NAPLES, FL—Although patients with symptomatic neurosarcoidosis account for approximately 5% to 15% of people with systemic sarcoidosis, making it a rare manifestation of an uncommon disorder, neurosarcoidosis is associated with substantial morbidity and with mortality rates ranging from about 1% to 7%. Steroids can be an effective treatment, but high doses over a long period of time are often required, relapse rates are relatively high, and a significant percentage of cases are refractory to first-line therapy. Additional therapies, including steroid-sparing immunosuppressive agents, show promise. Current evidence is based largely on small series of patients, however, and these treatments remain off-label, according to a presentation given at the 45th Annual Meeting of the Southern Clinical Neurological Society.
In the absence of accepted standards, treatment mainly is informed by small series and anecdotal experiences, said Christopher Eckstein, MD, Assistant Professor of Neurology at the Duke University School of Medicine in Durham, North Carolina. “Nobody really knows exactly what to do,” he said.
A Higher Cutoff for Recurrence
To compensate for this uncertainty, as well as for the lack of robust data, Dr. Eckstein offered clinical treatment strategies based on his own experience and other anecdotal sources. Steroids play a large role in treatment. For acute treatment, corticosteroids are the main first-line therapies and typically are administered in high doses for a long time. “It is not uncommon for me to start patients with clear neurosarcoidosis on 80 mg to 100 mg of prednisone a day, keep them there for four weeks, and then taper down by 10 mg every two weeks until I get to 40 mg,” he said. “Then I take it down by 5 mg every two weeks till I get to about 10 mg. The reason I slow it down is because, once I get [the dosage] to about 40 mg or below it, that is where I tend to see, anecdotally at least, my sarcoid patients relapse.”
For patients with cardiac sarcoidosis who present to Duke, clinicians usually reduce the dosage to 25 mg before patients start to have recurrent symptoms, said Dr. Eckstein. Recurrent symptoms usually do not arise until the dosage goes below approximately 10 mg for patients with pulmonary sarcoidosis. Patients with neurosarcoidosis often require higher doses, however, said Dr. Eckstein. “Frequently, when I hit that 35-mg mark, I do another MRI, and we will see patients who either have recurrence of their symptoms or their enhancement has returned. It is not unusual for patients to be on steroids sometimes up to a year.”
Cases of refractory or recurrent neurosarcoidosis generally are treated with broad-spectrum immunosuppression. Several steroid-sparing agents and mechanisms are available, and their use in neurosarcoidosis is based on case series involving small numbers of patients. The original case series for methotrexate included eight patients, that for mycophenolate included three patients, that for azathioprine included less than 12, that for cyclosporine had 13, and that for TNF-alpha inhibitors such as infliximab and adalimumab included 17.
Dr. Eckstein will often start patients on one of these agents when he is weaning them from a steroid. “I usually do repeat MRIs when I get them around 35–40 mg, when I get them below 20 mg, and then when I get them off prednisone,” he said. “If we see recurrence, or their symptoms start to recur, and we see that they are refractory to steroids alone, we will often add these in.”
These agents are increasingly being added to first-line therapy for neurosarcoidosis, along with prednisone, said Dr. Eckstein. “But I find that enough [patients] are steroid-responsive and do not need things like infliximab that I do not necessarily start them right away.”
Choosing Among Oral Agents
Among the oral therapies, he uses methotrexate most. “I previously used a lot of mycophenolate; however, a recent retrospective comparison found that methotrexate’s recurrence level was much lower than [that for] mycophenolate,” said Dr. Eckstein.
Hydroxychloroquine, which works well in treating mucocutaneous forms of sarcoidosis, does not seem especially effective for neurosarcoidosis, said Dr. Eckstein. He tends not to use cyclosporine often, considering that better tolerated therapies are available. For certain patients, cyclophosphamide is the only therapy that will control neurosarcoidosis, said Dr. Eckstein. These patients tend to be exceptionally refractory. “But generally with cyclophosphamide—with high enough doses for long enough—you can usually suppress it,” he said.
Adalimumab has been assessed mostly as a treatment for myelopathies. Studies suggest it to be effective and easy to tolerate.
Steroid-Sparing Agents Can Be Effective
The steroid-sparing agent that Dr. Eckstein currently uses the most is infliximab, which is administered IV. The patients tend to tolerate it well and have good outcomes. Dr. Eckstein usually starts treatment at the lowest dose he thinks will be efficacious. “Most neurologists have not used a lot of infliximab, but they send people to rheumatology for it,” he said. “I start at 5 mg/kg, I do an induction at day one, day 14, and then four weeks later, followed by maintenance dosing every eight weeks.”
For most of his patients, this regimen is sufficient, although some patients require doses of 8 mg/kg, and others need an infusion at that level every four to six weeks. These regimens are often effective. While such patients are usually on concurrent prednisone, a recent trend is to use concurrent methotrexate to prevent reactions to infliximab. A few patients who receive infliximab plus methotrexate tend to tolerate the combination fairly well, said Dr. Eckstein.
Researchers have studied one nonpharmacologic treatment for neurosarcoidosis: radiotherapy. Dr. Eckstein cited recent case reports that examined low-dose, whole-brain radiation in refractory cases. “This is not something I have any hands-on experience with,” he said. “Most of my patients have responded to one of the other steroid-sparing agents [listed] when they’re refractory. But this is something that may be looked at more in the next several years. If there are people who have a very focal kind of encephalitic nodules, they can [undergo] fractional or focal radiotherapy.”
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