Journal of Neuro-Ophthalmology, December 2012, Volume 32, Issue 4

Optic Nerve Biopsy in the Management of Progressive Optic Neuropathy

In cases of progressive optic neuropathy, diagnostic uncertainty often persists despite extensive work-up. Optic nerve biopsy (ONB) can be considered, especially when visual decline of the affected or fellow eye ensues despite empiric therapy. We aimed to evaluate both diagnostic and therapeutic utilities of ONB based on the long-term experience at a tertiary care institution. This was a retrospective chart review of biopsies over 20 years at a single institution involving intrinsic or adherent optic nerve masses. Main outcome measures included the impact of tissue sampling on reaching a diagnosis and on guiding treatment. Secondary measures included vision in the eye of the ONB and the fellow eye. Fifteen patients with a mean age of 51.7 - 17.4 years underwent biopsies. At the time of biopsy, visual acuity was no light perception in 8 (53%) eyes, light perception to counting fingers in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) experienced some degree of sequential vision loss before biopsy. Seven specimens included en bloc biopsy of the nerve, 7 contained the dural sheath (usually with a portion of the optic nerve), and 1 only of the compressive mass. Six patients (40%) had tumors. Six of 8 inflammatory lesions biopsied required further clinical data to arrive at specific diagnoses. In one case, a clinical diagnosis could not be made. No patients experienced further vision loss in the fellow eye at last follow-up (median, 8 months). In diverse circumstances of progressive optic neuropathy, ONB can be beneficial in establishing the diagnosis. ONB can help direct specific local or systemic treatment, particularly when infectious or inflammatory etiologies are identified. ONB, if considered early in the disease course, can potentially halt or prevent vision loss when the fellow eye is threatened.

Optic Nerve Biopsy in the Management of Progressive Optic Neuropathy Marc H. Levin, MD, PhD, Joshua J. Ney, MD, Sriram Venneti, MD, PhD, Mark L. Moster, MD, Laura J. Balcer, MD, Nicholas J. Volpe, MD, Roberta E. Gausas, MD, Grant T. Liu, MD, M. Reza Vagefi, MD, Steven L. Galetta, MD Background: In cases of progressive optic neuropathy, diagnostic uncertainty often persists despite extensive work-up. Optic nerve biopsy (ONB) can be considered, especially when visual decline of the affected or fellow eye ensues despite empiric therapy. We aimed to evaluate both diagnostic and therapeutic utilities of ONB based on the long-term experience at a tertiary care institution. Methods: This was a retrospective chart review of biopsies over 20 years at a single institution involving intrinsic or adherent optic nerve masses. Main outcome measures included the impact of tissue sampling on reaching a diagnosis and on guiding treatment. Secondary measures included vision in the eye of the ONB and the fellow eye. Results: Fifteen patients with a mean age of 51.7 ± 17.4 years underwent biopsies. At the time of biopsy, visual acu-ity was no light perception in 8 (53%) eyes, light perception to counting fingers in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) experienced some degree of sequential vision loss before biopsy. Seven specimens included en bloc biopsy of the nerve, 7 con-tained the dural sheath (usually with a portion of the optic nerve), and 1 only of the compressive mass. Six patients (40%) had tumors. Six of 8 inflammatory lesions biopsied required further clinical data to arrive at specific diagnoses. In one case, a clinical diagnosis could not be made. No patients experienced further vision loss in the fellow eye at last follow-up (median, 8 months). Conclusions: In diverse circumstances of progressive optic neuropathy, ONB can be beneficial in establishing the diagnosis. ONB can help direct specific local or systemic treatment, particularly when infectious or inflammatory etiologies are identified. ONB, if considered early in the disease course, can potentially halt or prevent vision loss when the fellow eye is threatened. Journal of Neuro-Ophthalmology 2012;32:313-320 doi: 10.1097/WNO.0b013e31825be81e © 2012 by North American Neuro-Ophthalmology Society Evaluation of a progressive optic neuropathy can be chal-lenging, at times yielding nonspecific laboratory results and equivocal neuroimaging findings in the setting of pro-found vision loss. Optic nerve biopsy (ONB) is considered a last resort when treatment risks outweigh benefits in pro-gressive optic neuropathy of uncertain etiology. It is reserved for patients who have lost vision in one eye and are losing or may lose vision in the fellow eye. Once the nerve is severed, there is no hope for visual recovery, making the decision to proceed with such a diagnostic procedure particularly diffi-cult. Even subtotal ONBs, which are occasionally done when vision is compromised but not completely lost, limit the potential for visual recovery. When possible, computed tomography (CT)-guided fine needle aspiration biopsy (FNAB) represents a minimally invasive alternate method for obtaining useful histopathology in cases of optic nerve tumors or inflammatory lesions (1). To date, most reports of ONBs in the literature have been limited to single case reports and highlight the need to consider a broad differential diagnoses and to perform Departments of Ophthalmology (MHL, JJN, LJB, NJV, REG, GTL, MRV, SLG); Pathology and Laboratory Medicine (SV); and Neurology (LJB, NJV, GTL, SLG), University of Pennsylvania School of Medicine Phil-adelphia, Pennsylvania; and Department of Neurosensory Sciences (MLM), Albert Einstein Medical Center Philadelphia, Pennsylvania. Dr Venneti is now with the Department of Pathology at Memorial Sloan-Kettering Hospital in New York, New York. Dr Moster is now with the Wills Eye Institute at the Thomas Jefferson School of Medicine in Philadelphia, Pennsylvania. Dr Volpe is now with the Department of Ophthalmology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. Dr Vagefi is now with the Department of Ophthalmology at the University of California, San Francisco, in San Francisco, California. Poster presented at the North American Neuro-ophthalmology Society meeting, February 2011, Vancouver, British Columbia, Canada. The authors report no conflicts of interest. Address correspondence to Steven L. Galetta, MD, Department of Neurology, Hospital of the University of Pennsylvania, 3W Gates Building, 3600 Spruce Street, Philadelphia, PA 19104; E-mail: steve. [e-mail] Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 313 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. extensive evaluations before biopsy (2-6). We performed a retrospective review at a tertiary care institute to identify patients who underwent ONB. We aimed to characterize the disease processes that required this highly invasive diagnostic surgery and evaluate the extent to which ONBs ultimately affected patient management and clinical outcome. METHODS This was a retrospective chart review of biopsies in a diverse set of clinical circumstances at the University of Pennsylvania from 1990 to 2010 involving intrinsic or adherent optic nerve masses. Cases were identified from digitized hospital pathol-ogy databases and from a survey of treating physicians in ophthalmology, neurology, neurosurgery, and otolaryngology departments. Patients were included if surgical biopsy of intrinsic or adherent optic nerve lesions was undertaken to clarify an uncertain diagnosis in the setting of progressive visual decline. Cavernous hemangiomas were excluded from the analysis because they are orbital masses distinct from the optic nerve, which also carry no risk to the fellow eye. Data collected from inpatient and outpatient medical records included demo-graphic information, ocular and systemic diagnoses, empiric treatments, differential diagnoses, and neuroimaging, surgi-cal, and pathological characteristics of optic nerve lesions. Five of 15 cases were previously reported as case reports in the literature (7-11). The Human Subjects Research Committee at the University of Pennsylvania provided the Institutional Review Board approval for this study. A waiver for patient consent was obtained based on the retrospective nature of this study. RESULTS Fifteen patients underwent biopsies (mean age of 51.7 ± 17.4 years) and were subsequently followed up for a median of 8 months after the procedure (range, 1 week to 15 years; mean, 2.5 ± 4.1 years) (Table 1). Surgical approaches depended on the location and extent of the tumors and in-cluded craniotomy (47%), orbitotomy (47%), and endonasal endoscopy (6%). The primary surgeons specialized in neuro-surgery (47%), oculoplastics (47%), and otolaryngology (6%). Combined approaches were sometimes used (20%). The amount of tissue obtained depended on the clinical findings, especially the pre-operative visual acuity, and goals of surgery, most notably the need to decompress the apical or intracanalicular optic nerve. Seven specimens (47%) included en bloc biopsy of the nerve, 7 contained the dural sheath (47%; usually with subtotal nerve), and one was limited to the compressive lesion (6%). In 3 cases, decompression was an additional goal of surgery. At the time of biopsy, visual acuity was no light perception (NLP) in 8 (53%) eyes, light perception (LP) to counting fingers (CF) in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) had experienced some degree of vision loss attributed to the optic pathway lesions before biopsy, which manifested as decreased visual acuity and/or visual field defects. In 14 of 15 cases, a specific diagnosis was established at least in part based on information obtained from the ONB (Table 1). In 8 cases, the ONB established the diagnosis, whereas in 6 cases, a presumed diagnosis was made using additional clinical data combined with a negative or non-diagnostic ONB. Six patients (40%) had tumors, and these included metastatic carcinoma (Case 1), anaplastic astrocy-toma (Cases 2 and 3), schwannoma (Case 4), and menin-gioma (Cases 5 and 6). Figure 1 demonstrates representative histopathology from this series. Eight patients (53%) were found to have infectious or inflammatory disorders after ONB. In most of these cases, the leading diagnostic consideration was tumor (glioma, meningioma, or lymphoma). In 6 of these 8 Cases (11-16), including 2 of 3 cases of sarcoidosis, revised clinical diagnoses were made based on optic nerve biopsies that excluded neoplasm, combined with imaging, laboratory analyses, or biopsies at other sites. The diagnoses in this category were Aspergillus (Case 7), sarcoidosis (Cases 8-10), sclerosing orbital inflammation (Case 11), varicella zoster optic neurop-athy (Case 12), rheumatoid pachymeningitis (Case 13), and tacrolimus toxicity (Case 14). The final diagnoses in cases of bilateral vision loss varied and included neoplastic, inflammatory, and infectious etiologies. In 5 of the 7 cases with fellow eye involvement at the time of ONB, management was altered based on biopsy results. Although no patient in this series regained significant vision in the affected eye, none experienced significant vision loss in the fellow eye at the last follow-up. Of the 7 patients undergoing subtotal ONB, 3 (Cases 5, 7, and 13) experienced at least temporary ipsilateral improve-ment in vision after biopsy. However, vision remained at NLP in Cases 8 and 9 and deteriorated in Case 3 (HM to NLP) and Case 6 (20/30 to CF) after biopsy. Two patients with ONB are described in detail to illustrate the diverse and unique circumstances that warrant this diagnostic procedure. Case 1 A 65-year-old woman presented with several weeks of decreased vision in the right eye. She had a history of non- small cell lung cancer with metastasis to the humerus that had been treated with radiation and chemotherapy 8 years earlier. Four years before presentation, she had undergone enucle-ation of the left eye for intractable neovascular glaucoma after a retinal vein occlusion. The central acuity on the right was 20/20, with superotemporal visual field loss and optic disc pallor. Magnetic resonance imaging (MRI) revealed a large nonhomogeneous enhancing mass involving both the left optic nerve and the optic chiasm. The differential diagnosis included glioma, metastasis, and lymphoma. A metastatic 314 Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Summary of cases undergoing optic nerve biopsy Case Age and Gender Presenting Complaint Clinical Evaluation Differential Diagnosis Surgical Approach Specimen Biopsy Pathology Presumed Clinical Diagnosis Revised Patient Management Follow-up After Biopsy (mo) 1 65 F Decreased vision MRI: heterogeneously enhancing nerve extending to chiasm Glioma, metastasis, lymphoma Craniotomy FT Metastatic carcinoma Radiation; steroids 10 2 78 M Ataxia, nausea, vomiting, decreased vision MRI: enhancing hypothalamic mass Glioma, metastasis, meningioma Craniotomy AM Anaplastic astrocytoma Radiation 1 Perimtery suggesting chiasmal and right optic nerve involvement 3 63 M Decreased vision MRI: enhancing nerve mass spreading into sella/frontal lobe Glioma, meningioma Craniotomy ST Anaplastic astrocytoma (7) Chemotherapy 84 Before ONB: nondiagnostic LP: nl 4 40 M Proptosis, decreased vision MRI: intrinsic optic nerve mass Glioma, meningioma, hemangioma, schwannoma Craniotomy FT Schwannoma 5 5 54 F Headache, decreased vision MRI: optic nerve mass Meningioma, metastasis Craniotomy ST Meningioma Radiation, repeat resection 180 LP: nl 6 49 F Proptosis, eye pain, decreased vision MRI: homogeneous nerve mass compressing posterior globe Meningioma schwannoma, fibrous tumor Orbitotomy ST Meningioma Radiation 51 7 74 F Proptosis, ocular dysmotility, eye pain, decreased vision CT: bony erosions Aspergillus, metastasis, vasculitis, sarcoidosis Endoscopic endonasal ST Aspergillus Antifungals 5 (Continued) Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 315 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. (Continued) Case Age and Gender Presenting Complaint Clinical Evaluation Differential Diagnosis Surgical Approach Specimen Biopsy Pathology Presumed Clinical Diagnosis Revised Patient Management Follow-up After Biopsy (mo) Sinus biopsy: acute/ chronic inflammation Temporal artery biopsy: neg 8 24 F Decreased vision MRI: heterogeneously enhancing compressive orbital mass; smooth bony remodeling Glioma, sarcoidosis, fungal, tuberculosis, meningioma Orbitotomy ST Sarcoidosis (8) Second steroid trial; chemotherapy stopped 1 9 15 M Headache, decreased vision MRIs: resolving optic nerve enlargement/ enhancement Lymphoma, leukemia, glioma, sarcoidosis, optic neuritis Orbitotomy ST Atrophy, inflammation Sarcoidosis Second steroid trial; immuno-suppression 16 Body imaging/PET: nl LPs: nl 10 42 M Decreased vision MRIs: optic nerve/ chiasmal enlargement; stable size, variable enhancement Glioma, paraneoplastic radiation neuropathy, sarcoidosis Orbitotomy FT Fibrosis, atrophy Sarcoidosis (9) Steroids; immuno-suppression 9 LP: nl Body imaging/PET: hilar adenopathy 11 42 F Eyelid swelling, ocular dysmotility, decreased vision MRI: enhancing, irregular mass surrounding nerve Glioma, meningioma, lymphoma, orbital pseudotumor, sarcoidosis Craniotomy FT Fibrosis, inflammation Sclerosing orbital inflammation (10) 8 Gallium scan: neg ONB: probable glioma 316 Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. (Continued) Case Age and Gender Presenting Complaint Clinical Evaluation Differential Diagnosis Surgical Approach Specimen Biopsy Pathology Presumed Clinical Diagnosis Revised Patient Management Follow-up After Biopsy (mo) 12 55 M Headache, decreased vision MRI: white matter hyperintensity, perivascular enhancement Lymphoma, syphilis, HIV invasion Orbitotomy FT Gliosis, atrophy VZV optic neuropathy 1 LP: nl Bilateral optic nerve pallor 13 47 F Ocular dysmotility, diplopia, decreased vision MRIs: homogeneously enhancing, hyperintense mass around nerve in apex/canal Meningioma, sarcoidosis, lymphoma Craniotomy ST Inflammation Rheumatoid pachy-meningitis Steroids; numerous immunosup-pressants 75 LP: nl 14 63 M Headache, decreased vision MRIs: stable nerve enhancement, occipital hyperintensities Lymphoma, tacrolimus toxicity, infection, vasculitis Orbitotomy FT Gliosis, demyelination Tacrolimus toxicity (11) IVIg; t acrolimus stopped 7 Temporal artery biopsies: neg Occipital lobe biopsy: neg LP: nl 15 63 F Headaches, ataxia, eye pain, ocular dysmotility, decreased vision Numerous imaging studies: unrevealing Aspergillus, tuberculosis, metastasis Orbitotomy FT Gliosis, fibrosis No diagnosis Second steroid trial 2 LPs: nl Bronchoscopy: nl Temporal artery biopsies: neg Differential diagnosis was based on laboratory data, radiographic findings, other diagnostic procedures, and/or response to empiric therapy. Fellow eye involvement was established by neuroimaging and examination findings consistent with a decrease in visual acuity and/or a loss of visual field. AM, adjacent compressive mass; bk, normal; CT, computed tomography; F, female; FT, full thickness; IVIg, intravenous immunoglobulin; LP, lumbar puncture; M, male; MRI, magnetic resonance imaging; neg, negative; ONB, optic nerve biopsy; PET, positron emission tomography; ST, subtotal; VZV, varicella zoster virus. Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 317 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. survey was unrevealing. Meanwhile, vision in the right eye dropped to 20/70. The decision was made to seek a tissue diagnosis with the hope of salvaging vision in the remaining eye and guiding systemic therapy. Biopsy of the infiltrated left optic nerve on the enucleated left side, obtained via a frontotemporal craniotomy, revealed poorly differentiated metastatic adenocarcinoma, pre-sumably from her primary lung tumor. She was treated with radiation and steroids, and she experienced initial improve-ment in her visual field deficit. Unfortunately, eventual tumor growth, including involvement of the left internal carotid artery, led to her death within 1 year of diagnosis. Case 7 A 74-year-old woman with a medical history of lung and breast cancer and amblyopia of the right eye presented with 2 months of progressive vision associated with left periorbital pain. She was started on prednisone for presumed giant cell arteritis at an outside hospital, and subsequent temporal artery biopsy was negative. On referral to our institution, visual acuity was CF, right eye, and LP, left eye. There was moderate left proptosis. The left pupil was miotic, and topical cocaine testing confirmed sympathetic denervation. Extraocular mo-tility of the left eye was impaired except in abduction and the left optic disc was pale. MRI demonstrated an enhancing left orbital apical mass infiltrating the optic nerve, and CT revealed erosion of the roof of the sphenoid sinus. Given concern for metastatic cancer, an endoscopic sinus biopsy was performed. The pathology showed acute and chronic osteomyelitis, with Aspergillus identified on culture. The patient was treated with systemic and topical antifungals and underwent several debridements of the sphenoid sinus. Because the suspicion for metastatic disease remained high, the patient underwent a subtotal left ONB and decompression via endoscopic sphenoethmoidectomy. Culture from the biopsy confirmed the diagnosis of Aspergillus osteomyelitis, and the patient continued systemic antifungals. Vision improved from LP to 20/100 on the biopsied left eye and remained stable at CF on the right eye during the ensuing 5 months. DISCUSSION We report the diagnostic and clinical outcome of a series of patients undergoing ONB over a 20-year time frame. These patients had experienced progressive visual loss in one or both eyes. Although the decision to proceed with ONB can be difficult and regarded as a test of last resort, we found that in 14 of 15 patients, we were able to establish a diagnosis, and in all 4 patients with useful visual acuity remaining in the unaffected fellow eye, prevent further vision loss. In all 6 patients with tumors (Cases 1-6), the final diagnosis confirmed what had been suspected clini-cally. However, among 8 patients found to have an infec-tious and inflammatory optic neuropathy, there was also a strong suspicion of optic nerve tumor in 6 patients (Cases 8-13). A number of these cases highlight unusual presenta-tions of progressive optic neuropathy. Although optic nerve schwannoma (encountered in Case 4) is on the differential of well-circumscribed optic nerve lesions, it is rarely encoun-tered. Aspergillus, diagnosed in Case 7, has been recognized as a rare cause of optic neuropathy and orbital apex syndrome (12). Rheumatoid pachymeningitis, encountered in Case 13, has also been described to affect the optic nerve (13,14). In our patient, visual acuity improved from CF to 20/40 after 2 years of treatment with cyclophosphamide and infliximab. Some of the other unique cases presented in this series have been previously reported including: radiation-induced chias-mal anaplastic astrocytoma (Case 3) (7); sarcoid optic neu-ropathies thought initially to be gliomas (Cases 8 and 10) (8,9); sclerosing orbital inflammation, also suspicious for gli-oma before biopsy (Case 11) (10); and tacrolimus optic nerve toxicity (Case 14) (11). Only the 2 patients with optic nerve sheath meningiomas (ONSMs) (Cases 5 and 6) and optic nerve surgery experienced significant changes in their central vision at the last follow-up. Although partial tumor resection confirmed the presumed diagnosis in both ONSM cases, the main goal of surgery was optic nerve decompression to halt progressive visual field loss. These 2 patients illustrate the highly variable visual outcomes after surgical decompression of ONSMs (15-17). Over the past 3 decades, fractionated stereotatic radiotherapy of vision-threatening ONSMs has been shown to stabilize or even improve vision much more reliably and has become the therapeutic option of choice for patients with an ONSM and progressive visual loss (18-20). In our series, 1 patient (Case 5) with an ONSM experienced improvement in visual acuity on the affected side from 20/80 to 20/25 after surgery. Although this patient had subsequent radiation and a second orbital surgery for further nerve decompression, vision has remained stable for 12 years. Conversely, in the other patient with ONSM (Case 6), acuity dropped from 20/ 30 to CF shortly after surgery and remained poor despite a subsequent course of fractionated radiotherapy. Of the 3 patients ultimately diagnosed with sarcoid optic neuropathy, only one of their biopsies demonstrated the characteristic noncaseating granulomas. One pediatric patient (Case 9) was presumed to have sarcoidosis based on concur-rent idiopathic thrombocytopenia purpura, an elevated serum angiotensin-converting enzyme level, optic nerve enhance-ment, and a biopsy that was negative for malignancy. He has been treated with intravenous immunoglobulin and long-term systemic immunosuppression without involvement of the fellow optic nerve. Another patient (Case 10) was treated presumptively with both proton beam radiation and chemo-therapy for a suspected optic nerve glioma, but vision declined to NLP. With clinical signs suggesting fellow eye involvement, left ONB was performed and the biopsy specimen showed scant nonspecific inflammation. The patient was soon diag-nosed with sarcoidosis from a transbronchial biopsy that contained noncaseating granulomas (9). This patient has been 318 Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. FIG. 1. Optic nerve biopsy specimens. Case 1: A. Metastatic adenocarcinoma composed of pleomorphic cells (hematoxylin and eosin, ·20). B. Cells stain for cytokeratin AE 1/3 (·20). Case 2: C. Anaplastic astrocytoma with pleomorphic glial cells (arrows) (hematoxylin and eosin, ·20). Case 4: D. Schwannoma composed of spindle cells arranged in alternating cellular and hypocellular regions (arrows) resembling Antoni A and B patterns (hematoxylin and eosin, ·5). E. Although classic Verocay bodies are not seen, Verocay-like bodies (arrowheads) and hyalinized blood vessels (arrows) are present (hema-toxylin and eosin, ·20). F. Tumor cells are strongly positive for protein S100 (·10). G. Reticulin stain shows pericellular basement membrane deposition (·20). Stains negative for epithelial membrane antigen, cytokeratin, neurofilament, glian fibrillary acidic protein, and Ki-67 (less than 1%) are not shown. Case 8: H. Sarcoidosis. Noncaseating and hyalinized granulomas (arrowheads) (hematoxylin and eosin, ·20). Stains were negative for acid-fast bacilli and fungal and bacterial organisms. Case 12: Presumed varicella zoster virus optic neuropathy. I. Optic nerve cross section with atrophied fascicles (hematoxylin and eosin, ·2). J. Loss of axons confirmed with neurofilament stain (·2). Case 13: Presumed rheumatoid pachymeningitis. K. Optic nerve meningeal biopsy with focal aggregates of chronic inflammatory cells, mainly lymphocytes (hematoxylin and eosin, ·20). Case 14: Presumed toxic optic neuropathy caused by tacrolimus. L. With routine staining, there is no apparent optic nerve abnormality (hematoxylin and eosin, ·20). M. Optic nerve axons show diffuse loss of myelin (luxol fast blue, ·20). Levin et al: J Neuro-Ophthalmol 2012; 32: 313-320 319 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. followed on mycophenolate mofetil for 4 years and has retained 20/20 acuity in the right eye. The lack of sensitivity for sarcoidosis in this small series does not necessarily argue against the value of ONB. In both patients with nondiagnostic biopsies, the ONB was important in excluding a neoplasm. Although no patient in our series lost further vision in the fellow eye, it should be noted that 3 patients with fellow eye involvement (Cases 12, 14, and 15) already had CF or worse vision in both eyes at the time of biopsy. In these patients, establishing a diagnosis was deemed important in potentially saving their life. The extremely poor bilateral vision at the time of biopsy raises the question of whether clinicians hesitate too long before obtaining ONBs. In addition, some of our patients had disease processes with poor prognoses, suggesting that visual decline was unavoidable. In this clinical series, open biopsies of the optic nerve were performed in the majority of cases. Although CT-guided FNAB represents a minimally invasive alternative, the technique has not gained popularity partly because of limited tissue sampling, decreased utility in lesions with high fibrous content, and preference for en bloc removal of benign tumors (22). We were able to obtain adequate tissue sampling and/or tumor removal from an open approach and save for possible inadequate tissue sampling in the 2 non-diagnostic cases of sarcoidosis (Cases 9 and 10) and in the one case where no clinical diagnosis was reached (Case 15). There are a number of limitations in this long-term retrospective chart review. These include subject or case selection bias in which severe visual loss prompted biopsy, small sample size, referral bias of difficult cases to a tertiary center, lack of a control group, and recall bias where cases seen many years ago were not as easily identified for inclusion. As a number of our patients were medically ill, the follow-up interval was limited. Soon after biopsy, several patients expired, while others were transferred to hospice or closer to their homes. In conclusion, ONB should be strongly considered in patients with progressive optic neuropathy causing profound vision loss and when standard testing is unable to ascertain an etiology. ONB carries significant risk of morbidity in cases where the biopsied side retains vision. However, biopsy may be beneficial in substantiating the diagnosis and, if performed early in the clinical course, possibly lead to treatment that would halt or prevent vision loss in the fellow eye. ACKNOWLEDGMENT The authors thank Molly Nadelson, MD, for contributing to data collection. REFERENCES 1. Kennerdell JS, Dubois PJ, Dekker A, Johnson BL. CT-guided fine needle aspiration biopsy of orbital optic nerve tumors. Ophthalmology. 1980;87:491-496. 2. Behbehani RS, Vacarezza N, Sergott RC, Bilyk JR, Hochberg F, Savino PJ. Isolated optic nerve lymphoma diagnosed by optic nerve biopsy. Am J Ophthalmol. 2005;139:1128-1130. 3. Dayan MR, Elston JS, McDonald B. 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