Visual Loss in Early-Stage Chronic Lymphocytic Leukemia

  1. Mrinal M. Patnaik
  1. Mayo Clinic, Rochester, MN
  1. Corresponding author: Mrinal M. Patnaik, MBBS, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: patnaik.mrinal{at}mayo.edu.

Introduction

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma is the most common lymphoproliferative disorder in North America.1 Although infiltration of the skin, lung, pleura, kidney, and GI tract by CLL cells is well described,2 involvement of the optic nerve is rare. We report a case of progressive visual loss that was caused by optic neuritis in a previously untreated patient with early-stage CLL, in whom a complete resolution of visual defects was achieved with chemoimmunotherapy using fludarabine and rituximab (FR).

Case Report

A 75-year-old man had lymphocytosis that was detected incidentally on a preoperative CBC that showed a normal hemoglobin level and platelet count. The total WBC was 11.9 × 109/L with an absolute B-cell lymphocyte count of 5.67 × 109/L. Peripheral blood flow cytometry showed a kappa light chain restricted B-cell clone (CD5+, CD23+, CD19+, and CD20 [dim]) that was ZAP-70+ and CD38+. Immunoglobulin variable region heavy chain gene (IgVH) sequencing did not detect a functional gene. The bone marrow biopsy was hypercellular (40%) with a nodular interstitial infiltrate of CLL cells (30% to 40%). Both conventional cytogenetics and interphase fluorescent in situ hybridization showed trisomy 12 (intermediate risk). There was no palpable lymphadenopathy or hepatosplenomegaly (clinical stage Rai 0), and the patient was observed. Approximately 1 year after diagnosis, the patient developed right eye pain associated with blurry vision, floaters, and bright halos. Funduscopic examination showed bilateral disc edema that was worse on the right. Magnetic resonance imaging (MRI) of his orbits was reported as normal. CSF analysis revealed lymphocytosis, but this was not characterized further by flow cytometry. The patient was treated empirically for a clinical diagnosis of optic neuritis with prednisone at a dose of 1 mg/kg for 14 days. He experienced marked improvement in his vision within a week of initiating the prednisone.

He was evaluated in the Mayo Hematology Clinic shortly after this event. His WBC had increased to 48.7 × 109/L with an absolute lymphocyte count of 34.9 × 109/L. Repeat CSF analysis demonstrated 29 total nucleated cells per μL, with 96% lymphocytes. The CSF glucose and protein levels were normal. Flow cytometry showed that 50% of the lymphocytes were clonal (kappa light chain restricted) with an immunophenotype that was compatible with CLL. No oligoclonal bands were seen in the CSF, and the CSF immunoglobulin G index was 0.6 (normal, < 0.85), thus lowering the probability of multiple sclerosis. Funduscopic examination showed persistent right eye disc edema, blurring, and peripapillary hemorrhages (Fig 1A). Because his visual defect had nearly completely resolved, he began a corticosteroid dose taper that was associated with recurrent visual symptoms. Examination showed marked visual field loss in the right eye, with progressive chronic changes of papilledema and disc blurriness that were suggestive of either perioptic nerve infiltration or chronic papilledema (Fig 1B). CSF analysis demonstrated 20 total nucleated cells per μL, with 87% lymphocytes (35% clonal). Serum and CSF testing were negative for Cryptococcus, toxoplasmosis, herpes zoster, John Cunningham virus, human herpesvirus 6, herpes simplex, Epstein-Barr virus, and cytomegalovirus infections. Serum angiotensin-converting enzyme was not elevated. MRI T1-weighted images showed abnormal enhancement of the right optic nerve (Fig 2A, red circle). A diagnosis of optic nerve infiltration by CLL was made by exclusion, and the patient was treated with two cycles of FR (fludarabine, 20 mg/m2 per day on days 2, 3, and 4; and rituximab, 375 mg/m2 on day 1).3 His visual symptoms progressively improved and had fully resolved by the end of the second cycle of treatment. Examination of the fundi showed a marked decrease in the optic disc edema in both eyes (Fig 1C), and the resolution of optic neuritis was confirmed by an MRI of his orbits (Fig 2B, red circle).

Discussion

Optic nerve infiltration by CLL cells that causes neuritis and visual impairment is a rare but devastating condition that can lead to permanent blindness if left untreated. Unfortunately, identifying this condition in the clinical setting before there is permanent loss of vision is challenging because the radiographic manifestations on MRI or computed tomography are not specific,4 and the definitive diagnosis of CLL nerve infiltration requires a nerve biopsy.5 Because a biopsy of the optic nerve is quite destructive, the ante-mortem diagnosis of CLL optic neuritis is one of exclusion. There is an extensive differential diagnosis for optic neuritis in patients with CLL. The more common considerations are inflammatory disorders such as sarcoidosis6 and opportunistic infections by fungi (eg, Cryptococcus), parasites (eg, toxoplasmosis), viruses (eg, herpes zoster, herpes simplex, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, John Cunningham virus) and bacteria. Optic neuritis may also be an initial presentation in approximately 20% of patients with multiple sclerosis and is often associated with the detection of an oligoclonal band in the CSF.7 An additional consideration is infiltration of the optic nerve by diffuse large B-cell lymphoma (Richter's transformation).8 These alternative etiologies were excluded to the best of our ability in the evaluation of this patient.

CSF analysis by flow cytometry is a sensitive method of detecting clonal B-cell populations in patients with neurologic symptoms. However, the presence of a monoclonal B-cell clone population with normal lymphocyte morphology in the CSF of patients with CLL is not diagnostic of clinically significant involvement of the CNS by CLL. In patients with CLL, clonal lymphocytes can enter sites of CNS inflammation as part of a reactive process and are not necessarily involved in the primary CNS pathology.9,10 In addition, oligoclonal B-cell expansion with a dominant clone can be caused by CNS inflammation.11 Consequently, it is difficult to determine if a monoclonal B-cell clone population in the CSF is causing neurologic pathology, and management decisions have to be based on a comprehensive assessment of all available data.

In this patient, a therapeutic trial was performed because there was no alternative explanation for the patient's progressive visual deficit. Effective treatments for CLL optic neuritis include orbital or whole-brain radiation, intrathecal therapy with methotrexate, and systemic chemotherapy with chlorambucil and fludarabine.4,12,13 Fludarabine, a purine nucleoside analog, is capable of penetrating the CNS to treat CLL infiltration,14 and FR has been reported to be effective in the treatment of peripheral mononeuropathies caused by CLL.5 This patient case demonstrates the efficacy of FR in the management of CLL optic neuritis. In this scenario, systemic chemoimmunotherapy has an advantage over other described treatment modalities because it is less invasive and has the ability to treat CLL disease that is present at other sites. Furthermore, treatment with FR improves the complete response rates in CLL compared with previous chemotherapy regimens that used chlorambucil or fludarabine alone.15,16 However, this combination is immunosuppressive, increasing the patient's risk for opportunistic infections.17 Finally, although this patient had symptomatic relief with systemic corticosteroids, these drugs should not be used long-term because of adverse effects such as hypertension, hyperglycemia, osteoporosis, myopathy, cataracts, and glaucoma. Corticosteroids also have a demarginating effect in blood, giving rise to leukocytosis and neutrophilia, a factor that has to be taken into account when interpreting blood tests in these patients. Randomized clinical trials to determine optimal therapy of CLL optic neuritis are unlikely because of the rarity of this complication. Nevertheless, our experience suggests that established fludarabine-based chemoimmunotherapy regimens are an additional therapeutic modality for this condition.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Clive S. Zent, Genentech Expert Testimony: None Other Remuneration: None

REFERENCES

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  1. JCO vol. 31 no. 17 e280-e282

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