WASHINGTON, D.C.—Speakers discussed some key characteristics, diagnostic challenges and treatment considerations for neurosarcoidosis at an ACR Convergence 2024 session, Neurosarcoidosis: Sharing the Headache, in which they emphasized the importance of collaborative care.
Neurosarcoidosis Features & Diagnostics
The multi-system inflammatory disorder sarcoidosis requires extensive diagnostic exclusion. It is a rare condition characterized by the formation of noncaseating granulomas in various organ systems. A minority of these patients have symptoms related to granulomas in the nervous system, termed neurosarcoidosis.
Dr. Agnihotri
One of the speakers, Shruti Agnihotri, MD, director of the Division of Comprehensive Neurology at the University of Alabama at Birmingham, noted a 2017 study that found that 34% of sarcoidosis patients had neurological involvement, although previous estimates placed this lower.1 Neurologic manifestations are the presenting features in around 50% to 70% of neurosarcoidosis patients, so people with neurosarcoidosis don’t always carry a previous diagnosis of sarcoidosis. In patients with known sarcoidosis, about 5% eventually develop neurological involvement.2
The severity and specific clinical manifestations of neurosarcoidosis are highly variable. Cranial neuropathies are the most frequent presentation, most commonly involving the optic or facial nerve. Optic neuropathy tends to cause subacute vision loss, usually with retrobulbar pain.
Myelopathy is another common presentation, but neurosarcoidosis can also present as an aseptic meningitis or as parenchymal disease (e.g., of the pituitary gland). Peripheral nervous system symptoms can also occur, although less commonly than central nervous system disease, for example, a large fiber-type neuropathy with a mononeuritis multiplex presentation.
Dr. Agnihotri added that small fiber neuropathies seem to be quite common in sarcoidosis. Current consensus is that these should qualify as para-neurosarcoidosis, as they don’t seem to directly result from granulomatous infiltration nor respond well to standard sarcoidosis treatments.
Diagnosis of neurosarcoidosis is typically a challenging, multistep process often necessitating collaboration between multiple specialties, as symptoms overlap with those of many other neoplastic, autoimmune, infectious and cardiovascular diseases.
Achieving a diagnosis of definite neurosarcoidosis is relatively uncommon, as it requires specific clinical features, consistent diagnostics (e.g., magnetic resonance imaging, cerebrospinal fluid and/or electromyography/nerve conduction studies) and nervous system histology, and neural samples are difficult to obtain for the latter.2,3 More often, patients are diagnosed with probable neurosarcoidosis, in which clinical presentation and diagnostics are consistent with neurosarcoidosis, and histology confirms sarcoidosis in another system. These features without any histologic confirmation may be termed possible neurosarcoidosis.3
Management
Because most of the data in neurosarcoidosis derive from retrospective, single-center trials, treatment is heavily reliant on expert opinion, and only two therapies for sarcoidosis have achieved official approval by the U.S. Food & Drug Administration.2 The European Respiratory Society (ERS) released a helpful guideline on the management of sarcoidosis in 2021, under the leadership of sarcoidosis expert Robert Baughman, MD, a pulmonologist and professor of medicine at the University of Cincinnati.4
Huzaefah Syed, MD, MPH, FACR, associate professor at Virginia Commonwealth University (VCU) and co-director of the multidisciplinary sarcoidosis program, pointed out that although corticosteroids are still the backbone of treatment for neurosarcoidosis, steroid-sparing agents, such as methotrexate, azathioprine and tumor necrosis factor inhibitors, have been playing a larger role in recent years.
Dr. Syed
Under the ERS guideline, glucocorticoids are the recommended first-line agents but may eventually be tapered if a patient has a good response. Patients with continued disease or flare could start a glucocorticoid-sparing agent, such as methotrexate. Mycophenolate mofetil (MMF) and azathioprine are additional glucocorticoid-sparing options (but with lesser evidence). Glucocorticoids can then be tapered if patients are doing well.
Dr. Syed noted that at the VCU Sarcoidosis Clinic, they move to methotrexate relatively quickly, or to azathioprine if methotrexate is contraindicated. Less commonly they might employ leflunomide or MMF.
The next options for persisting disease are adalimumab or infliximab per the ERS guideline and per the general practice at the VCU Sarcoidosis Center.
If patients have significant symptoms from small nerve neuropathy para-neurosarcoidosis, clinicians can also consider adding standard approaches for neuropathic pain, such as gabapentin, duloxetine or tricyclic antidepressants.
Refractory Disease
For patients who still have poorly controlled disease on infliximab or adalimumab, Dr. Syed recommends checking for antidrug antibodies, which can make these drugs ineffective. She explained that adding an oral immunosuppressant can decrease the risk of such antibodies; at VCU they prescribe methotrexate (or azathioprine or MMF if methotrexate is contraindicated) to most of their patients who are taking adalimumab or infliximab.
Neurosarcoidosis can mimic a great number of diseases. “So you always have to consider another diagnosis like infection or malignancy if your patient is not improving when you think they really should be,” said Dr. Syed.
Dr. Agnihotri concurred that particularly for refractory patients with possible neurosarcoidosis or isolated neurosarcoidosis without other systemic findings, it’s important to reexamine the diagnosis.
If the diagnosis is clearly established and still refractory to treatment, options include cyclophosphamide, rituximab, tocilizumab or tofacitinib, but the data for these agents are of even poorer quality.
Tapering Medications
Dr. Syed shared that although many patients would like to taper off their medications, little is known about the best ways to do this. She noted that some cases of sarcoidosis do go into remission, but more is known about this in the pulmonary setting than in sarcoidosis with other types of organ involvement.
“When it comes to neurosarcoidosis, I think overall we’re probably just more nervous to taper these drugs off,” Dr. Syed said.
True relapse rates are unclear, but may be high, even when medications are tapered and not stopped suddenly. “If you do decide to taper a medication, consider closely monitoring symptoms and employing imaging while you slowly taper,” said Dr. Syed. “And consider continuation of at least methotrexate or another oral steroid-sparing agent.”
Dr. Agnihotri added that cranial neuropathy manifestations of neurosarcoidosis can sometimes be monophasic and self-limiting, so some patients may not require long-term treatment.
Collaborative Care
Dr. Syed also highlighted the importance of collaborative care for sarcoidosis, as specialists from neurology, ophthalmology, pulmonary, cardiology, rheumatology and other disciplines may need to coordinate both initial diagnostic evaluation and ongoing care.
Although not every patient can be seen in a dedicated sarcoidosis center, Dr. Syed touted their benefits. Such clinics allow patients to see multiple providers and get much of their lab work and imaging done in a single day, and the close collaborative contact also benefits and informs providers. Such centers are well situated to advance high quality patient-centered care and also provide important avenues for research, teaching and community outreach.5
“Multi-disciplinary clinics can really help improve the efficiency of patient care while increasing communication between providers,” Dr. Syed concluded.
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
References
- Joubert B, Chapelon-Abric C, Biard L, et al. Association of prognostic factors and immunosuppressive treatment with long-term outcomes in neurosarcoidosis. JAMA Neurol. 2017 Nov 1;74(11):1336–1344.
- Fritz D, van de Beek D, Brouwer MC. Clinical features, treatment and outcome in neurosarcoidosis: Systematic review and meta-analysis. BMC Neurol. 2016 Nov 15;16(1):220.
- Stern BJ, Royal W III, Gelfand JM, et al. Definition and consensus diagnostic criteria for neurosarcoidosis from the Neurosarcoidosis Consortium Consensus Group. JAMA Neurol. 2018 Dec 1;75(12):1546–1553.
- Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021 Dec 16;58(6):2004079.
- Kron J, Syed A, Iden T, et al. Tackling health care disparities: How to build a sarcoidosis center. Sarcoidosis Vasc Diffuse Lung Dis. 2022;39(3):e2022024.
