Optic Neuropathy Due to Chronic Lymphocytic Leukemia Proven With Optic Nerve Sheath Biopsy

A 64-year-old woman, with a history of diabetes and melanoma, developed a central retinal vein occlusion (CRVO) in her left eye. On exam, she had severe disc edema with retinal nerve fiber layer thickening, and anterior deformation of the peripapillary retinal pigment epithelium (RPE)/Bruch membrane layer (ppRPE/BM) toward the vitreous on spectral domain optical coherence tomography (SD-OCT) suggesting an optic nerve sheath (ONS) meningioma. Magnetic resonance imaging findings and ONS biopsy later confirmed a metastatic melanoma. This case demonstrates that the shape of the RPE/BM on SD-OCT may aid in the decision to consider imaging in patients with isolated CRVO.

Clinical Observation Optic Neuropathy Due to Chronic Lymphocytic Leukemia Proven With Optic Nerve Sheath Biopsy Khurrum Khan, BS, Amina I. Malik, MD, Sumayya J. Almarzouqi, MD, Michael L. Morgan, MD, Sushma Yalamanchili, MD, Patricia Chevez-Barrios, MD, Andrew G. Lee, MD Abstract: Central nervous system involvement from chronic lymphocytic leukemia (CLL) occurs infrequently, and manifestations include cognitive and cerebellar dysfunction and cranial nerve palsies. We report a 45-year-old man with CLL believed to be in clinical remission, who presented with vision loss and bilateral optic disc edema. His optic neuropathy due to CLL was proven by optic nerve sheath biopsy, and he experienced visual recovery after treatment with ibrutinib and intrathecal methotrexate. Journal of Neuro-Ophthalmology 2016;36:61-66 doi: 10.1097/WNO.0000000000000300 © 2015 by North American Neuro-Ophthalmology Society C hronic lymphocytic leukemia (CLL) is the most common leukemia in the United States with approximately 15,000 new cases each year. The average age at the time of diagnosis is 72 years, and 5-year survival varies from 29% to 87% for high-risk and low-risk patients, respectively (1). Peripheral nervous system involvement in CLL has been well described, and multiple reports document CLL involving skin, lung, pleura, kidney, and gastrointestinal tract. However, central nervous system (CNS) involvement in CLL is rare and has been reported in 0.8%-2% of antemortem studies (2). The most common CNS manifestations of CLL include cognitive and cerebellar dysfunction and cranial nerve palsies, most often Baylor College of Medicine (KK, AGL), Houston, Texas; Department of Ophthalmology (AIM, SJA, MLM, SY, PC-B, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medical College, Houston, Texas; Department of Ophthalmology and Visual Sciences (AGL), The University of Texas Medical Branch, Galveston, Texas; The University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; The University of Iowa Hospitals and Clinics (AGL), Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Houston Methodist Hospital, 6560 Fannin Street, Scurlock 450, Houston, TX 77030; E-mail: [e-mail] Khan et al: J Neuro-Ophthalmol 2016; 36: 61-66 affecting the first, fifth, and sixth nerves (3-5). We report an unusual case of optic neuropathy presenting with optic disc edema and vision loss in a patient with CLL believed to be in remission. His optic neuropathy was due to CLL and diagnosed by optic nerve sheath biopsy and successfully treated with ibrutinib and intrathecal methotrexate. CASE REPORT A 45-year-old man presented with a 3 week history of painless visual loss in the right eye. Medical history was significant for medically controlled hypertension and hyperlipidemia. He had CLL, which had been in clinical remission for 2 years. CLL was originally diagnosed based on bone marrow aspirate flow cytometry, which revealed monoclonal B-cell lymphoproliferative disease. Specifically, the findings showed kappa light chain-restricted B-cell population as 51% of total cellularity, with 15% granulocytes, 1% monocytes, 3% natural killer (NK) cells, 15% T cells, ,1% plasma cells, ,1% immature Bcell precursors, ,1% monocytes, 3% NK cells, 16% T cells, ,1% plasma cells, ,1% immature B-cell precursors, and ,1% myeloblasts, and was CD5, CD19, CD20, CD22, and CD23 positive. On examination, visual acuity was 20/25 for right eye, and 20/20 for left eye, with a right relative afferent pupillary defect. Slit lamp biomicroscopy, intraocular pressures, and ocular motility were normal. Automated visual field testing showed mild depression of the right visual field (Fig. 1). Ophthalmoscopy disclosed bilateral optic disc edema, more prominent in the right eye (Fig. 2). Brain magnetic resonance imaging (MRI) showed bilateral optic nerve enlargement with patchy enhancement (Fig. 3A). In addition, there was an enhancing lesion abutting the frontal horn of the right lateral ventricle (Fig. 3B). Initial lumbar puncture (LP) revealed an opening pressure of 11 cm of water. Cerebrospinal fluid (CSF) 61 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Automated visual fields demonstrate mild inferior field loss in the right eye. FIG. 2. Bilateral optic disc edema is present, more marked in the right eye. FIG. 3. Postcontrast fat suppressed T1 axial (A) and coronal (B) magnetic resonance imaging shows enlarged optic nerves with patchy enhancement and an enhancing lesion (arrow) next to the frontal horn of the right lateral ventricle. 62 Khan et al: J Neuro-Ophthalmol 2016; 36: 61-66 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 4. One month after initial presentation, there is increased bilateral optic disc edema. analysis showed 12 white blood cells per microliter (94% lymphocytes) and negative cytology. Complete blood count revealed a hemoglobin of 12.2 g/dL a (normal: 12-16 g/dL) and 3,840 white blood cells per microliter (normal: 450011,000 WBC/mL) with a differential of 34% neutrophils and 60% lymphocytes. The patient returned 1 month later with worsening vision of 20/25 in the left eye and increased bilateral optic disc edema (Fig. 4). Repeat visual field testing showed worsening field loss in the right eye (Fig. 5). Optic nerve sheath biopsy demonstrated a friable nerve sheath with grayish discoloration. Histopathology disclosed a perivascular B-cell lymphocytic infiltrate, with more than 90% of cells staining positive for CD20 (Fig. 6). The patient was started on ibrutinib and underwent intrathecal methotrexate treatment. Repeat CSF analysis at the time of intrathecal methotrexate infusion showed 11 WBC/mL of which 100% were lymphocytes with flow cytometry showing 21% kappa restricted lymphocytes consistent with CLL. At last follow-up examination, 3 months postoperatively, the patient's vision had improved to 20/20 in each eye with reduction in optic disc edema. FIG. 5. Automated visual fields 1 month after initial presentation show progression of right field loss. Khan et al: J Neuro-Ophthalmol 2016; 36: 61-66 63 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 6. Optic nerve sheath biopsy. A. Lymphocytic infiltrate is present in perioptic nerve adipose tissue (H&E, ·20). B. Lymphocytic infiltrate shows irregular nuclear contours with "notching" and angulation of cell membranes consistent with CLL cells (H&E, ·100). C. B-cell immunohistochemistry of lymphocytic infiltrate using CD20 antibody, DAB chromogen, and H counterstain demonstrates membranous staining (·100). D. T-cell immunohistochemistry of the lymphocytic infiltrate using CD3 antibody, DAB chromogen, and H counterstain. Note the single lymphocyte positive for T-cell marker (·100). H&E, hematoxylin & eosin; DAB, 3,3'-Diaminobenzidine. DISCUSSION In a review of the literature, Mozzam et al (2) reported 78 cases of CLL with CNS involvement. The mean survival from onset of CNS symptoms was 12 months, with average overall survival from time of diagnosis of 3.79 years. The average latency period between the diagnosis of CLL and first signs of CNS involvement was 2.6 years. The review 64 also documented that B-cell leukemias accounted for 93.5% of cases, with T-cell leukemias making up 6.5% (5). The most common ocular manifestations of CLL include retinal hemorrhages and leukemic infiltrates in the retina and choroid (6-9). When optic neuropathy has been reported, it is typically associated with a hematological relapse (3-10). Optic disc edema may or may not be present (3). Vision loss is thought to be because of distension of Khan et al: J Neuro-Ophthalmol 2016; 36: 61-66 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Not reported Yes Khan et al: J Neuro-Ophthalmol 2016; 36: 61-66 LE, left eye; RE, right eye. 1 Gonsalves et al (11) CLL Not reported No Neoplastic B cells 6 Moazzam et al (2) Neoplastic B cells 10 No Lymphocytosis 12 Yes Lymphocytosis 11 No Improvement to 20/20 bilaterally Improvement with chlorambucil and intrathecal methotrexate to 20/80 within 5 wk of treatment and 20/30 at 18 mo follow-up Improvement with intrathecal methotrexate Initially steroids; subsequently chlorambucil and intrathecal methotrexate Initially, orbital radiation, steroids, and temozolomide; subsequently intrathecal methotrexate Steroids, fludarabine, and rituximab High dose steroids and radiation High dose steroids and radiation Improvement within days of treatment; RE: 20/30, LE: 20/30 Within 5 wk of treatment RE: 20/30; LE: 20/90; at 9 mo vision 20/125 bilaterally Within 6 mo of treatment RE: 20/25; LE: 20/30 High dose steroids and radiation RE: 20/50; LE: 20/20 RE: 20/200; LE: 20/200 RE: 20/40; LE: 20/60 RE: Count Fingers Yes Lymphocytosis 2 Currie et al (6) Currie et al (6) Currie et al (6) Mowatt et al (3) Treatment Optic Disc Visual Acuity Edema Before Treatment CSF Findings Time Since Diagnosis of CLL, yr Author/ Reference TABLE 1. Reported cases of optic neuropathy due to chronic lymphocytic leukemia Effect on Visual Functions Clinical Observation optic nerve septae by leukemic cells, with axonal compression and impairment of axoplasmic flow (6). A literature review of CLL with optic neuropathy revealed 6 reported cases (Table 1). Currie et al (6) documented 3 patients and all had CSF lymphocytosis at the time of visual symptoms. CLL had been present for 2, 11, and 12 years in these cases, and the optic neuropathy preceded clinical worsening of the disease in all 3 patients. All patients underwent treatment with high-dose steroids and radiation (24-30 Gy), and noted visual improvement, although residual disc edema remained in each case. However, all 3 patients died within months of treatment despite stabilization of visual symptoms. Of the other 3 patients with optic neuropathy associated with CLL, 2 experienced improvement in vision after treatment (3,11) while 1 did not (2). Two patients were alive at follow-up, 1 at 4 years after initial evaluation. The diagnosis of CNS involvement in CLL can be difficult. The literature indicates that imaging studies may play an adjunctive role in making the diagnosis in CNS-associated CLL cases. Radiographic findings described include a diffuse coating of the leptomeninges by thin layer of leukemic cells, as well as plaque-like deposits and intraparencymal infiltration. However, less than 30% of cases have demonstrable neuroimaging findings. CSF analysis is necessary to make the diagnosis, through identification of malignant lymphocytes (12,13). However, CLL cells are not easily distinguished from reactive CSF lymphocytes by morphology alone. Flow cytometry increases detection of malignant cells by differentiating polyclonal reactive B-cell population from monoclonal malignant population. Often a series of LP is needed to definitely make the diagnosis. The sensitivity from initial CSF analysis has been reported to be as low as 50%, (14), and our patient's initial CSF cytology was negative. In our review of the literature, optic nerve sheath biopsy establishing the diagnosis has not been reported. We acknowledge that a single LP for CSF cytology may not be sufficient in the diagnosis of infiltrative neoplastsic disease (e.g., carcinomatous meningitis), and that several LPs may be necessary to establish the correct diagnosis. The medical team caring for our patient chose to proceed with optic nerve sheath biopsy after the initial CSF analysis was nondiagnostic. However, a LP before the second CSF sample obtained immediately before intrathecal methotrexate infusion was positive for leukemic cells. The mechanism for CNS entry in CLL remains uncertain. Proposed hypotheses involve migration of malignant cells across perforating vessels into the subarachnoid space, direct extension from seeded meninges into CSF, or spread through perineural sheaths on cranial and spinal nerves. Leukemic cells are most populous along meninges and peripheral nerve sheath. When optic nerve infiltration occurs, it is thought to be due to extension of these 65 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation leukemic cells along the septae of the nerve with accumulation around blood vessels (2). Timely treatment of cases of CNS involvement with CLL is important. Once the CNS has been invaded, leukemic cells can produce neurologic injury through parenchymal ischemia from blood supply occlusion and competition for oxygen and metabolites. CLL invasion of the CNS also may lead to hydrocephalus. Historically, optic neuropathy in CLL has been treated with optic nerve irradiation and high-dose corticosteroids, intrathecal methotrexate, or a combination of the 2, but the patient we report is novel in the use of ibrutinib. Ibrutinib is a selective inhibitor of the enzyme Bruton tyrosine kinase, which plays a critical role in B-cell maturation and mast cell activation through the high-affinity IgE receptor. Because ibrutinib is a relatively new drug and given the sparse number of cases of ophthalmic involvement in CLL, further study is needed to determine its efficacy in treating patient with CLL and CNS involvement. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee; b. Acquisition of data: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee; c. Analysis and interpretation of data: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee. Category 2: a. Drafting the article: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee; b. Revising it for intellectual content: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee. Category 3: a. Final approval of the completed article: K. Khan, A. I. Malik, S. J. Almarzouqi, M. L. Morgan, S. Yalamanchili, P. C.-Barrios, A. G. Lee. 66 REFERENCES 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30. 2. Moazzam AA, Drappatz J, Kim RY, Kesari S. Chronic lymphocytic leukemia with central nervous system involvement: report of two cases with a comprehensive literature review. J Neurooncol. 2012;106:185-200. 3. Mowatt L, Matthews T, Anderson I. Sustained visual recovery after treatment with intrathecal methotrexate in a case of optic neuropathy caused by chronic lymphocytic leukemia. 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