Clinical and MRI phenotypes of sarcoidosis-associated myelopathy

Discussion

We have described the clinical characteristics, CSF findings, and distinct neuroimaging phenotypes seen in a cohort of 62 patients with SAM. Epidemiologic and clinical factors may act as clues to the diagnosis of SAM. The incidence of sarcoidosis is known to be increased in African Americans,¹⁸ and in recent years, the genetic contribution to sarcoidosis and neurosarcoidosis risk has become more clearly elucidated.^19,20 This is borne out by the substantial proportion of African American patients in our cohort (48%) and the relatively frequent family history of sarcoidosis (16%). Clinically, we have shown that SAM typically has a chronic temporal evolution dominated by sensory symptoms (in keeping with the dorsal-predominant location of medullary inflammation). Unsurprisingly, our study showed that CSF studies in SAM typically reveal nonspecific markers of inflammation (i.e., pleocytosis and elevated protein). However, the presence of CSF-restricted oligoclonal bands in around 20% of samples tested was a notable finding and emphasizes that differentiating SAM from other neuroinflammatory disorders based on clinical and imaging factors is crucial.

As a rare manifestation of sarcoidosis and a rare cause of myelopathy, SAM can be challenging to diagnose and may be mistaken for idiopathic transverse myelitis,⁸ NMOSD,¹⁰ compressive myelopathy,²¹ meningeal metastatic disease,²² or a spinal cord tumor.²³ Moreover, compared with many pathologies affecting the spinal cord, neurosarcoidosis is a treatable condition—often responding well to steroids, immunosuppressive therapies, or certain monoclonal antibodies.^24,25 Of interest, although disability status of SAM in a subset of patients in our cohort showed improvement in 52% after 1-year follow-up, almost 26% had worsening disability, a finding that may reflect the refractory and aggressive neuroinflammatory process in SAM in some patients or the delay in diagnosis and treatment that may also affect the overall outcome. Thus, it is essential for clinicians to recognize the clinical characteristics, CSF, and imaging findings associated with this disorder.

An enhancing MRI lesion was demonstrated in all but 1 patient during evaluation of their myelopathy (often many months after symptom onset), and the central findings of our study were the 4 distinct radiologic phenotypes of SAM identified. Our finding that longitudinally extensive myelitis with predominantly dorsal subpial ± meningeal enhancement was the most common imaging pattern is in agreement with a previous study that focused on comparing longitudinally extensive lesions of SAM with NMOSD.¹⁰ Taken together, these findings suggest that this can be considered the classic imaging phenotype of SAM. However, given that this MRI lesion pattern was only present in 45% of our cohort, our description of other distinct imaging phenotypes occurring in SAM is of particular importance. Short tumefactive lesions may cause the most diagnostic difficulty, and indeed, 4 of our patients with this lesion type actually underwent spinal cord biopsy (before attendance at our clinic). Spinal cord biopsy carries a risk of substantial morbidity^26,27 and should be avoided except in circumstances where there is a high likelihood of a tumor. We suggest that dorsal-predominant enhancement or the trident sign¹¹ in a tumefactive lesion should be considered clues to SAM. Once SAM is suspected, a diagnosis of sarcoidosis can usually be established based on body imaging (CT or PET-CT) and targeted systemic biopsy (most frequently of involved lymph nodes).^1,14

The patterns of spinal meningeal involvement we identified in SAM are also interesting. We have shown that meningeal and/or nerve root enhancement can occur in isolation or in conjunction with frank subpial enhancement. Furthermore, although leptomeningitis is often described as typical of spinal meningitis in sarcoidosis,²⁸ we have demonstrated that pachymeningitis also occurs, sometimes in the form of mass lesions with a substantial compressive effect on the spinal cord. In comparison to our study, some previous case series describing neurosarcoidosis have reported that spinal meningitis is far more frequent than intramedullary inflammation.¹ On the one hand, this difference could be due to referral bias (our clinic is a specialist referral center), with intramedullary inflammation posing more diagnostic challenges. On the other hand, differentiating meningeal from subpial MRI enhancement can be difficult, and there is likely to be overlap in what has been described as leptomeningeal in some case series and what we (and other recent radiologic studies of SAM)¹⁰ have described as subpial.

An intriguing and novel finding in our study was the presence of a ventral thoracic spinal cord lesion in 6 patients, with enhancement occurring in close relationship to areas of disc degeneration abutting the cord. In all of these 6 patients, clinical improvement and resolution of MRI enhancement was achieved with medical treatment alone (without surgery). A similar case has been recently described.¹⁷ Furthermore, we also noted that areas of enhancement in SAM frequently occurred at areas of structural change, such as cervical spondylosis. To help differentiate the primary disease process in these cases, subpial enhancement in SAM is typically greater in linear than transverse extent and is continuous across multiple vertebral levels, whereas the pancake-like enhancement seen in spondylotic myelopathy occurs in a transverse pattern over ≤1 vertebral level.²⁹ In some cases, both SAM and cervical spondylosis may be contributing to the clinical and neuroimaging picture—sometimes necessitating surgical decompression in addition to medical management of sarcoidosis. Indeed, the coexistence of SAM and cervical spondylosis has been previously noted in a number of small case series.^30,–,32 Collectively, we interpret these observations as suggesting that the inflammation of SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress, potentially providing clues to the pathophysiology of this condition. The impact of chronic compression of the spinal cord has been well studied in cervical spondylotic myelopathy, with chronic mechanical pressure inducing localized tissue hypoxia, persistent disruption of the blood-spinal cord barrier (BSCB), secondary inflammation (sometimes manifesting with mild CSF pleocytosis), microglial activation, and infiltration of peripheral immune cells.^29,33,34 We hypothesize that in SAM, increased permeability of the BSCB at sites of mechanical stress could be a key step in the evolution of inflammatory lesions, allowing meningeal-based inflammation to spill into the parenchyma. Indeed, pathologic studies suggest that parenchymal brain and spinal cord lesions in neurosarcoidosis occur when leptomeningeal-based granulomatous inflammation (which can be present histopathologically even in the absence of clinical symptoms)³⁵ spreads in a perivascular distribution along small- and medium-sized vessels.^5,36,–,38 Our finding that medullary enhancement in SAM was always contiguous with the surface of the spinal cord supports this theory. Of interest, the spinal meningeal lymphatics are thought to be predominantly dorsally situated,^3,39 where the BSCB is also thought to be most permeable¹⁰ and where subpial enhancement is most frequent in SAM. In addition, longitudinally extensive myelitis of SAM has many radiologic similarities to lesions of NMOSD—a disease characterized by extensive BSCB disruption.⁴⁰ We suggest that BSCB disruption in SAM may not simply be a secondary effect of focal inflammation, but could actually be an important factor in the development and localization of medullary granulomatous lesions.

We found that time to diagnosis was shortest in patients with longitudinally extensive myelitis. This may be because the clinical syndrome is severe and the radiologic features in these lesions are recognized as typical for SAM, prompting appropriate investigation. However, our findings go somewhat against the hypothesis previously described by Junger et al.,²⁶ who postulated that the natural history of spinal cord sarcoidosis was a stepwise evolution from leptomeningeal inflammation to parenchymal inflammation to mass-like lesion formation before the inflammatory process abates and the cord atrophies. Specifically, we found that time to diagnosis was frequently many months or years even in patients in whom enhancement was restricted to the meninges. This suggests that the development of parenchymal inflammation is not determined only by time but perhaps by other factors (such as BSCB permeability).

Our study is the largest study to date of the clinical and neuroimaging phenotypes of SAM. However, our work has some limitations. We reviewed clinical MRI studies acquired at multiple facilities, so sequences were not standardized, and some patients did not have imaging of the whole spinal cord. We only analyzed MRI at the time of presentation—future studies are needed to explore lesion evolution and how this correlates with clinical outcomes. As our study was based on the cohort of patients who attended our specialist clinic, there was almost certainly some referral bias toward more diagnostically challenging or severe cases. In addition, even with the application of the most recent diagnostic criteria, neurosarcoidosis remains a diagnosis lacking certainty in most patients (except those who have undergone CNS biopsy). It is possible that some patients who met the criteria for probable neurosarcoidosis actually had a different underlying pathology of myelopathy (indeed, we suspect this was a possibility in 1 patient in our cohort who had an atypical nonenhancing spinal cord lesion). Finally, CSF findings were not available for all included patients.

SAM is a rare disabling manifestation of neurosarcoidosis, which typically presents as a chronically evolving myelopathic syndrome with predominant sensory symptoms and often poses a diagnostic challenge—potentially resulting in delayed treatment and irreversible disability. Through detailed neuroimaging review of a large number of cases, we have identified a number of characteristic lesion patterns (all demonstrating subpial and/or meningeal enhancement as a key feature)—potentially aiding physicians in the recognition and diagnosis of SAM. Furthermore, our observations regarding postgadolinium enhancement occurring in areas of the spinal cord susceptible to mechanical stress provide interesting clues to the pathophysiology of spinal cord lesions in this elusive disorder.