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Show Treatment of Neuro-Ophthalmic Sarcoidosis Larry P. Frohman, MD Background: Because of the rarity of neuro-ophthalmic sarcoidosis, there are no therapeutic guidelines based on evidence-based medicine for this disorder. Evidence Acquisition: Review of literature combined with personal experience. Results: Corticosteroids are the preferred initial therapy for neuro-ophthalmic sarcoidosis. If patients cannot tolerate the requisite dose of corticosteroid needed to control their disease, or if corticosteroids fail to adequately control the disease process, the choices of a second agent are based on the consideration of rapidity of clinical response and the safety profile. Conclusions: Although methotrexate and mycophenolate mofetil are the medications that are often selected after corticosteroid failure, more rapidly acting agents that have been used are infliximab and intravenous cyclo-phosphamide. Journal of Neuro-Ophthalmology 2015;35:65-72 doi: 10.1097/WNO.0000000000000170 © 2014 by North American Neuro-Ophthalmology Society The prevalence of sarcoidosis is 6-10/100,000 world-wide. In the United States, this figure varies by race: in whites, it is 5/100,000 and in African Americans it is 40/ 100,000. Ocular involvement occurs in the course of 22% of cases. Neurosarcoid refers to sarcoidosis involving the brain, cranial nerves, and spinal cord. Neuro-ophthalmic sarcoid is a subset of neurosarcoid that involves the afferent and efferent visual systems. The facial nerve is the most commonly affected cranial nerve in sarcoidosis reported in 5%-16% of patients (1). Neuro-ophthalmic involvement most typically presents as visual loss, diplopia, or homonymous visual field defects. The frequency of neuro-ophthalmic disease is not known, but that of optic nerve involvement ranges from 1% to 5%. The natural history of neuro-ophthalmic sarcoid is unknown. There is neither consensus on the need to treat all cases nor agreement on the optimal therapeutic approach (2,3). Asymptomatic cases of neurosarcoid might not require treatment (4). This is generally not a consideration for neuro-ophthalmic sarcoid. METHODS Personal case records of sarcoid patients with neuro-ophthalmic manifestations is evaluated by the neuro-ophthalmology service of New Jersey Medical School from 1989 to 2012 were reviewed, combined with an OVID-MEDLINE search. The search covered 1945 to 2013. Each individual therapeutic agent was cross-referenced with the search terms "sarcoid" and "neurosarcoid." Relevant papers were reviewed. RESULTS In 1985, Stern et al (5) reported treatment of 33 neuro-sarcoid patients. Optic neuropathy (ON) was infrequent in his series (1/33 patients). Improvement on prednisone alone was seen in 19/21 patients. Other reports supported the efficacy of corticosteroid treatment (6-10), including that by Beardsly et al (9) in which 6/11 (55%) of their patients with ON responded to steroids. Another series (10) docu-mented the clinical course in 20 patients with neuro-ophthalmic sarcoid and 14 with ON. With steroid therapy, 5 showed improvement in vision, 5 remained stable, and 4 worsened. Six of the 14 patients subsequently received immunosuppressive treatment: 1 improved, 3 stabilized, and 2 worsened. In a series of 69 patients with neurosar-coid, Zajicek et al (11) included 26 with ON. Improved optic nerve function with corticosteroids varied, with relapse common as corticosteroids were tapered. The au-thors concluded that "Although this is the largest single series of patients with neurosarcoidosis yet reported, with Departments of Ophthalmology & Visual Sciences and Neurology & Neurosciences, Rutgers-New Jersey Medical School, Newark, New Jersey. Supported by an unrestricted grant to the Department of Ophthal-mology and Visual Sciences from the Lions Eye Research Foundation of New Jersey. The author reports no conflicts of interest. Address correspondence to Larry P. Frohman, MD, Departments of Ophthalmology & Visual Sciences and Neurology & Neurosciences, Rutgers-New Jersey Medical School, 90 Bergen Street, Newark, NJ 07103; E-mail: frohman@rutgers.edu Frohman: J Neuro-Ophthalmol 2015; 35: 65-72 65 State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. the most extensive follow-up detailed, it remains impossible to identify those patients in whom early aggressive immu-notherapy would be beneficial." Although corticosteroids are the preferred initial therapy for neuro-ophthalmic sarcoid, 1 large retrospective study highlighted the variability of response to medication (12). The records of 54 patients with neurosarcoid, 19 patients with optic nerve disease, and 3 with other neuro-ophthalmic signs (ptosis = 1 and diplopia = 2) were re-viewed. Treatment data were provided in 53 patients, of whom 35 were begun on corticosteroids alone, 12 received no specific treatment, 5 received immunosuppressants with-out corticosteroids, and 1 received corticosteroids with an immunosuppressive agent. At the conclusion of the study, 6 patients were on corticosteroids and 15 required steroids with immunosuppressives. Many of the patients with ON had a poor visual outcome. Therapeutic outcomes were assessed in a retrospective study of 47 patients with definite or probable neurosarcoid (13). Although 6 cases had ON, the specific outcomes in this subgroup were not reported. The study had an intentional treatment bias where those patients (n = 26) considered at high risk for neurologic progression were treated at the onset with corticosteroids and immunosuppressives. Those not felt to be at high risk received corticosteroids alone (n = 20) or no treatment (n = 2). Despite this treatment assignment bias, after a mean observation period of 44 months, of the group perceived to be at higher risk, 18/26 had improvement, 4/26 remained stable, and 4/26 worsened. Of those with milder disease receiving steroids alone, only 7/20 patients improved, 11/20 remained stable, and 2/10 worsened. It has become clear that treatment of sarcoid ON is a continuum, ranging from a case of ON with spontaneous recovery (14) to patients who may progress to blindness despite aggressive therapy. That cases without preexisting sarcoid and without classic fundus findings are now being diagnosed as sarcoid instead of labeled as idiopathic optic neuritis may contribute to the dichotomy of opinion on corticosteroid sensitivity of ON. Although corticosteroids are first-line therapy, there is recognition that not all cases of neurosarcoid are controlled with corticosteroids, and the concept of initial multidrug therapy has been raised. Hoitsma et al (15) have noted that "Combination therapy of corticosteroids and alternative immunosuppressive agents immediately at the time of ini-tial diagnosis are recommended in cases with poor prognosis such as intracranial masses and myelopathy." It is unknown whether neuro-ophthalmic disease should be included in this therapeutic recommendation. ALTERNATE THERAPEUTIC AGENTS Choosing an alternate drug requires considering its safety and efficacy profile, and the lag time until clinical response might be expected (Table 1). In the neurosarcoid literature, a commonly used surrogate measure of efficacy is the mean reduction in corticosteroid dose achieved with the initiation of an additional therapeutic agent. One series reported that 26 patients with neurosarcoid in whom a variety of different medications including chlorambucil, cyclosporine, cyclo-phosphamide, azathioprine, and methotrexate as well as radiation therapy (RT) led to a decrease in prednisone dos-age of 10-20 mg/d in only 38% of cases (81). In another series of patients with neurosarcoid, corticosteroids alone led to improvement in 14/48 (29%) patients, methotrexate in 17/28 (61%), and cyclophosphamide in 9/10 (90%) (21). In a study of 40 patients with neurosarcoid where corticosteroids alone proved beneficial in 40% of patients, several immunosuppressants were used in the remaining patients. Overall, only 13/40 (32.5%) had complete recov-ery (82). Of 54 patients with neurosarcoid (35% with ON), 6 (11%) required long-term maintenance on predni-sone, 37 (69%) required an immunosuppressant with or without corticosteroid, and 11 (20%) required no maintenance therapy (12). In a report of 15 patients with neuro-ophthalmic sarcoid other than ON, 13/15 (87%) responded to oral corticosteroids and the other 2 required cyclosporine (1). Agents to Consider as Alternate Therapy Methotrexate was initially used in a patient with sarcoid who had failed the treatment with corticosteroids and vinblastine (16). Baughman et al (17) reported a randomized study of 15 patients with systemic (not neurologic) sarcoid prescribed pred-nisone with methotrexate vs prednisone and placebo. At 12 months, the group treated with methotrexate achieved a 50% reduction in the corticosteroid dose. In another study, 17/28 (61%) patients with neurosarcoid who failed the treatment with corticosteroids responded to methotrexate (84). It has been suggested that in neurosarcoid, one may need to use combination therapy with methotrexate at the onset (3). Meth-otrexate has been used in a series of 3 patients with ON intolerant of high-dose corticosteroids. All stabilized, or improved and required less corticosteroids (18). In 6 cases of sarcoid ON refractory to steroids, 4 (67%) had a good response to methotrexate (1 in conjunction with corticosteroids and thalidomide) and 2 (33%) were treatment failures (19). There is some consensus that in the treatment of neurosarcoid, meth-otrexate is the drug of choice when corticosteroids fail (20). Cyclophosphamide, in selected cases of neurosarcoid, is a useful drug, especially if rapid onset is required (22). A 46- year-old man with bilateral eighth cranial nerve dysfunction and radiculomyelitis who progressed to complete flaccid para-plegia despite intravenous and intrathecal methylprednisolone showed dramatic response to cyclophosphamide infusion within 2 weeks (23). One study reported that cyclophospha-mide controlled 9/10 (90%) the neurosarcoid cases, which was a statistically significant benefit over corticosteroids alone (84). Another report (24) documented symptomatic improvement in 66 Frohman: J Neuro-Ophthalmol 2015; 35: 65-72 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 4/7 (57%) of patients with neurosarcoid treated with cyclo-phosphamide, and all showed improvement in magnetic reso-nance imaging (MRI) or cerebrospinal fluid findings. The mean prednisone dose was reduced from 42 mg to 18 mg daily. Of 17 patients with spinal cord involvement from sar-coidosis, 7/7 showed improvement with cyclophosphamide compared with 5/10 (50%) treated with methotrexate (25). Cyclophosphamide was one of the several drugs that failed to control a very aggressive case of ON (24). It did stabilize and permit some recovery in a case of bilateral ON that had progressed to blindness despite high-dose corticosteroids (Frohman, unpublished data). Mycophenolate mofetil was first reported to be effective for pulmonary sarcoidosis (26) and subsequently has proven to be successful rescue therapy for uveitis (27,28). It may be efficacious in refractory neurosarcoid, often when other medications have been ineffective (29,30). In 1 series of 8 patients with neurosarcoid, the mean dose of prednisone was reduced from 59 mg to 6 mg (30). Infliximab is an anti-tumor necrosis factor alpha (TNF-a) agent. Hostettler et al (31) described 16 patients with corticosteroid-resistant sarcoid treated with infliximab for at least 12 months. Six of the 11 (55%) had complete remission, and 4/11 (36%) had a partial response. In only 1 patient, the infliximab had to be discontinued due to an adverse event. Neurosarcoid has been reported to be respon-sive to infliximab even after resistance to multiple other agents. One patient with no light perception due to ON recovered to 20/20 (32). Like cyclophosphamide, inflixi-mab often has rapid onset. In a report of 343 sarcoid pa-tients, 43 patients treated with anti-TNF agents showed improved cognition compared with those treated with cor-ticosteroids or corticosteroids and methotrexate (33). There are single-case reports of optic nerve or chiasmal involve-ment refractory to multiple agents in which patients improved on infliximab (34-37). While reporting 3 of their own patients with refractory neurosarcoid successfully trea-ted with infliximab, Pereira et al (38) reviewed the literature TABLE 1. Pharmcologic agents for treatment of neuro-ophthalmic sarcoidosis Drugs Mechanism of Action References Comment First-line agents Methotrexate Folate metabolism inhibitor 2,3,16-20 Must prescribe folate Cyclophosphamide Alkylating agent 19,21-25 Mycophenolate mofetil Inhibitor of purine synthesis 26-30 Infliximab Monoclonal antibody against TNF-a 4,15,31-44 Possibility of inducing sarcoid Potential tachyphylaxis raises issue of concomitant treatment with MTX or other immunosuppressant Second-line agents Leflunomide Pyrimidine synthesis inhibitor 45-47 Cyclosporine A IL-2 inhibitor, reduces T-cell activation 10,19,48-52 Not effective in pulmonary disease Thalidomide TNF-a blocker 53-59 Azathioprine Purine analog 12,19,60-62 Possibly efffective agents Adalimumab Human monoclonal IgG1 TNF-a antibody 63,64 Possibility of inducing sarcoid Chlorambucil Alkylating agent 62,65-67 Rituximab Monoclonal antibody that depletes circulating B-cell lymphocytes 68,69 Cladribine Purine analog 70 Agents with unproven efficacy Hydroxychloroquine and chloroquine Inhibition of antigen presentation and processing 1,71,72 Tetracyclines Anti-infectious and nitric oxide synthase inhibitor 52,73-76 Probably ineffective agents Tacrolimus Inhibition of T-cell-mediated responses 77,78 Etanercept TNF-a receptor blockade 2,79 Possibility of inducing sarcoid Intravenous immunoglobulin Multiple; principal action not established 80 Frohman: J Neuro-Ophthalmol 2015; 35: 65-72 67 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. and found 17 additional cases treated with infliximab. All showed clinical improvement, with adverse effects in 4/16 (23%). There are 2 particular concerns with the use of infliximab. First, tachyphylaxis may occur due to antibody formation. Concomitant immunosuppression may prevent this occurrence. Second, anti-TNF therapy can lead to auto-immune disorders such as systemic lupus erythematosus. While unusual, patients treated with anti-TNF agents may develop sarcoidosis. Sturfelt et al (39) described a patient treated with infliximab for rheumatoid arthritis who developed neurosarcoid with papilledema, sixth nerve palsy, uveitis, and retinal periphlebitis. Removal of the drug, placement of a ventriculoperitoneal shunt, and treatment with corticosteroids and methotrexate led to resolution. Induction of what is pathologically indis-tinguishable from sarcoidosis with anti-TNF therapy for autoimmune diseases is not restricted to infliximab as it has been reported with entanercept (40) and adalimumab (41,42). In reviewing the literature, Tong et al (43) found 37 such cases [etanercept 22/27 (59.5%), adali-mumab 5/37 (13.5%), and infliximab in 10/37 (27%)]. The cause of this phenomenon is unknown. Lamrock and Braun (44) proposed that this may be due to cytokine imbalance. Although TNF-a may suppress autoreactive T-cells, loss of this suppression may facilitate granuloma formation. In addition, entranercept increases the pro-duction of interferon-g, which is vital for granuloma for-mation (83). Agents to Consider for Use in Refractory Neurosarcoid/Neuro-Ophthalmic Sarcoid Leflunomide was successfully used in a sarcoid patient with pulmonary, sinus, and cutaneous involvement who had failed the treatment with corticosteroids, azathioprine, methotrexate, and hydroxychloroquine (45). In a report of 32 patients (mainly with ocular and pulmonary disease) treated with leflunomide, 15 were also given methotrexate. Leflunomide was effective in 12/17 (71%) patients and with methotrexate in 13/15 patients (46). In another study, 76 patients were prescribed leflunomide, 86% of whom had been on another immunomodulating agent, or corticoste-roids (47). Among all patients with nonpulmonary disease, 32% had a partial response. Of 8 patients with ocular involvement, 5 (62.5%) had a good response, 2 (25%) had a partial response, and 1 (12.5%) had no response, and of the 3 patients with neurosarcoid, 1 (33%) had a good response but 2 (67%) had no response. Cyclosporine has been used in neurosarcoid with vari-able results (48). It was successfully used in a patient with sarcoid uveitis and ON (49). Stern et al (50) treated 6 patients with refractory neurosarcoid. Although this medi-cation allowed a reduction in corticosteroid dose by 30%- 58%, 4 patients deteriorated and 1 died. Cyclosporine was shown not to be effective for pulmonary sarcoidosis in a randomized controlled trial of 37 patients (51). This resulted in abandoning cyclosporine in the treatment of all forms of sarcoid. That cyclosporine is lipid soluble, which potentially makes it attractive in patients with neurosarcoid. Yet in 1 case series, it only controlled 2/7 (29%) cases of ON (18). With questionable efficacy and significant toxic-ity, the role of cyclosporine in neuro-ophthalmic sarcoid remains unclear (52). Thalidomide was reported effective in patients with refractory cutaneous sarcoid (53,54) and shown to be of benefit with paranasal sinus involvement (55). The first neurosarcoid patient treated with thalidomide had bilateral ON and had failed multiple 2 and 3 drug regimens (56). Thalidomide stabilized this patient allowing corticosteroid doses to be reduced. Although there are other reports of patients with refractory neurosarcoid who responded to thalidomide (57-59), its potential use is limited due to teratogenicity. Azathioprine has been used effectively in cases of pulmonary sarcoid (60,61). However, there is limited literature on azathioprine use for neurosarcoid. Pawate et al (12) reported that 8/54 neurosarcoid patients were maintained on either azathioprine alone or in combina-tion with prednisone. Azathioprine was successfully used in 2 patients with neurosarcoid with ON after treatment with corticosteroids and RT was unsuccessful (62), but in another report it failed in patients with refractory ON. Agents With Possible Efficacy in Refractory Neurosarcoid/Neuro-Ophthalmic Sarcoid Adalimumab has been shown to be effective in refractory sarcoid uveitis (63). It also has been used successfully in a patient with neurosarcoid resistant to a combination of corticosteroids and methotrexate (64). Rituximab has had limited use in sarcoid and neuro-sarcoid. It did control 1 patient with neurosarcoid who had been resistant to corticosteroids, cylophosmanide, and methotrexate (68,69). Chlorambucil was used in 10 cases of pulmonary sarcoid after failing the treatment with corticosteroids, of whom 8 patients (80%) showed improvement (65). In 31 patients with refractory systemic sarcoidosis trea-ted with chlorambucil, marked improvement was seen in 15/31 (48%) and 13/31 (42%) showed moderate improvement. However, patients often relapsed with drug withdrawal (66). A case of orbital sarcoidosis with proptosis and ophthalmoplegia that responded to chlor-ambucil and corticosteroids has been reported (67) as well as a patient refractory to corticosteroids and RT whose chiasmal sarcoidosis responded to treatment with chlorambucil (62). Cladribine was used in a patient with sarcoid ON who was refractory to cyclosporine and cyclophosphamide (70). 68 Frohman: J Neuro-Ophthalmol 2015; 35: 65-72 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The visual loss recurred within a year of the completion of cladribine therapy, but recovered when this medication was restarted. Agents Effective in Some Forms of Sarcoid, Yet, Are Untested/Unproven in Neurosarcoid/ Neuro-Ophthalmic Sarcoid Chloroquine may be effective as maintenance therapy in patients with pulmonary sarcoid (71); yet, the effectiveness of hydroxychloroquine and chloroquine in neurosarcoid is less convincing (2,72). Tetracycline has been used with success in some forms of sarcoidosis. One purported etiology of sarcoid-osis is altered immunity to Propionibacterium acnes. A subset of patients with sarcoid are sensitive to tetracy-clines, which are effective against P. acnes. Minocycline has anti-inflammatory and antibacterial properties. Its use in cutaneous sarcoid has been reported (73). Others have documented its success in cases with ocular or orbital involvement (74,75). Its use in neurosarcoid has not been reported. Caution is needed to avoid a potentially life-threatening Jarisch-Herxheimer reac-tion that may occur when patients with sarcoid are trea-ted with antibiotics (76). Agents without established efficacy in neurosarcoid/ neuro-ophthalmic sarcoid are listed in the Table 1 (2,80-83). COMBINATION DRUG THERAPIES When a patient fails corticosteroid therapy, there are no established guidelines to institute a 2 or multidrug regimen. Moravan and Segal (84) reported 6 patients with neurosarcoid refractory to corticosteroids who were treated with infliximab and mycophenolate mofetil. All demonstrated clinical improvement by the fourth course of infliximab, and all showed improvement on MRI scan of the brain. No significant side effects were seen in the follow-up period. When deciding to institute multidrug therapy, it is best to individualize treatment with consid-eration of factors such as rapidity of onset and side effects of each medication. RADIATION THERAPY RT generally is reserved for patients who fail medical therapy. Gelwan et al (62) treated 4 patients with ON with radiation who did not respond to steroid therapy. Although there was a transient improvement, visual loss recurred within 3 months. Others have reported single cases in which RT was beneficial (85-87). A literature review on the use of radiotherapy for refractory neurosarcoid con-cluded that such therapy might stop disease progression, but would not likely restore function (88). TREATMENT GUIDELINES Terushkin et al (4) published a neurosarcoid treatment strategy, suggesting mycophenolate mofetil for patients with severe disease who fail corticosteroids and do not need rapid therapeutic effect, and infliximab with cyclophosphamide as an option for those requiring rapid onset. For mild to moderate cases failing corticosteroids, they propose myco-phenolate mofetil, methotrexate, azathioprine, or hydroxy-chloroquine, and possibly RT. Terushkin et al propose that symptomatic cases of neurosarcoid may be treated with either corticosteroids or hydroxychloroquine. For neuro-ophthalmic sarcoid, we recommend an approach similar to Baughman et al (89); either intravenous or high-dose oral corticosteroids as initial therapy, which is tapered after 4-6 weeks. If corticosteroids fail, consider add-ing mycophenolate mofetil, azathioprine, or methotrexate as a second agent. Once on a second agent, attempt to taper the patient off corticosteroids. If this cannot be accom-plished, a third medication may be added, either anti- TNF agent or intravenous cyclophosphamide. Our specific treatment regimen for neuro-ophthalmic sarcoid (Fig. 1) is to prescribe patients with acute severe disease 1 g of solumedrol daily in divided doses for 3-5 days, followed by 1 mg/kg of oral prednisone. Less acute cases may be started on 1.0 mg/kg of oral prednisone. If there is favorable response after the first month, we begin a 3-6 month corticosteroid taper. If the patient had a favor-able response to corticosteroids, but worsens with taper, rather than start a second agent, we may repulse with intra-venous corticosteroids, followed by slower taper of oral cor-ticosteroids over approximately 1 year. If a rapid clinical response is needed, we begin a second agent, either intravenous cyclophosphamide or infliximab. We recommend that the dosing and monitoring for side effects not be performed by the neuro-ophthalmologist alone, but rather by rheumatologist, oncologist, or other physician familiar with these medications. When cyclo-phosphamide is selected, Doty et al (24) propose the fol-lowing regimen: intravenous cycloophoshamide initially at a dose of 500 mg, then 750 mg for the second dose, and a maintenance dose of 1 g. After 5 doses, treatment is reevaluated, and if possible, a less toxic drug used. If infliximab is selected, Moravan and Segal (84) propose that the patient receives 5 mg/kg intravenously every 2 weeks for a total of 3 doses. This dose is repeated every 5-6 weeks as maintenance therapy but a decision will have to be made about the possibility of tachyphylaxis. In some patients, retreatment with intravenous cortico-steroids may have sufficient therapeutic effect that a second agent with slower onset may be used. In this case, we typically use methotrexate, as it is relatively well tolerated. Generally, we start with a dose of 10 mg weekly. The patient's white cell count must be monitored, and folate is given concurrently (90). Frohman: J Neuro-Ophthalmol 2015; 35: 65-72 69 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Mycophenolate mofetil also is well tolerated and often used if methotrexate is ineffective. The initial dose is 500 mg twice daily and is gradually increased to 1 g twice daily as tolerated (30,89). However, a major concern is the risk of progressive multifocal leukoencephalopathy (91). Patients who fail methotrexate and mycophenolate mofetil may be offered infliximab or cyclophosphamide, mindful that in-fliximab could potentially worsen the disease. With a patient on 2 medications that are controlling disease, we maintain the corticosteroid dose at 0.5-1 mg/kg for 1 month and then begin to taper corticosteroids over 3-6 months. If this is successful, we maintain the patient on the single immunosuppressant for 12 months, and if the clinical and neuroimaging results are favorable, taper the drug over the ensuing 6 months. 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