Neurosarcoidosis and Ocular Inflammation: A Case Series and Literature Review

Objective: To describe the ocular findings of neurosarcoidosis (NS) through a case series and review the current literature on the ocular complications of NS. Methods: Case series of 4 patients with a literature review. Results: Ophthalmic involvement in NS includes scleritis, cranial nerve palsies, uveitis, optic nerve granulomas, and occlusive retinal vasculitis. Conclusion: NS is an uncommon, but potentially life-threatening, manifestation of sarcoidosis with ocular involvement up to 25% of patients. Patients presenting with neuro-ophthalmic manifestations of sarcoidosis are more likely to have other sites of involvement requiring ophthalmologists to maintain a high index of suspicion for systemic disease.

Trainees’ Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD Neurosarcoidosis and Ocular Inflammation: A Case Series and Literature Review Aishwary Desai, BS, Benjamin Chaon, MD, Meghan Berkenstock, MD Objective: To describe the ocular findings of neurosarcoidosis (NS) through a case series and review the current literature on the ocular complications of NS. Methods: Case series of 4 patients with a literature review. Results: Ophthalmic involvement in NS includes scleritis, cranial nerve palsies, uveitis, optic nerve granulomas, and occlusive retinal vasculitis. Conclusion: NS is an uncommon, but potentially lifethreatening, manifestation of sarcoidosis with ocular involvement up to 25% of patients. Patients presenting with neuro-ophthalmic manifestations of sarcoidosis are more likely to have other sites of involvement requiring ophthalmologists to maintain a high index of suspicion for systemic disease. Journal of Neuro-Ophthalmology 2021;41:e259–266 doi: 10.1097/WNO.0000000000001117 © 2020 by North American Neuro-Ophthalmology Society S arcoidosis is an autoimmune disorder with an unknown cause. Although commonly leading to the development of nonnecrotizing granulomas in the skin and lungs, any organ system may be affected. With an incidence of 10.9– 35.5/100,000 person years in the United States, only a fraction of these patients develop neurologic manifestations, including cranial neuropathies, cerebrovascular accidents, and aseptic meningitis (1,2). Although clinically up to 16% of patients with sarcoidosis are diagnosed with neurosarcoidosis (NS), postmortem studies suggest that this represents only half of those with central nervous system (CNS) involvement (3). Neurologic manifestations typically occur within the first 2 years of disease activity and disproportionately affect younger patients with a median age of 39 years at onset (2,4,5). Drexel University College of Medicine (AD), Philadelphia, Pennsylvania; and Ocular Immunology Division (BCC, MKB), Wilmer Eye Institute, Baltimore, Maryland. The authors report no conflicts of interest. Address correspondence to Meghan Berkenstock, MD, Wilmer Eye Institute, 600 N. Wolfe Street, Maumenee Third Floor, Baltimore, MD 21287; E-mail: [e-mail] Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 The gold standard for NS diagnosis involves evaluation of a central nervous system biopsy for noncaseating granulomas. However, given the location, pathologic diagnosis is not always possible (2,4). Thus, patients with suspected NS require both systemic radiographic evaluation for involvement in other organ systems and sites amenable for biopsy (2). Neuroimaging with an MRI of the brain or a head computed tomography (CT) with contrast is required to assess for inflammatory changes, including granulomatous involvement of brain parenchyma and the spinal cord (2,4). Finally, a lumbar puncture (LP) is required to rule out infection or alternative autoimmune causes, including multiple sclerosis (2,4). This workup constitutes Zajicek criteria, which defines probable NS by looking for evidence of systemic sarcoidosis and excluding alternative diagnoses (4,6). Given the embryonic origin of the eye and the ability to directly visualize structures on examination, ophthalmic involvement can raise suspicion for or support the diagnosis of NS. Occurring in one-third of patients with NS or up to 5% of all cases of sarcoidosis, there is a range of neuroophthalmic manifestations. First, granulomatous inflammation directly within ocular structures and the adnexa can cause uveitis and infiltration of the lacrimal gland, orbit, and the optic nerve (7–13). Additional ophthalmic findings can develop secondary to compression and inflammation within the CNS. Elevated intracranial pressure can result from intracranial granulomas due to mass effect, blocking of cerebrospinal fluid (CSF) flow, or meningoencephalitis leading to papilledema and cranial nerve palsies (11,13,14). Herein, we present a case series describing these ocular manifestations seen in patients with NS and review the current literature. METHODS This is a retrospective series of 4 patients with biopsyproven or presumed NS evaluated at the Ocular Immunology Division of the Wilmer Eye Institute from January 1, 2016, to March 30, 2020. Clinical data collected include e259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner age, race, sex, and ophthalmic and neuro-radiologic examination findings. The study was approved by the Johns Hopkins School of Medicine Institutional Review Board and followed the tenets of the Declaration of Helsinki. Intraocular inflammation was graded according to the Standardization of Uveitis Nomenclature (SUN) grading system (15). CASE REPORTS Case 1 A 66-year-old Caucasian woman with a medical history significant for hypertension and arthritis presented after seeing a translucent circle in the superior-temporal visual field of the left eye for several weeks. She was initially diagnosed by another provider with peripapillary chorioretinitis and was started concurrently on methotrexate 20 mg weekly and an oral prednisone taper for 9 months. Although her symptoms resolved with prednisone, she could not taper to less than 20 mg of prednisone without worsening of the visual field defect. Before the start of the methotrexate, she underwent an autoimmune and infectious serologic workup, which was unrevealing. She established care in our clinic due to the visual field defect increasing in size. On examination, her best-corrected vision (BCVA) was 20/35 in the right eye and 20/25 in the left eye. No anterior chamber or vitreous cells were noted, and an elevated mass confluent with the optic nerve was noted (Fig. 1). With the development of this new lesion in the setting of immunosuppression, the initial diagnosis was questioned, and an LP and an MRI of the brain were ordered. Neuroimaging showed inflammation of the fat surrounding the left optic nerve and punctate foci of enhancement in the intracranial region involving the right temporal, right frontal, and right hippocampi regions. Focal leptomeningeal enhancement was also noted. The LP showed clear CSF with 100 white blood cells (95% lymphocytes and 5% monocytes), a high protein level of 76 mg/dL, and a low glucose of 43 mg/dL. In the setting of the abnormal outpatient LP and a worsening superior-temporal visual field in the left eye, she was referred to the emergency department for intravenous antibiotics and neurological evaluation. She was admitted and underwent a repeat LP, which again showed the same results in addition to negative venereal disease research laboratory (VDRL), herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and enterovirus polymerase chain reaction testing. Flow cytometry, as well as mycobacterial, fungal, and bacterial cultures, was negative. Her brain MRI was highly suggestive of NS, given the round foci of enhancement of the optic nerve and brainstem, the leptomeningeal enhancement around the brainstem, the optic nerve inflammation, and the CSF profile. To identify a lesion amenable for biopsy to definitively e260 FIG. 1. Color fundus photograph of the left eye showing a gray, elevated mass confluent with the optic nerve and corresponding with the area of the subjective superotemporal visual field defect. Blurred margins and peripapillary hemorrhages are also noted. diagnose sarcoidosis, a positron emission tomography (PET) CT scan was performed and moderate hypermetabolism within the parasagittal S2 sacral segment was seen. An MRI of the lumbosacral spine was ordered to further characterize this lesion, which showed abnormal marrow signal in the sacrum and bilateral acetabula. After biopsy of the sacrum, the final pathology did not show any abnormality. The patient received a dose of 1 g of intravenous (IV) methylprednisolone and the triangular visual field defect subjectively improved. A third LP was repeated to repeat infectious studies, given prior immunosuppressed status. Viral, bacterial, and fungal studies were again negative. Two more doses of 1 g of methylprednisolone daily were given and the patient was discharged on 3 additional days of oral 1,250 mg methylprednisolone daily to complete a 5-day pulse thereafter to start a prednisone taper to 10 mg daily as a maintenance dose. On follow-up after discharge, the patient denied a change in vision, pain, and no new floaters or flashes of light. There was an interval resolution of the scotoma as well. Her vision with correction was 20/40 with pinhole to 20/25 in the right eye and 20/160 with pinhole to 20/80 in the left eye. There was a new afferent pupillary defect (APD) on examination in the left eye. Confrontational visual fields showed a larger, temporal visual field defect. On dilated fundus examination, the area of the previous optic nerve elevation had resolved and peripapillary atrophy was seen with resolution of the blurred disc margin and hemorrhages (Fig. 2). The patient was to start mycophenolate mofetil by neurology 2 weeks later, but was lost to follow-up. Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 2. Color fundus photograph of the left eye status after intravenous and oral corticosteroid use. There is resolution of the elevated, gray lesion surrounding the optic nerve with new peripapillary atrophy. Unfortunately, the patient presented 18 months later with acute mental status change and twitching of her extremities. She was taken to an outside hospital, where she was sedated and intubated for approximately 24 hours due to suspected seizures. A repeat MRI of the brain at that time demonstrated meningitis and repeat LP yielded CSF studies significant for pleocytosis and negative bacterial and fungal cultures. A biopsy of the right frontal dura was performed, which demonstrated noncaseating granulomas consistent with NS. She was treated with 5 days of IV steroids followed by an oral prednisone taper over 1 month. After discharge, she slowly regained her memory and her behavior returned to baseline. She was started on mycophenolate mofetil 1 g twice a day and prednisone 10 mg for long-term management. Case 2 A 34-year-old African American man with a medical history of asthma, seizure disorder, and SIADH was incarcerated for the previous 24 months and transferred from an outside hospital for progressive failure to thrive. Over the prior 3 to 4 months, he developed a severely blunted affect with an elevated lipase and abdominal pain, nausea, and vomiting. Most concerning was his progressive 30-pound weight loss over the past 6 months with a persistent leukocytosis of 14,000 cu/mm. A CT of the abdomen identified nonspecific hepatic and peripancreatic lymphadenopathy, which was further evaluated by a PET scan. Diffuse fluorodeoxyglucose uptake was seen in the cervical, mediastinal, right hilar, mesenteric, retroperitoneal, and pelvic lymph nodes with increased metabolic activity in spleen and bone marrow. He underwent a cervical lymph node biopsy, which showed necrotizing and nonnecrotizing granulomas, which were AFB negative on staining. Further imaging with an MRI of the brain was performed, demonstrating leptomeningeal enhancement, hyperintensity of hypothalamus and posterior optic tracts, asymmetric enlargement of left medial rectus muscle and lacrimal glands, and possible chronic embolic cerebrovascular accidents (Fig. 3). Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 FIG. 3. Postcontrast T1 axial MRI image showing leptomeningeal nodular enhancement along the inferior and lateral cerebellar folia. Given these findings and the patient developing photophobia, ophthalmology was consulted. On questioning, he noted progressive dimming of the vision in the left eye over the prior 3 months. He denied flashes, floaters, eye redness, or foreign body sensation. Ophthalmic examination showed an uncorrected vision of 20/20 in both eyes with full visual fields, and an IOP of 24 in the right eye and 22 mm Hg in the left eye. The anterior chamber examination was remarkable for scattered posterior synechiae in the right eye leading to a limited view to the posterior pole. The anterior chamber was without cells in both eyes, and in the left eye, a vitreous hemorrhage was seen on dilated examination with inferior debris and multifocal, white retinal lesions with perivascular chorioretinal scarring, sclerotic vessels, and rare intraretinal hemorrhages. Peripheral vascular sheathing was noted in the right fundus (Figs. 4 and 5). On fluorescein angiography, there was bilateral peripheral dropout with vascular anastomoses. In the left eye, there was staining of perivascular chorioretinal scars temporally (Figs. 6 and 7). With his recent incarceration and weight loss, tuberculosis was high in the differential diagnosis, given a positive quantiferon gold test. However, repeated sputum and bronchoscopy cultures were negative for AFB. This pointed toward presumed NS; however, given the difficulty in distinguishing between these 2 diagnoses, the decision was made to treat the patient for both conditions. He was e261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 4. A color fundus photograph of the right eye showing peripheral vascular sheathing with sclerosis. started on 12 months of rifampin 600 mg daily, pyrazinamide 1500 mg daily, and isoniazid 300 mg daily with B6 supplementation. He was also started on 30 mg of oral prednisone on taper at discharge. He was subsequently lost to follow-up to the ophthalmology service. Case 3 A 24-year-old African American man with no medical history developed redness and blurred vision over 4 weeks. He was seen by an outside provider and diagnosed with iridocyclitis and an optic nerve mass in the right eye. He was initially started on unknown doses of prednisolone acetate 1% and 0.5% cyclopentolate, and then switched to difluprednate 0.5%, 6 times a day in the left eye due to continued inflammation. He was then referred to our clinic for evaluation and a serological workup. Prior records revealed the patient’s best-corrected visual acuity was 20/ 20 in both eyes 1 year before. The patient’s review of sys- FIG. 5. A color fundus photograph of the left eye with clear media despite a vitreous with inferior debris showing multifocal, white retinal lesions with perivascular chorioretinal scarring near sclerotic vessels and rare intraretinal hemorrhages. e262 FIG. 6. A late fluorescein angiography of the right eye showing optic nerve leakage, pinpoint leakage nasally, and significant nasal and temporal peripheral drop out with vascular anastomoses. tems was only positive for shortness of breath. On examination, his uncorrected vision was 20/20 in the right eye and 20/100 in the left eye, with a round and reactive pupil in the right eye and a pharmacologically dilated pupil in the left eye with an APD by reverse. Slitlamp evaluation showed 3+ cell with 2+ flare and granulomatous keratic precipitates in Arlt triangle and scattered posterior synechiae in the left eye (Fig. 8). Rare cells with trace flare were noted in the anterior chamber of the right eye. In the vitreous, 2+ cell was seen in both eyes with snowballs inferiorly in the right eye and 2+ haze in the left eye. Overlying the optic nerve in the right eye was a 4-to-5-disc diameter, lobulated mass FIG. 7. A late fluorescein angiography of the left eye showing optic nerve leakage, peripheral dropout with vascular anastomoses, and staining of perivascular chorioretinal scars temporally. Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 10. A B-scan ultrasound of the right eye showing the lesion overlying the optic disc with irregular reflectivity. FIG. 8. A slitlamp photograph of the left eye showing scattered posterior synechiae and granulomatous keratic precipitates clustered inferiorly in Arlt triangle. with adjacent hemorrhages and subretinal fluid (Fig. 9). The differential diagnosis for the optic nerve mass and bilateral panuveitis was sarcoidosis vs. granulomatous inflammation due to an infectious etiology. A B-scan ultrasound was performed, and an irregular, dome-shaped lesion with irregular internal reflectivity was noted overlying the right optic disc. The lesion had a thickness of 2.4 mm and dimension of 4.9 mm laterally and 3.8 mm radially. Opacities were noted to be overlying the lesion, and the peripapillary retina was detached. There were no vascular pulsations detected inside the tumor and no evidence of extrascleral extension (Fig. 10). Further testing with fluorescein angiography showed diffuse leakage in the lesion over the optic nerve with peripheral vascular leakage (Fig. 11). Optical coherence tomography was also performed and showed subretinal fluid in the area around the optic nerve with vitreous cells at the posterior hyaloid interface (Fig. 12). Serological workup was negative for T. pallidum IgG and RPR, HIV, and T-spot. A CT of the chest showed diffuse FIG. 9. A color fundus photograph of the right eye showing an elevated lesion with vascular tortuosity overlying the optic nerve with obscuration of the optic disc. Surrounding subretinal fluid and hemorrhages are noted. Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 centrilobular pulmonary micronodules with mediastinal and bilateral hilar adenopathy suggestive of miliary sarcoidosis. Concurrently, an MRI of the brain was completed to assess for orbital extension of the optic nerve lesion. Extensive subarachnoid nodular densities were noted throughout the brain parenchyma with prominent involvement of the suprasellar cistern and the prechiasmatic segments of the optic nerve and optic tracts (Fig. 13). A 4-millimeter nodular enhancement was also noted at the right optic disc. These findings were highly suggestive of NS or less likely, tuberculosis or fungal disease. Given the CT of the chest and MRI of the brain results, a bronchoscopy and a lymph node biopsy were performed showing granulomatous inflammation with negative AFB cultures. With the CNS and pulmonary findings, the patient was then admitted for 5 days of 1 g daily of methylprednisolone and was discharged on prednisone 60 mg per day, difluprednate in both eyes 4 times a day, and cyclopentolate twice a day in the left eye. FIG. 11. A late fluorescein angiogram of the right eye showing diffuse leakage over the optic nerve lesion and peripheral small vessel leakage temporally. e263 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 12. A spectral domain optical coherence tomography of the retina in the right eye showing the subretinal fluid adjacent to the optic nerve and vitreous cells in posterior hyaloid. On follow-up examination, his uncorrected visual acuity improved to 20/60 in the left eye. No anterior chamber cell or flare was noted in the right eye, but trace cells and keratic precipitates were still noted in the left eye. There was interval improvement with 1+ vitreous cell noted in both eyes. Two weeks after initiation of treatment, the optic nerve granuloma in the right eye was smaller, and there was less adjacent subretinal fluid surrounding the optic nerve in the right eye. Case 4 A 50-year-old Caucasian woman with a PMH of type 2 diabetes, hypertension, peptic ulcer disease, and Sjogren syndrome was referred to our clinic for evaluation of episcleritis. She was previously treated with loteprednol 0.2% 3 times a day for a week then daily for 1 week to treat episcleritis in the left eye. She described her pain as 10/10, which worsened with extraocular movements (EOM). On examination, her BCVA was 20/25 in the right eye and 20/ 40 in the left eye, with normal visual fields, IOP, and EOM. She had 3+ injection without blanching temporally in the left eye with tenderness to palpation. The rest of the anterior and posterior chamber examinations in both eyes were normal. No T-sign was seen on B-scan in both eyes. She was initially treated with difluprednate 0.5% 4 times a day in the left eye to avoid use of corticosteroids or nonsteroidal anti-inflammatory medications, given her brittle control of type 2 diabetes and history of peptic ulcer disease, for which she was on H. pylori treatment. She returned 1 week later with continued pain and redness. Her examination remained unchanged from prior, and after phone consultation with both her gastroenterologist and endocrinologist, she was started on 60 mg of oral prednisone. The patient continued to have 10/10 pain in the left eye with the development of horizontal, binocular diplopia, and was referred to the emergency department for imaging. A CT of the head with and without contrast showed a minimally enlarged left lacrimal gland and soft tissue thickening of the sclera. She was referred to the oculoplastic and reconstructive service for lacrimal gland biopsy and continued on an oral prednisone taper with resolution of the pain and diplopia. Repeated CT of the head 2 months later showed no enlargement of the lacrimal e264 gland or orbital abnormalities, and a biopsy was not performed. She developed several side effects with the prednisone including extreme anxiety, hyperglycemia despite use of a sliding scale insulin, and dyspepsia. Given this, the start of mycophenolate mofetil was discussed. Due to the anxiety and social stressors, she was lost to follow-up for 6 months and self-tapered the prednisone. She acutely presented to our clinic after dental work to remove an abscess with 10/10 pain in the left eye and binocular, horizontal diplopia. Her vision was 20/20 in the right eye and 20/30 in the left eye. EOM were normal without ptosis, and 2+ scleral injection without blanching and tenderness to palpation was again noted in the left eye anteriorly. However, there was a new blurring of the optic nerve margin the left eye with hemorrhages on dilated examination and a pupil-involving, left third nerve palsy. She was sent to the emergency department and a CT of the head showed a 0.5 · 0.4 · 0.3-cm ovoid lesion in the posterolateral of the left carotid sinus. Follow-up MRI of the brain showed thickening and enhancement of the left orbital apex, including the superior orbital fissure and optic canal. The differential diagnosis included presumed NS vs. FIG. 13. T2 fluid-attenuated inversion recovery images showing nodular enhancement of the chiasm, prechiasm, and optic nerves. Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner Tolosa–Hunt syndrome. The enhancing lesion previously seen on CT was characterized as an asymmetric dural sinus with inferior petrosal sinus enhancement. An LP was performed with negative flow cytometry, elevated white blood cells with 74% neutrophils, and both elevated glucose and protein levels. CSF analysis was negative for viral titers and bacterial cultures. Likewise, testing of the CSF for Cryptococcus antigen and VDRL were negative. Serological testing was negative for HIV, T. pallidum IgG, Lyme titers, and galactomannan antigen. A PET scan showed no extracranial evidence of sarcoidosis. The patient was started on 5 days of 1 g of IV methylprednisolone and then discharged on an oral prednisone taper. On follow-up examination, the patient had a BCVA of 20/25 in both eyes with full EOM and was orthophoric at distance. Two millimeters of ptosis were noted on external examination in the left eye, but the sclera was white and quiet. The optic nerve edema and retinal hemorrhages had almost completely resolved and she was to start mycophenolate mofetil to prevent recurrence of dacryoadenitis, scleritis, and cavernous sinus inflammation. DISCUSSION NS causes a myriad of ocular complications, which can present diagnostic challenges for the clinician. As seen in patients 2 through 4, the most common neuro-ophthalmic findings include an optic neuropathy, optic disc edema, papilledema, and optic nerve granulomas (12). Cranial neuropathies can also occur either in isolation or with multiple nerves involved, most commonly the facial nerve (12). Abnormal pupillary responses and anisocoria caused by tonic pupils or Horner syndrome have also been reported (6). In addition, patients may develop visual field defects due to lesions of the optic tract, chiasm, or postchiasmal visual pathways (11,12). This was seen in patient 1 as an early clue of an ongoing disease process suggestive of NS. The presence of a left optic nerve granuloma and a visual field defect, which worsened on the taper of prednisone, were suggestive of a progressive granulomatous or infiltrative optic neuropathy. Furthermore, leptomeningeal involvement in NS may itself or as a result of metabolic derangements due to hypothalamic–pituitary axis dysfunction cause headache, acute confusion, seizure, and mental status changes (5,17). The development of an altered mental status in patient 1 led to the fulfillment of Zajicek criteria through identification of noncaseating granulomas on dural biopsy. By contrast, the patient in case 2 illustrated the difficulty that sometimes exists in distinguishing NS from infectious causes of granulomatous inflammation, such as tuberculosis. Nonspecific findings of a 30-pound weight loss, leukocytosis, photophobia, and dim vision in the left eye required further evaluation. Bilateral lacrimal gland enlargement on MRI, cervical lymph node histology, and bronchoscopy Desai et al: J Neuro-Ophthalmol 2021; 41: e259-e266 with sputum cultures negative for acid-fast bacilli staining were all suggestive of presumed NS. Exclusion of tuberculosis and other infectious etiologies is required before the initiation of corticosteroid and immunosuppressive therapy to prevent reactivation or disseminated disease. Similarly, patient 4 also was diagnosed with presumed NS due to the inability to biopsy the lesion near the cavernous sinus. Although definitive diagnosis requires pathologic evaluation of a tissue sample for noncaseating granulomas, a biopsy may not be possible, given the anatomical location or the medical stability of the patient. Thus, presumed NS remains a diagnosis of exclusion after ruling out all other conditions on the differential diagnosis. Ocular involvement is seen in only approximately 25% of patients with sarcoidosis (16,17). Uveitis is most commonly the initial manifestation of the disease, but patients presenting with neuro-ophthalmic manifestations of sarcoidosis are more likely to have other sites of systemic involvement (13, 18). Thus, the patient in case 3 with the constellation of granulomatous keratic precipitates, a suspected optic nerve granuloma, and an exudative retinal detachment in the setting of mild shortness of breath suggested multisystem sarcoidosis and was highly suspicious for NS at initial presentation to our clinic. By contrast, the patient in case 4 presented with scleritis and a pupil involving third nerve palsy. This represents a case of isolated NS characterized by CNS and orbital involvement with no evidence of extracranial manifestations on PET imaging. Nonetheless, the majority of patients with NS will have evidence of disease affecting other organ systems at the time of diagnosis, given isolated central nervous system sarcoidosis has been reported to occur in only 10% of patients (19). In summary, NS is an uncommon, but potentially lifethreatening, manifestation of sarcoidosis. All patients in this series presented with variable but characteristic neuro-ophthalmic findings, which ultimately led to a diagnosis of biopsy-proven or presumed NS. It is essential for clinicians to exclude alternative etiologies through ancillary testing with neuroimaging, an LP, and an extensive laboratory investigation to assess for occult infection or malignancy. Therefore, it is important for ophthalmologists to maintain a high index of suspicion for ocular findings suggestive of sarcoidosis and recognize features suggestive of neurologic involvement in these patients. REFERENCES 1. Tavee JO, Stern BJ. Neurosarcoidosis. 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