Optic nerve infiltration in systemic non Hodgkin lymphoma

ABSTRACT Optic nerve infiltration secondary to systemic non-Hodgkin lymphoma (NHL) is a rare phenomenon. We present a 55-year-old man with low-grade systemic NHL who initially presented with an isolated optic neuropathy and non-specific neurological symptoms. We further present a literature review of systemic NHL with radiological evidence of optic nerve infiltration. On magnetic resonance imaging, the characteristic features include optic nerve enhancement and enlargement, while leptomeningeal enhancement is uncommon. Cerebrospinal fluid analysis and optic nerve sheath biopsy can return false negative results, and when such investigations are inconclusive, biopsy of the optic nerve substance has a high diagnostic yield. Although rare, lymphomatous optic nerve infiltration must be considered in the differential diagnosis of a pale swollen optic disc.

Lymphomatous infiltration of the optic nerve can occur with primary central nervous system (CNS), systemic or intraocular lymphoma, or the disease may arise within and remain localised to the optic nerve itself. 1 The optic nerve is an uncommon site of lymphoma, and reports are limited. [1][2][3][4][5][6][7][8][9][10][11][12][13] Diagnosis is often challenging, due to the overlap of clinical and radiological features with those of other neoplastic and inflammatory diseases. 1, 14 We report a case of low-grade systemic non-Hodkgins lymphoma (NHL) with associated infiltration of the optic nerve, presenting with diffuse neurological deficits and progressive vision loss in an otherwise healthy individual. This study adhered to the tenets of the Declaration of Helsinki.

Case presentation
A 55-year-old male presented to the ophthalmology clinic for fundal examination following an episode of unexplained seizures, confusion, and hallucinations. He reported a 14-month history of headaches, frequent hemiplegic migraines, progressive right-sided hearing loss and paresthesia of the legs. His previous medical history was significant only for hypertension, and his past ocular history included left amblyopia, Ophthalmic examination revealed evidence of bilateral optic neuropathy, with a visual acuity of 20/30 OD and 20/60 OS. The left eye showed a relative afferent pupillary defect, impaired colour vision, brightness desaturation to 70%, and superonasal field loss. There was bilateral disc swelling, more pronounced on the left. There was no evidence of anterior or posterior segment inflammation. Magnetic resonance imaging (MRI) revealed dilated optic nerve sheaths bilaterally without evidence of orbital lesions ( Figure 1A,B). A lumbar puncture revealed increased opening pressure of 43 cmH 2 O, and cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis and elevated protein. The patient was diagnosed and treated for unspecified viral meningoencephalitis. His examination was stable at 4 months follow-up.
One year later, he developed sudden vision loss in the left eye to 6/60. Examination revealed 5 mm of left-sided proptosis, limitation of left supraduction and a pale swollen ipsilateral optic disc. Repeat MRI revealed enlargement of the left optic nerve sheath, extending from the globe to within 5 mm of the optic chiasm ( Figure 1C,D). Diffusion-weighted imaging showed restricted diffusion and corresponding low apparent diffusion coefficient (ADC) signal within the left optic nerve. A wide differential of infiltrative, inflammatory, and infective causes was considered. Serology for angiotensin converting enzyme, antineutrophil cytoplasmic antibody, antinuclear antibody, varicella zoster virus immunoglobulin M, quantiferon gold, and syphilis were all negative. A left optic nerve sheath decompression was performed and a biopsy of the sheath revealed only benign fibrous tissue, with no features suggestive of meningioma or malignancy Flow cytometry analysis was inconclusive. Given there was no confirmed diagnosis, no treatment was given. Post-operatively, his left vision improved to 6/12 with subjective light brightness of 90% and normal motility. At 4 months follow-up, the left vision further improved to 6/9 and though there was no disc swelling, there was residual pallor.
Five years later, he presented with a three-month history of progressive reduction of left eye vision to hand movements. He was also experiencing frequent night sweats, weight loss, anemia, and gait abnormality. MRI of the brain showed recurrent left optic nerve sheath swelling, enhancement of the leptomeninges ( Figure 1E), and left orbital fat, while spinal MRI revealed thickening of the lumbosacral nerve roots.
Given his worsening left optic neuropathy, a left orbital biopsy was performed via a lateral orbitotomy. Intraoperatively, the orbital fat had a firm rubbery consistency with a pink amorphous appearance. Histopathology revealed a lymphomatous infiltrate comprising monoclonal, kappa-restricted small B-cells, with immunostaining confirming strong expression of CD20 and Bcl-2. A subsequent positron emission tomography scan and bone marrow biopsies revealed extensive lymphadenopathy and bone marrow involvement. On account of these findings, he was diagnosed with systemic marginal zone B-cell lymphoma with optic nerve infiltration. Orbital radiotherapy was commenced alongside an immunochemotherapy regimen comprising rituximab, cyclophosphami de, vincristine, prednisolone, and intrathecal methotrexate. His disease remained under control, however, there was no recovery of vision in the left eye.

Discussion
Systemic NHL arising in the CNS is relatively scarce, constituting approximately 10% of cases, of which only 5% develop optic nerve involvement. [15][16][17] Kim et al. proposed a revised classification system for optic nerve lymphoma comprising four distinct categories; 1) isolated/primary optic nerve involvement; 2) optic nerve involvement with CNS lymphoma; 3) optic nerve involvement with systemic lymphoma; and 4) optic nerve involvement with primary intraocular lymphoma. 18 Systemic lymphoma with optic nerve metastasis, as seen in our case, is rare. 18 Within the subgroups of NHL, marginal zone B cell CNS lymphoma is typically indolent in nature, presenting with gradually progressive neurological symptoms and focal seizures, in contrast to the aggressive clinical course and high mortality of diffuse large B-cell disease. 19,20 A literature search was performed to identify case reports of systemic NHL with optic nerve infiltration. All articles containing the terms optic and lymphoma were reviewed. Inclusion criteria were: 1) diagnosed systemic lymphoma and 2) radiological evidence of intraorbital and/or intraocular optic nerve. Patients with intraocular or primary CNS lymphoma without systemic involvement were excluded. Myers et al. summarized 30 cases of optic nerve infiltration from lymphoma, but the authors did not distinguish between isolated, primary CNS, and systemic disease. 21 This review identified fourteen separate cases of systemic NHL with optic nerve infiltration, the clinical and radiological features of which are summarized in Table S1. 1,15,17,[22][23][24][25][26][27][28][29][30][31][32] All patients presented with symptomatic vision loss, of which six had vision <20/200 and eleven had optic disc swelling. Most cases were characterized radiologically by enlargement and significant enhancement of both the optic nerve and sheath. 1 It is worth noting, however, that the enlargement of the optic nerve or its sheath is a non-specific finding and may occur with non-malignant conditions such as optic neuritis, Graves' ophthalmopathy, or intracranial hypertension. 33 The radiological features of ocular adnexal lymphoma are variable, and thus the disease is often challenging to differentiate from inflammatory or other neoplastic processes. 5,34 Furthermore, initial investigations frequently appear normal and require repeat examination in order to detect the disease. 1 On MRI, the characteristic appearance of lymphoma typically includes one or more mass lesions that are isointense on T1, isointense to slightly hyperintense on T2, with homogenous enhancement following contrast. 5 Lymphomatous lesions also characteristically reveal restricted diffusion, appearing with low signal on an ADC map, reflecting increased cellularity. 34 Sudhakar et al. reported a case of B cell lymphomatous optic nerve infiltration, with high DWI signal and a corresponding region of hypointensity on the ADC map. 28 Although an accurate diagnosis was not reached until an orbital fat biopsy was performed several years after presentation, there were earlier radiological signs such as low ADC signal that were, in retrospect, consistent with optic nerve lymphoma.
The delay to diagnosis in our case was possibly confounded by the equivocal results on CSF analysis and optic nerve sheath biopsy. In hindsight, the initial diagnosis of unspecified viral meningoencephalitis may have been erroneous, as the CSF findings were more in keeping with lymphomatous meningitis, despite the absence of atypical cells. In our review of the literature, five out of nine patients who had a lumbar puncture recorded no abnormal cells, and the only two patients who had an optic nerve biopsy had a diagnostic result only on sampling of the optic nerve substance (Table  S1). Yang et al. found 5 out of 10 patients had elevated CSF protein and IgG levels, while only 1 patient had histological detection of tumor cells. 1 Wirth et al. reported one patient with abnormal peripheral blood count suggestive of lymphocytosis, but this did not correlate with CSF analysis, which had no malignant features. 15 While this may be influenced by an insufficient CSF sample, conventional cytology has a low sensitivity and 20-60% false negative rate. 16 Definitive diagnosis usually requires surgical biopsy of the optic nerve substance; a procedure which itself carries a significant risk of permanent vision loss. 1,5,26 Kitzmann et al. reported a case of peripheral T cell NHL with bilateral optic nerve enhancement and a negative sheath biopsy; a repeat biopsy of the intraorbital segment of the optic nerve showed diffuse lymphocytic infiltration. 26 Mavrikakis et al. and Dayan et al. both reported a positive diagnostic result only from the optic nerve substance with no malignant cells found from the sheath tissue. 23,25 In summary, this case presented a diagnostic dilemma due to an initial presentation of isolated optic nerve sheath dilatation in the absence of malignant cells on lumbar puncture, and insidious leptomeningeal involvement occurring seven years later. 2,11 Systemic NHL may arise within or infiltrate the optic nerve and is a rare but sinister cause of unexplained, progressive vision loss and optic neuropathy. Particularly when there is isolated optic nerve involvement initially, the disease frequently evades radiological and CSF investigations. If there is high clinical suspicion for lymphomatous involvement of the optic nerve and other investigations are nonrevealing, biopsy of the optic nerve substance should be considered. As imaging alone is insufficient to distinguish optic nerve lymphoma from other tumors of the visual pathway, careful clinical correlation and thorough consideration of alternative diagnoses remain essential in patients with optic nerve lesions.

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Funding
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