Clinical-Pathological Case Study
A 63-year-old white woman with a history of previously treated tuberculosis and a 10-year history of bilateral hearing loss presented with a complaint of progressive visual loss in both eyes over the last 2 years. She denied tobacco, alcohol, or drug abuse. At the time of initial vision loss, she had been found to have a swollen right optic disc; however, 2 weeks later, she was noted to have bilateral optic disc swelling. Initial brain and orbital MRI was interpreted as showing no abnormalities. Repeat MRI 9 months later showed marked bilateral optic nerve enhancement. The patient was treated with high-dose corticosteroids without improvement. In the meantime, a variety of serologic and blood studies were performed, including complete blood count, erythrocyte sedimentation rate, C-reactive protein, Lyme, Bartonella, Brucella, Toxoplasma, rickettsial, and antinuclear antibody titers, serology for syphilis, and testing for human immunodeficiency virus. All gave negative or normal results. A lumbar puncture revealed no abnormalities other than 10 white blood cells, all monocytes. The cerebrospinal fluid (CSF) glucose was 73 mg/dL (normal: 40-80 mg/dL), and the CSF protein was 34 mg/dL (normal: 15-45 mg/dL). The fluid was negative for cryptococcal antibody, there were no oligoclonal bands, and cultures for bacteria, including acid-fast bacteria, showed no growth. Cytology was negative for malignancy but showed small mature lymphocytes. CT of the chest and a gallium scan showed no lesions. Bilateral temporal artery biopsies showed no evidence of vasculitis. The patient was referred to our institute for an assessment.
On examination, the patient's vital signs were normal. Her visual acuity was light perception, right eye, and no light perception, left eye. Color vision was absent on the right. The pupils measured 7 mm with the right pupil minimally reactive to direct light stimulation, and the left was nonreactive. There was a left relative afferent pupillary defect. Extraocular movements were full, but there was a 40-prism diopter comitant right exotropia by Krimsky testing. There was no proptosis. Slit-lamp examination revealed normal corneas, anterior segments, and intraocular pressures. The ocular fundi showed bilateral optic disc pallor. There was no vascular sheathing, and there were no retinal hemorrhages or exudates. Trigeminal and facial nerve function were normal bilaterally.
The patient was treated with another course of systemic steroids without improvement in vision. In the meantime, further blood tests were ordered, including tests for the common Leber hereditary optic neuropathy mitochondrial mutations and assays for collapsin response mediator protein-5, angiotensin-converting enzyme (ACE), and aquaporin-4 antibody. All gave negative or normal results. A third brain and orbital MRI was performed (Figs. 1-3).
Repeat MRI performed 9 months after initial vision loss demonstrated mild optic nerve enlargement and marked enhancement bilaterally, extending from the orbital portions of the optic nerves to the optic chiasm. The enhancement involved predominantly the nerve sheaths and the pial surface of the chiasm. The remainder of the orbits and brain were normal. The third MRI of the brain and orbits (Figs. 1-3) now shows progression of involvement of the optic nerves and chiasm with an increase in the asymmetric enlargement of the optic nerves, left greater than right. There is now uniform enhancement throughout the cross-sectional area of the nerves. In addition, there is now thickening and enhancement of the pituitary stalk and bilateral asymmetric enhancement of the oculomotor and trigeminal nerves as well as the facial and vestibulocochlear cranial nerve complexes in the internal auditory canals. The brain parenchyma and the remaining leptomeninges demonstrated no abnormal enhancement.
T1 MRI also revealed bilateral enhancement of the oculomotor and trigeminal nerves and bilateral enhancement in the internal auditory canals. The brain parenchyma and the remaining leptomeninges demonstrated no abnormal enhancement (Figs. 1-3). It was decided to perform a biopsy of the left optic nerve in an attempt to obtain a definitive diagnosis of the cause of the patient's bilateral optic neuropathy. This was done via a medial transconjunctival approach, at which time a 1-cm segment of the optic nerve was removed.
Biopsy of the left optic nerve showed numerous, well-formed, non-necrotizing granulomas associated with a marked chronic inflammatory infiltrate composed of lymphocytes and plasma cells (Figs. 4-6). Scattered multinucleated giant cells were seen in the granulomas (Fig. 7). Gram, Grocott methenamine, and Ziehl-Neelsen for acid-fast bacilli stains were all negative.
Non-necrotizing granulomatous inflammation with giant cells consistent with sarcoidosis of the left optic nerve.
After the optic nerve biopsy, the diagnosis of sarcoidosis was made, and the patient was treated with intravenous cyclophosphamide. She did not respond to this medication and was switched to methotrexate. However, she continued to worsen, becoming completely deaf and blind. She is currently in hospice care.
This patient presented with a bilateral, almost simultaneous, anterior optic neuropathy that gradually progressed and was associated with the enhancement of and thickening of the optic nerves on MRI. Conditions most likely to produce this constellation of clinical and imaging findings include bilateral optic neuritis, especially that which occurs in the setting of neuromyelitis optica, bilateral optic nerve sheath meningiomas, and various infiltrative processes such as lymphoma, leukemia, and sarcoid. The persistence of enhancement in this patient effectively eliminated typical optic neuritis as a diagnostic consideration, as gadolinium enhancement is transient, remitting in days, in optic neuritis (1-3).
Sarcoidosis is an inflammatory condition of unknown etiology usually seen in patients 20-55 years of age (4). The diagnosis can be suspected when appropriate results are obtained through a variety of tests including an ACE level in the serum, CSF, or both; a chest x-ray or CT scan; a gallium citrate scan; a positron emission tomographic scan; bronchial washings; brain MRI; and a lumbar puncture. The diagnosis is made within the appropriate clinical setting in conjunction with the histopathologic evaluation of the affected tissue (5).
Approximately, 5% of patients with systemic sarcoidosis develop central nervous system (CNS) involvement, that is, neurosarcoidosis (6). Very few patients present with neurosarcoidosis alone, without the involvement of any other organs, and isolated optic nerve sarcoid is extremely rare (7). CNS sarcoidosis may manifest as headache, encephalopathy, meningitic symptoms, stroke, seizures, hydrocephalus, transverse myelitis, peripheral neuropathy, or a combination of these manifestations (5). Clinically, optic nerve involvement may manifest as papilledema, papillitis, retrobulbar neuritis, a compressive optic neuropathy associated with an extra-axial mass lesion, or an infiltrative optic neuropathy. Optic nerve findings thus can mimic a meningioma (5,8), idiopathic orbital inflammation, leptomeningeal spread of tumor, idiopathic or demyelinating optic neuritis, or optic glioma (4). Because of the diverse range of its clinical features, the diagnosis of neurosarcoidosis can be quite challenging, and although MRI is sensitive, it is nonspecific (9). Nevertheless, optic nerves in which inflammation or infiltration is a prominent feature typically show perineural enhancement and thickening (5,9), findings that are especially useful in cases with a negative systemic workup (9). In such cases, as in ours, an optic nerve biopsy may be required to establish a diagnosis. For example, Robert et al (10) reported a case of isolated CNS sarcoidosis that was limited to the optic nerve. A “shave” biopsy of the intracranial portion of the affected optic nerve provided a definitive diagnosis without loss of vision. Ng et al (9) described chiasmal involvement with sarcoidosis. The patient was thought to have an optic pathway glioma until a biopsy of the chiasm established the correct diagnosis. Pelton et al (11) reported a patient with increased intracranial pressure and a clinical picture that mimicked pseudotumor cerebri except that neuroimaging disclosed enhancement of the optic nerves and chiasm. Optic nerve sheath biopsy through a transcranial approach revealed pathology consistent with sarcoidosis. Beck et al (12) reported 4 patients with sarcoidosis of the anterior visual pathways, all of whom required optic nerve biopsy to establish the diagnosis. They concluded that treatment requires systemic immunosuppression, in addition to corticosteroids, to prevent permanent visual loss. Frohman et al (13) reported 24 patients with anterior visual pathway sarcoidosis, 71% of whom were not previously known to have the disorder. The authors concluded that anterior visual pathway disease may be under-recognized as a presentation of sarcoidosis and that the fundus findings of periphlebitis and optic granuloma are typically absent in such cases, thus requiring optic nerve biopsy to establish the diagnosis.
The optic nerve biopsy in this case revealed the classic histopathologic findings consistent with sarcoidosis, including well-formed non-necrotizing granulomas, giant cells, and a diffuse chronic inflammatory infiltrate (14). No foreign bodies or microorganisms were identified in the tissue specimen. Systemic corticosteroids are the first-line treatment of neurosarcoidosis; however, some patients do not respond to or cannot tolerate them, in which case, other options include both other immunosuppressive agents (15) or fractionated radiotherapy (16).
Our case of neurosarcoidosis was a diagnostic challenge because of its unusual presentation as an isolated bilateral progressive optic neuropathy with no systemic or other ocular manifestations. Ultimately, as in rare similar cases, the diagnosis required an optic nerve biopsy. This case also reminds us that neurosarcoidosis should always be in the differential diagnosis of a bilateral optic neuropathy because of its variability of presentation and potential for visual recovery with treatment.
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© 2010 by North American Neuro-Ophthalmology Society
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