Levin, Marc H. MD, PhD; Ney, Joshua J. MD; Venneti, Sriram MD, PhD; Moster, Mark L. MD; Balcer, Laura J. MD; Volpe, Nicholas J. MD; Gausas, Roberta E. MD; Liu, Grant T. MD; Vagefi, M. Reza MD; Galetta, Steven L. MD
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 Philadelphia, Pennsylvania; and Department of Neurosensory Sciences (MLM), Albert Einstein Medical Center Philadelphia, Pennsylvania.
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: firstname.lastname@example.org
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.
Evaluation of a progressive optic neuropathy can be challenging, at times yielding nonspecific laboratory results and equivocal neuroimaging findings in the setting of profound vision loss. Optic nerve biopsy (ONB) is considered a last resort when treatment risks outweigh benefits in progressive 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 difficult. 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 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.
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 pathology 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 demographic information, ocular and systemic diagnoses, empiric treatments, differential diagnoses, and neuroimaging, surgical, 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.
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 included craniotomy (47%), orbitotomy (47%), and endonasal endoscopy (6%). The primary surgeons specialized in neurosurgery (47%), oculoplastics (47%), and otolaryngology (6%). Combined approaches were sometimes used (20%).
TABLE 1-a Summary of...Image Tools
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 nondiagnostic ONB. Six patients (40%) had tumors, and these included metastatic carcinoma (Case 1), anaplastic astrocytoma (Cases 2 and 3), schwannoma (Case 4), and meningioma (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 neuropathy (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 improvement 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.
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 enucleation 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 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, presumably from her primary lung tumor. She was treated with radiation and steroids, and she experienced initial improvement 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.
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 motility 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.
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 clinically. However, among 8 patients found to have an infectious 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 presentations 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 encountered. 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 chiasmal anaplastic astrocytoma (Case 3) (7); sarcoid optic neuropathies thought initially to be gliomas (Cases 8 and 10) (8,9); sclerosing orbital inflammation, also suspicious for glioma 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 concurrent idiopathic thrombocytopenia purpura, an elevated serum angiotensin-converting enzyme level, optic nerve enhancement, 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 chemotherapy 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 diagnosed with sarcoidosis from a transbronchial biopsy that contained noncaseating granulomas (9). This patient has been 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 nondiagnostic 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.
The authors thank Molly Nadelson, MD, for contributing to data collection.
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