and (0.796; enhan for blasts and CAR-T (IV) BVZ (IO) 0.398) cement of intraorbital optic nerves bilaterally, and R retinal detachments February February 20/20 Mild T2 Rare blasts VIC (IT), ARA-C (IT), DEX (IV), 2017 2017 and NLP hyperintensity and blinatu MP (IV), (0; and enhan momab (IV) DEX (IV), 3.204) cement and surrounding L orbital optic nerve, T2 RT hyperintensity, and enhancement of posterior R optic nerve Rare blasts MTX (IT) and ARA-C PDN (PO), December December 20/40 Foci of (IT) DEX 2017 2017 and LP enhancement (PO), (0.301; in L optic nerve and 2.903) and no high T2 signal wholebrain RT March 2017 December 20/20 Mildly elevated T2Rare blasts DEX (IV) and CAR-T DEX (IV) 2017 and signal in orbital (IV) 20/20 portion of R (0; 0) optic nerve, without swelling/ enhancement May 2019, November NLP and Enhancing mass Atypical DEX (PO), MTX (IT), DEX (PO) November 2019 20/50 in medial R lymphoid ARA-C (IT), HCT 2019, and (3.204; temporal lobe cells (IT), and CAR-T (IV) October 0.398) and L frontal 2020 lobe, likely involving optic tracts HM and 20/40 (2.602; 0.301) A 20/20 and NLP (0; 3.204) D 20/30 and NLP (0.176; 3.204) D 20/40 and 20/30 (0.301; 0.176) D – A Trainees’ Corner e798 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Reported cases of optic neuropathy Lee et al: J Neuro-Ophthalmol 2021; 41: e796-e802 Case Age/Sex Number of Date of Diagnosis Diagnosis Relapse Date of Relapse VA at Prior Onset OD CNS Date of CNS Date of Eye and OS Relapse Diagnosis Involvement (logMAR) 6 17/F T-lympho February blastic 2015 lymphoma 3 April 2016, 0 December 2016, and June 2017 7 64/M Mycosis 2002 fungoides and largecell transfo rmation 0 — 0 MRI Findings Treatment Final VA Systemic Treatment of Optic OD and OS CSF Findings at Onset Neuropathy (logMAR) Mortality December December 20/20 No specific orbitalBlasts 2016 and 2016 and lesions June 2017 20/800 identified (0; 1.602) July 2016 July 2016 20/20 High T2 signal in Large and CF oblique and atypical 1 ft (0; rectus T cells 2.301) extraocular muscles and diffuse enhancement of oculomotor nerves DEX (IV and PO), VIC DEX (IV 20/50 (IV), HCT (IT), MTX and PO), and (IT), ARA-C (IT), PDA 20/80 and nilotinib (PO) (ED), (0.398; and 0.602) cranio spinal RT DEX (IV), MTX (IT), DEX (IV) 20/20 and HM ARA-C (IT), ARA-C (IV), and ETP (IV) (0; 2.602) D D 6-MP, 6-mercaptopurine; A, alive; ARA-C, cytarabine; BVZ, bevacizumab; CAR-T, chimeric antigen receptor T Kymriah CD19 CAR–T-cell therapy; CF, count fingers; CNS, central nervous system; CSF, cerebrospinal fluid; D, deceased; DEX, dexamethasone; ED, eye drops; ETP, etoposide; F, female; HCT, hydrocortisone; HM, hand motion; IO, intravitreal; IT, intrathecal; IV, intravenous; L, left; left eye, left eye; logMAR, minimum angle of resolution; LP, light perception; M, male; MP, methylprednisolone sodium succinate; MTX, methotrexate; NLP, no light perception; NR, not reported; PDN, prednisone; PDA, prednisolone acetate; PO, oral; R, right; right eye, right eye; RT, radiotherapy; VA, visual acuity; VIC, vincristine; WBC, white blood cell. Trainees’ Corner e799 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Trainees’ Corner Three weeks later, the visual acuity significantly improved to 20/20 with full visual fields in both eyes. There was no RAPD, and color vision was normal in both eyes. Fundus examination revealed no hemorrhages but trace elevation of the optic disc in both eyes. The left optic disc also showed trace pallor. The patient’s visual function remained stable until 6 months later, when she presented with acute onset blurred vision bilaterally. She was noted to have had a second CNS relapse 1 month before her presentation and had received IT cytarabine, IT methotrexate, IV vincristine, and IV nilotinib. The visual acuity was 20/200 in both eyes, and color vision was diminished bilaterally. She had full visual fields bilaterally and no RAPD. Fundus examination showed flame hemorrhages, worsening edema, and slight pallor of the optic disc in both eyes. There was severe arteriolar attenuation, whitening of the retina, and macular edema bilaterally. These findings were suspicious for potential vascular infiltration or compression from optic nerve infiltration and were concerning for impending vascular compromise. Lumbar puncture was positive for blasts, consistent with a second CNS relapse. MRI again showed no orbital masses and no abnormal orbital enhancement, and the optic nerves were of normal caliber and were free of pathological signal. The patient was treated with IV dexamethasone, craniospinal RT, and bilateral prednisolone acetate eye drops. Three weeks later, the visual acuity improved to 20/50 in the right eye and 20/80 in the left eye. Color vision was normal with full visual fields bilaterally and no RAPD in either eyes. Fundus examination showed improved optic disc swelling with pallor and macular edema. There remained retinal vasculitis, hemorrhage, and edema with exudation in both eyes, but these were much improved. The patient did not have another ocular examination before her death. DISCUSSION It is well established that the optic nerve can be the site of CNS relapse in leukemia and lymphoma, despite presumed systemic and medullary remission (5,10–12). Although most optic neuropathy cases occur in the setting of preexisting CNS disease, there are cases in which leukemic optic neuropathy is the first manifestation of CNS involvement (2–4,13–16). Leukemic infiltration into the optic nerve is postulated to occur through the leptomeninges through infiltration of the perivascular spaces within the pial septa of the nerve (15). Furthermore, the posterior pole of the optic nerve is suggested to be a potential “pharmacological sanctuary” for leukemic cells because the blood– brain and blood–ocular barrier may limit the penetration and concentration of chemotherapeutic agents at this site (1,16,17). This can lead to incomplete eradication of leukemic cells and poses a challenge to successful treatment e800 and intervention. It has been proposed that the posterior pole of the optic nerve should be targeted during RT as a “prophylactic” measure to prevent CNS relapse, although this strategy remains theoretical (18). Visual prognosis in leukemic or lymphomatous optic neuropathy is variable, with some patients being able to retain relatively preserved vision after treatment and some losing vision completely. In our study, there was a wide range of visual acuity at the onset of optic neuropathy and after treatment. Although it is hard to draw conclusions about vision, the presence of optic neuropathy carries a poor prognosis and death often occurs within 1–2 years of diagnosis (9). Five of 7 patients in our case series were deceased within 2 years; three patients died within 6 months of the diagnosis of optic neuropathy with CNS relapse. Although reports of optic nerve infiltration in patients with leukemia and lymphoma have increased since its first description in the late 1960s (1,9,16), its low incidence within the general population has limited efforts to study and establish effective methods for diagnosis and management. To date, diagnostic modalities include the ophthalmologic examination, MRI of the brain and orbits, cytology and flow cytometry analyses of the CSF and peripheral blood, as well as bone marrow biopsy. The diagnosis is usually presumed in the setting of decreased vision and optic nerve edema on examination in conjunction with optic nerve enhancement on MRI (19,20). Concurrent CNS relapse is determined by the presence of malignant cells in the CSF, but these may not always be present at the time of onset of optic neuropathy, as in our series (21,22). In addition, MRI findings of optic nerve enhancement may not be present in up to 40% of cases (17), and in our series, only 3 of 7 patients had definitively abnormal optic nerve findings on imaging. A minority of case reports have recommended the use of optic nerve biopsy to establish a diagnosis in patients with inconclusive preliminary testing (6,17,23,24). However, optic nerve biopsy is an invasive procedure that carries a significant risk of further vision loss because it is difficult to get an adequate biopsy from the optic nerve without damaging it further. This should be considered when weighing the risks and benefits of this approach and whether it will change management. In this regard, the role of optic nerve biopsy has remained controversial and is not currently the standard of care. The management of leukemic optic neuropathy requires a multidisciplinary approach. Owing to the limited penetration of chemotherapeutic agents across the blood–brain barrier, IT chemotherapy is often required in the treatment of CNS disease and relapse (19,25,26). In addition, cranial, orbital, or craniospinal RT is typically used in combination with IT chemotherapy (19,25,27). Adjunctive corticosteroids may also be used but considerations should be made regarding the timing of corticosteroids administration relative to MRI acquisition and CSF collection because steroids Lee et al: J Neuro-Ophthalmol 2021; 41: e796-e802 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner may affect the results of various diagnostic techniques (17). Although these approaches have had success in bringing vision back, in many cases, both systemic and optic nerve diseases recur (9). Thus, there is still a need for better therapies to treat CNS relapse and optic neuropathy. The emergence of CAR T-cell therapies as a powerful treatment modality for hematologic malignancies shows promise in this domain yet also adds another layer of complexity (28). Because many existing approaches to the treatment of leukemic optic neuropathy (corticosteroids, RT, and chemotherapy) involve the systemic or local ablation of immune cells, there is debate as to whether one should hold existing therapies to allow the CAR T-cells to induce the destruction of the leukemic cells within the optic nerve (29,30). CAR T-cells have been identified in the CSF of patients with CNS lymphoma who had previously received systemic CAR T-cell infusion, confirming the ability of these cells to cross the blood–brain barrier (31). Consequently, in CAR T-cell recipients, it may be difficult to discern whether optic nerve enhancements seen on MRI studies reflect leukemic infiltrates, CAR T-cell infiltrates, or a combination of the 2. Our series highlights a case of a patient with CNS relapse of pre–B-cell acute lymphoblastic leukemia and on CAR T-cell therapy, for whom RT and steroids were deferred out of concern that they may interfere with the CAR T-cell response against the malignancy. Indeed, the extent of exudation seen on examination was highly suspicious for an inflammatory response driven by the CAR T-cell destruction of leukemic cells rather than leukemic infiltration alone. The patient’s visual function remained stable, despite withholding steroids and RT. The cases highlighted in this series underscore the need for effective coordination between the radiology, oncology, ophthalmology, and radiation oncology teams when managing patients with leukemic optic neuropathy, especially with the advent of new oncologic treatments. This disease is difficult to treat and must be approached on an individual basis and in a multidisciplinary fashion to correctly diagnose and treat the vision loss, while considering the patient’s long-term prognosis based on their systemic disease. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. Lee, A. V. Farooq, and H. A. Shah; b. Acquisition of data: V. Lee, A. V. Farooq, and H. A. Shah; c. Analysis and interpretation of data: V. Lee, A. V. Farooq, and H. A. Shah. Category 2: a. Drafting the manuscript: V. Lee, A. V. Farooq, and H. A. Shah; b. Revising it for intellectual content: V. Lee, A. V. Farooq, and H. A. Shah. Category 3: a. Final approval of the completed manuscript: V. Lee, A. V. 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