Approach Considerations
Neurosarcoidosis has no known cure. Spontaneous remission has been observed, but long-term therapy often is required. Treatment alleviates symptoms that are severe or progressive.
Immunosuppression is the principal method of controlling the disease, and corticosteroids are the cornerstone of therapy. In cases of exacerbation, intravenous pulsed methylprednisolone followed by oral taper may be necessary. Treatment is guided by the clinical response to corticosteroids. If the response is favorable (ie, steady amelioration of symptoms), then the dose may be tapered over several months. Follow-up by a neurologist every 3-6 months to monitor the progress of the disease is important.
Relapses may respond poorly, however, requiring long-term steroid therapy. The prognosis with peripheral neuropathy is more favorable than with central nervous system involvement.
A variety of immunosuppressant agents (eg, cyclosporine, methotrexate, cyclophosphamide) have been used in patients with refractory neurosarcoidosis, with varying results. Almost all of the studies completed to date have involved treatment of central nervous system sarcoidosis as opposed to peripheral neuropathy.
There have been anecdotal reports of improvement with intravenous immunoglobulin therapy in patients in whom conventional therapy has failed. [35] The response may be related to amelioration of vasculitic neuropathy.
In patients with brain involvement, low-dose radiation has produced clear symptomatic benefits in some patients. Since the adverse effects of low-dose cranial irradiation are minimal, using radiation therapy may be prudent for patients whose disease is refractory to steroids or who have had adverse responses to high-dose steroids. Removal of the space-occupying lesions in the brain has little or no benefit and should be attempted only in extreme cases. Hydrocephalus may require ventriculoperitoneal shunting.
Adjunctive measures for specific neurologic manifestations include the following:
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Dementia: safety intervention and assistance
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Hypopituitarism: hormone replacement therapy
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Psychosis: risperidone and other antipsychotic drugs
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Foot involvement or balance problems: physical therapy with activity recommendations for decreasing falls
Consultation with the following specialists is advisable in the management of neurosarcoidosis:
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Rheumatologist
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Endocrinologist
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Neurosurgeon
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Pulmonologist
Immunosuppressant Therapy
Immunosuppressants such as cyclosporine, methotrexate, and cyclophosphamide have been used with varying results. Almost all of the studies completed to date have involved treatment of CNS sarcoidosis as opposed to peripheral neuropathy.
A retrospective report of 26 patients with refractory neurosarcoidosis monitored for a mean of 81.2 months demonstrated steroid sparing in 10 of 26 patients and clinical improvement in 15 of 26 patients treated with alternative medications or irradiation. Medications and results were as follows:
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Azathioprine : positive response in 8 of 14 patients
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Cyclophosphamide: positive response in 11 of 14 patients
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Cyclosporine: positive response in 2 of 3 patients
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Chloroquine: positive response in 1 of 1 patient
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Methotrexate: positive response in 1 of 3 patients
On the basis of this experience, the authors recommend azathioprine and cyclophosphamide as the alternative agents of choice in corticosteroid-resistant neurosarcoidosis, with methotrexate reserved for patients who either do not respond to those alternative agents or are intolerant of them. Azathioprine has been used as an alternative to corticosteroids when the adverse effects are intolerable, but reports in the literature are sparse.
Cyclosporine has been reported to lead to improvement in some patients. It has been successful in controlling the disease in patients undergoing transplantation. In one series, the response rate was 75%, but the patients had relapses once the therapy was stopped.
Methotrexate can be used as a steroid-sparing agent. It is generally well tolerated, with minimal adverse effects except for potential liver toxicity. Thus, patients on long-term dosing need to have careful monitoring of liver function, including liver biopsies. In one study, the remission rate for patients on methotrexate was 61%.
Cyclophosphamide use has been more limited. Short-term therapy has not been associated with good response. Therapy lasting at least several months is needed to determine efficacy. In one study, intermittent intravenous cyclophosphamide was associated with better compliance and lower risk of malignancy, especially bladder malignancy; however, bladder toxic effects did occur. Patients showed improvement in the course of the disease.
Chloroquine and hydroxychloroquine also have been used. In a study by Sharma, chloroquine and hydroxychloroquine were effective in controlling neurologic sarcoidosis in patients who did not respond to corticosteroids or developed severe adverse effects. These agents stabilized or controlled symptoms in 10 of 12 patients.
Several recent reports have shown successful treatment with infliximab, [36, 37, 38] rituximab, [39] mycophenolate mofetil. [38, 40] Mycophenolate was not effective in treating sarcoid myopathy, however. [40] Combination treatment with infliximab and mycophenolate mofetil also appears promising. [38]
Tumor necrosis factor–α (TNF-α) is believed to be a key cytokine in the pathogenesis of sarcoidosis, and TNF-α inhibitors are being increasingly used to treat refractory sarcoidosis. Several cases of refractory neurosarcoidosis treated with thalidomide have been reported. Treatment ranged from 4 weeks to 6 months. [41] Similarly, preliminary evidence suggests a possible benefit from infliximab in the treatment of neurosarcoidosis. [42, 43, 44]
Radiation
A case of neurosarcoidosis involving the pituitary gland and hypothalamus treated with stereotactic radiotherapy described in the literature showed excellent results. [45] For localized lesions, stereotactic radiotherapy may be indicated, although the responses so far have been variable.
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Atrophic right optic disc of a 37-year-old man with neurosarcoidosis and involvement of both optic nerves. Vision was lost. The disc is pale with sharp borders.
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Atrophic left optic disc of a 37-year-old patient with neurosarcoidosis and involvement of both optic nerves. The disc is pale with sharp borders. Vision was largely preserved.
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MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye for 2 months and occasional blurry vision in the left. T1-weighted sagittal image shows intact optic nerves.
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MRI of the brain in a 37-year-old man with neurosarcoidosis who had complete loss of vision in the right eye and mild left eye blurriness. This fluid-attenuated inversion recovery (FLAIR) axial image shows a wedge-shaped area of infarction in the right temporo-occipital area. The optic nerves exhibit abnormal signal.
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MRI of the brain in a 37-year-old patient with sarcoidosis who had right eye blindness and mild blurry vision in the left eye. This postgadolinium, T1-weighted axial image shows right optic nerve enhancement along almost the entire intraorbital portion and a small amount in the prechiasmatic portion. The left optic nerve enhances from the level of the optic chiasm to the distal intraorbital portion. The right temporo-occipital infarct is seen as a faint hypodensity; it does not enhance after gadolinium administration.
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MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left eye. This scan was taken 6 months after the scan shown in Pictures 3, 4, and 5. Both the right and left optic nerves are enlarged and show abnormal signal on this T1-weighted axial image. The patient remained on oral prednisone from the time of the first scan and did not exhibit any further loss of vision in the left eye. Vision in the right eye never returned.
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MRI of the brain in a 37-year-old man with sarcoidosis who had loss of vision in the right eye and blurry vision in the left. This postgadolinium, T1-weighted axial image shows abnormal enhancement of both optic nerves, with the left optic nerve appearing worse on this study than in the study shown as Picture 5, which was done 6 months earlier. The right temporo-occipital hypodensity represents the old infarction.
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Early chest radiograph findings in sarcoidosis.
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Advanced chest radiograph findings in sarcoidosis.
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Noncaseating granuloma surrounded by epithelioid cells, from the medulla oblongata. Also shown are nodular inflammatory infiltrates consisting of multinucleated giant cells, macrophages, and lymphocytes (hematoxylin and eosin, 40x).
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Noncaseating granuloma in medulla oblongata showing the granuloma surrounded by epithelioid cells and nodular inflammatory infiltrates (hematoxylin and eosin, 20x).
