A young man with numbness in arms and legs

Pathobiological mechanisms of noncaseasting granulomatous inflammation

CNS involvement from sarcoidosis occurs in approximately 5%–15% of sarcoidosis patients and can manifest with variable combinations of leptomeningitis, meningoencephalitis, pachymeningitis, optic neuropathy, other cranial neuropathies, hypothalamic/pituitary involvement, myelitis, or radiculitis.⁷ While sarcoidosis is classically and formally described as a multisystem disease, about 10%–20% of neurosarcoidosis cases have seemingly exclusive CNS involvement.^7,8

On MRI, neurosarcoidosis spinal cord parenchymal involvement can appear longitudinally extensive, smaller segmental or multifocal.^7,9 In addition to the enhancement pattern seen in this case, there may also be enhancement involving the central canal, nerve roots, meninges, or other parts of the CNS if also affected by neurosarcoidosis.⁹ Neurosarcoidosis lesions can exhibit persistent T1 post-gadolinium enhancement for months or years at a time, even with treatment, whereas inflammatory-demyelinating lesions of MS and NMO typically remit within 1–2 months.^4,8,10,11

Our patient's chest CT revealed bilateral hilar and mediastinal calcified lymph nodes and perilymphatic pulmonary nodules, consistent with pulmonary sarcoidosis. If the CT is negative, a whole-body Fludeoxyglucose Positiron Emission Topography (FDG-PET) can be diagnostically valuable to look for metabolically active but still normal sized lymph nodes that may be targets for biopsy. A skin examination looking for evidence of cutaneous sarcoidosis and eye examination (and sometimes conjunctival biopsy) may also be helpful in this context.

Angiotensin-converting enzyme (ACE) level is commonly considered in the diagnostic evaluation for sarcoidosis, but it is a nonspecific marker. While serum ACE tends to be higher on average in patients with sarcoidosis (and especially active pulmonary sarcoidosis) compared to those without sarcoidosis, sensitivity for sarcoidosis is low, 29%–60%, with specificity of about 89%.^12,–,15 Similarly, in the CSF, sensitivity and specificity of ACE for neurosarcoidosis are 24%–55% and 94%, respectively.^16,17 In summary, a normal ACE should not exclude neurosarcoidosis, and an elevated ACE can be nonspecific and sometimes seen in association with other inflammatory, infectious, malignant, or metabolic processes or polymorphisms in the ACE gene.

The inflammation of sarcoidosis is characterized by well-formed, noncaseating (nonnecrotizing) granulomas containing monocytes and macrophages, T lymphocytes, B lymphocytes, and fibroblasts, among other cell types (figure 2).^18,19 Granulomas in the CNS tend to have a perivascular predilection. The granulomatous inflammation of sarcoidosis is primarily T cell mediated, and classically considered Th1 driven, but emerging evidence promotes a Th17-driven process, at least in the lungs and mediastinal lymph nodes.^20,21 Common cytokines involved in signaling in sarcoidosis include IFNγ, TNFα, and various interleukins and chemokines.^18,19 Environmental and infectious exposures have been proposed as possible contributors to sarcoidosis susceptibility, but none have yet been convincingly demonstrated.¹⁹ Genetic susceptibility to sarcoidosis has been associated with specific human leukocyte antigen alleles, supporting an autoimmune etiology.¹⁹

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Figure 2 Putative mechanisms of noncaseating granulomatous inflammation in neurosarcoidosis

This figure illustrates putative mechanisms the assembly and organization of the complex coordination of putative cellular and molecular mechanisms, which are thought to represent the pathobiological underpinnings for noncaseating granulomatous inflammation in neurosarcoidosis. Immune cells traffic into the “target tissue” via arterioles and can subsequently exhibit properties of antigen presentation. A collection of various immune cell types (e.g., B and T cells, macrophages, and plasma cells) acquire an affinity to become part of what we analogize as an “island of inflammatory cells,” delimited by a perimeter principally composed of hyaline collagen (shown on the figure). As opposed to granulomatous inflammation associated with tuberculosis and other processes, those compositional cellular elements in sarcoidosis usually do not undergo necrotic granulomatous transformation. The M1 designated macrophage is an important constituent of the sarcoid granuloma, and most particularly with respect to its ability to coordinate the inception and prolongation of “pro-inflammatory” cascades, thereby representing a key feature of the noncaseating granuloma of sarcoidosis. Alternatively, the M2 macrophage is characterized by its ability to provide reciprocal properties, in striking contradistinction, to the M1 macrophage, by exhibiting cardinal anti-inflammatory characteristics, including, but not limited to, the elaboration of a highly stereotyped set of anti-inflammatory cytokines and chemokines. Taken together, the repertoire and heterogeneity of intragranulomatous mononuclear cells serve to orchestrate the immune regulatory networks that provide for both the ignition and the complex coordination of the cellular and humoral factors, which have now become classic hallmarks of granulomatous inflammation. The noncaseasting granuloma is equipped with counterbalancing mechanisms (i.e., the inflammatory “braking system”) capable of both high precision attenuation, as well as a corresponding ability to abolish those cascades that serve to provoke and perpetuate granulomatous inflammation in nearly every organ and tissue within the human body. TCR = T cell receptor.

Several proposed diagnostic approaches to neurosarcoidosis have been used in the literature over the years.^22,23 Updated consensus diagnostic criteria for neurosarcoidosis were published in 2018.²⁴ Diagnosis of “definite” neurosarcoidosis is supported by a confirmatory biopsy from the nervous system consistent with sarcoidosis in the context of a consistent clinical phenotype and rigorous exclusion of other causes, particularly infection and malignancy. However, CNS biopsy is often not preferable or advisable due to risk of morbidity. A diagnosis of “probable” neurosarcoidosis, as in this case, can be made with a syndrome consistent with granulomatous inflammation of the CNS and a confirmatory biopsy of sarcoidosis from another organ system. Cases in which sarcoidosis is suspected but in which there is no biopsy confirmation are best designated as “possible” neurosarcoidosis.

There are no randomized controlled trials of treatment of CNS neurosarcoidosis. While glucocorticoids are effective for most patients with neurosarcoidosis, the doses needed to achieve or sustain remission can be prohibitive due to glucocorticoid toxicity.²² Common steroid-sparing therapies in clinical practice include methotrexate, azathioprine, mycophenolate mofetil, leflunomide, hydroxychloroquine, and, increasingly, infliximab.²⁵ Retrospective analyses suggest that mycophenolate mofetil may be less effective than methotrexate (at least for preventing “relapse”), but such studies risk confounding by indication.^25,26 In retrospective analyses, infliximab, a TNFα inhibitor, is associated with favorable outcomes, including some cases refractory to other therapies.⁸

In the patient presented here, given concern about glucocorticoid adverse effects, the patient elected to initiate infliximab with weekly oral methotrexate and tapered off glucocorticoids completely within 4 months with gradual resolution of symptoms without functional limitation. Surveillance MRIs at 7 and 12 months showed complete remission.