Vascular Involvement in Neurosarcoidosis

Discussion

Vascular manifestations in NS are likely more common than previously reported. These may involve both large and smaller vessels and may result from primary vascular involvement or occur secondarily to involvement of surrounding structures. Although our study noted various imaging findings suggestive of vascular involvement, it is noteworthy that most of these studies were performed on patients who were already on treatment and clinically improved. That patients with positive VWI findings tended to have more imaging abnormalities overall may imply that these patients have more extensive disease. It is also possible that the prevalence of vascular involvement may be even higher in patients with NS who are treatment naive.

Involvement of the larger intracranial internal carotid artery vessels is generally considered rare and may not translate into ischemic strokes.⁵ As such, the occurrence of lacunar strokes is much more common in NS compared with territorial infarcts.^4,5,16,17 As noted in P12, large vessel involvement may also be seen with leptomeningitis secondarily involving the vessel wall. In our cases with vessel wall enhancement, there was no intraluminal thrombus, significant stenosis, or presence of larger infarcts in the involved vascular territory. This may also help explain why thrombotic complications with large vessel involvement are not common in NS.

Arterial perforator involvement at the level of basal ganglia was relatively common in our cohort. Unlike patients with small vessel disease related to stroke or chronic hypertension, we noted increased tortuosity of the perforator vessels.^18,19 Tortuous lenticulostriate perforators may be seen with increasing age or in patients with subcortical vascular dementia.^20,21 However, the involvement of perforator vessels was seen in about 46% (6/13) of our patients and is therefore unlikely to be a chance finding or simply related to age. It is pertinent to point here that one of these patients had a lacunar infarct, whereas another had a microhemorrhage in the basal ganglia region.

Involvement of the medullary veins was seen in 38% of cases. This is similar to the previously reported prevalence of medullary venous involvement of about 33% in NS.¹⁰ In all cases, findings were seen both on VWI-MRI and SWI, with the findings appearing more apparent on the SWI sequences. It is possible that SWI findings may reflect both a combination of slow flow and underlying vascular tortuosity secondary to wall involvement. Because the T1 SPACE primarily captures the anatomic distortion/tortuosity and not the contributory effect of deoxygenated blood or slow flow, it likely only reflects part of the underlying pathologic process. It is therefore possible that the T1WI images likely only reflect the permanent vessel injury. Nevertheless, the discordance between the SWI and T1-SPACE images may be relevant in terms of underlying pathophysiologic effects and needs to be compared against age-matched healthy controls to better define their clinical relevance.

All cases with medullary venous involvement showed parenchymal microhemorrhages to a variable degree, often in the same region as the venous findings on SWI suggesting that the underlying venous involvement could be contributing to the microhemorrhages. Besides NS, engorged medullary veins may also be seen with dural sinus thrombosis or fistula. A prior study noted mild paucity of cortical veins in patients with NS, although the difference was not statistically significant.¹⁰ However, they used postcontrast magnetization-prepared rapid acquisition with gradient echo images for assessment of the cortical veins. Because our study used a different imaging sequence, the cortical veins could not be assessed.

Involvement of the longitudinal and transverse caudate veins tended to follow a similar distribution and was seen in all patients with medullary venous involvement. In addition, 1 patient had isolated involvement of the caudate veins. Imaging assessment of the deep cerebral veins, sagittal sinuses, and cortical veins was, however, more technically complicated, partly due to a component of physiologic variability in venous anatomy and partly due to flow artifacts from slow flow. Although some patients with parenchymal venous involvement had prominent signal along the cortical veins, underlying flow artifact or anatomical variation could not be excluded with certainty. Their assessment was therefore not included in the analysis.

Our study, although performed on a small patient cohort, provides insights into the spectrum of vascular involvement in patients with NS using dedicated VWI-MRI. Our findings support prior observations that cerebrovascular manifestations are likely more common than previously realized and involve both arterial and venous structures, similar to primary angiitis of the CNS.^5,7 This is also supported by the review of brain histopathology slides, which were available in 6/13 patients with NS.

Our findings are also concordant with previously reported autopsy literature. Delaney et al.,²² for example, reviewed brain autopsy cases in 14 patients with NS and noted subclinical infarctions in 9 cases. Presence of infarcts and hemorrhage on autopsy studies in NS has also been reported in multiple prior case reports.^5,7,23 Our findings are also similar to the reported autopsy literature in terms of distribution of involvement of vessels.^23,24 For example, among arterial structures, involvement of the small arterial perforators is reportedly most frequent. In terms of venous involvement, granulomatous phlebitis has been most frequently noted in the paraventricular veins along the lateral and third ventricles. This is similar to our observations where involvement of either or both these vessels was seen in 8/14 cases (57%). Systemic vasculitis associated with sarcoidosis has been previously reported.^25,26 More recent sporadic case reports have also noted CNS vasculitis on conventional angiography or VWI, albeit in patients presenting with stroke.^27,28 Our study, however, documents the extent and distribution of vascular abnormalities in patients with NS without a distinct stroke-like syndrome.

The imaging findings described here are not necessarily specific to NS and may be seen with other intracranial pathologies and vasculitides, although it is possible that when combined with the constellation of other findings (e.g., meningitis, white matter lesions, and cranial nerve involvement), they may be more indicative of NS than primary angiitis of the central nervous system or infectious/inflammatory vasculitis. The emphasis of the current work is to highlight that these imaging findings in NS exist and are more common than previously recognized.

Finally, given that 9/13 (69%) patients had some evidence of vascular involvement, our findings would support having a dedicated imaging protocol for patients with NS that can capture these abnormalities. The sequences that we found most useful in the analysis included 3D T1W black-blood fast-spin echo imaging sequences using variable flip-angle refocusing pulse. These are available under different names across vendors, such as SPACE (Siemens, Erlangen, Germany); volume isotropic turbo spin echo acquisition; Philips Healthcare, Best, The Netherlands; and CUBE (GE Healthcare, Milwaukee, Wisconsin).¹³ In addition, we used SWI that is again available under different names across vendors (SWI for Siemens; susceptibility-weighted angiography for GE and SWI phase for Philips). Including other routine sequences such as FLAIR, T2-WI, and diffusion-weighted imaging, our study protocol had a cumulative time of 30–35 minutes, which is a clinically reasonable time frame and should be easily adaptable in the clinical workflow. An important point is the need for the scans to be acquired at a higher magnet strength (such as 3T), given the requirement for higher spatial resolution.

Limitations of our study include the small sample size and absence of a control group which restricted a more detailed analysis between individual imaging manifestations and clinical features. However, our current work presents a preliminary study evaluating the spectrum of imaging findings in a rare disease. The mean cardiovascular risk factors in our study were 1.3 per patient, and their confounding effects on large vessel enhancement or NEWM remain unaddressed. A prior study previously reported a prevalence of about 39% for NEWM changes in healthy subjects who had mean cardiovascular risk factors of 1.04.²⁹ In addition, because a number of patients were clinically improved and on therapy, the prevalence of PVE on VWI is likely underestimated in the current cohort. PVE has been shown to be significantly associated with cerebrovascular events in NS, and it is possible that their assessment in treatment-naive patients may provide additional insights in the frequency of vascular involvement.⁴ Finally, we used black-blood imaging with a voxel size of 0.63 mm³. Although it provides much better resolution than routine clinical imaging, a voxel size of 0.5 mm³ would be more optimal for flow suppression and vessel wall characterization.

In conclusion, involvement of intracranial arterial and venous vessels in NS is more common than previously considered. Our preliminary work outlines the spectrum of imaging findings and their distribution. It is possible, given the high prevalence, that these findings may be useful in differentiating NS from other neuroinflammatory disorders like multiple sclerosis and neuromyelitis optica spectrum disorders where vascular involvement is not well documented. Finally, our work would support having a dedicated VWI protocol to evaluate patients with NS to better understand the evolution of these findings with therapy.