Evaluation of Parenchymal Neuro-Behçet Disease by Using Susceptibility-Weighted Imaging

Discussion

In the initial studies regarding parenchymal NBD, swelling of the brain stem, multiple foci of cell infiltration, and perivascular inflammatory cell cuffs were pathologically demonstrated.^15,16 Rubinstein and Urich¹⁷ supported these neuropathologic findings and reported that lesions became increasingly chronic with extensive gliosis; atrophy; thickening and fibrosis of the meninges in some cases; and chronic relapse of inflammatory cellular infiltration around venules, capillaries, and occasionally arteries. In other studies, perivascular lymphocytic infiltration without fibrinoid necrosis, thrombosis, or endothelial degeneration were reported.^18–21 In 1996, Hadfield et al²² reported the neuropathologic findings of an NBD patient in whom the frontal lobe, capsula interna, basal ganglia, cerebellum, and brain stem had acute, multifocal encephalitis, indicating numerous foci. In the conclusion of their report, it was noted that vasculitis and consequent superimposed thrombosis for necrotizing lesions in NBD were seen in the absence of vessel wall inflammation. However, necrotizing lesions may be present because of primary acute neutrophilic inflammation. In 2004, Mirsattari et al¹¹ hypothesized that an NBD patient with prompt atrophy of the brain and of generally all parts of the central nervous system (particularly the brain stem) involved chronic meningoencephalomyelitis. T-lymphocytes were exclusively present and showed perivascular cuffing. In 2008, Hirohata²³ evaluated biopsied or autopsied brain tissues from acute NBD, chronic progressive NBD, and NBD in long-term remission. In acute NBD, infiltration of mononuclear cells around small vessels was revealed, as was apoptosis of most neurons. Infiltration of mononuclear cells also was observed around small vessels in the pons, cerebellum, medulla, capsula interna, and midbrain in the acute attack phase of chronic progressive NBD. In the biopsy of the inactive NBD patient, the most prominent features were atrophy of the brain stem and gliosis. Foci of mild infiltrations of mononuclear cells were still detected around small vessels. Hirohata²³ suggested that soluble factors, including proinflammatory cytokines, were produced in neuronal apoptosis. Despite these findings, Scardamaglia et al²⁴ reported a case with NBD where prominent fibrinoid necrosis was observed in small postcapillary venules, and there was surrounding acute and chronic inflammation, consistent with vasculitis, in a brain biopsy. Thus, the pathogenesis of NBD remains unclear, and the most accepted findings are perivascular lymphocytic infiltration without objective vasculitic infiltration.

SWI is a 3D, long echo time, T2*GE sequence technique that allows enhancement of local contrast by using a high-pass filtered phase mask, exploiting the magnetic properties of tissues, such as blood or iron-containing cells, that affect magnetic field inhomogeneity.^25–27 SWI exploits the magnetic susceptibility differences between tissues, resulting in phase differences between regions containing paramagnetic deoxygenated blood products (deoxyhemoglobin, intracellular methemoglobin, or hemosiderin) and surrounding tissue.²⁸ This method allows visualization of veins with diameters in the submillimeter range even with conventional 1.5T whole body MR imaging systems.²⁵ To detect venous vessels, the deoxygenation state of hemoglobin is used as an intrinsic contrast mechanism.²⁹ SWI has been applied to various pathologies of the brain that affect magnetic inhomogeneity, such as stroke,³⁰ trauma,³¹ cerebral cavernous malformation,³² arteriovenous malformation,³³ pathophysiology affecting iron-storage conditions,³⁴ intratumoral hemorrhages,³⁵ and cerebral amyloid angiopathy.³⁶ SWI is particularly helpful for the evaluation of diffuse axonal injury that is often associated with punctate hemorrhages in the deep subcortical white matter, which are not routinely visible on CT or conventional MR imaging sequences.²⁸ Tong et al^31,37 and Babikian et al³⁸ have both shown that SWI has 3–6 times the sensitivity of conventional T2*GE sequences for detecting the size, number, volume, and distribution of hemorrhagic lesions in diffuse axonal injuries.

In our study, we detected the hemorrhagic component with SWI in 42 of a total of 53 lesions. Despite the SWI data, T2*GE and T2 FSE could only detect 3 and 2 hemorrhagic lesions, respectively. In addition to hemorrhagic lesions in SWI, 6 lesions exhibited prominent venous structures, 2 displayed occlusion of thalamostriate veins, and 1 revealed a collateral venous structure. Eight lesions were shown with SWI, but these lesions were not detected with T2*GE or T2 FSE. Nine lesions that were detected with SWI could not be observed with T2 FSE, and 14 lesions that were detected with SWI could not be detected with T2*GE. However, 2 lesions were not detected with SWI, but they were observed to be hyperintense with T2*GE and T2 FSE. In this condition, despite hemorrhagic lesions that accompanied other venous pathologies shown sensitively by SWI, some of the nonhemorrhagic lesions could not be determined, probably because of low anatomic resolution or because of nonhemorrhagic gliosis in the chronic period. Thus, although SWI shows almost all of the hemorrhagic lesions, it is insensitive to some of the nonhemorrhagic lesions. Therefore, T2 FSE and T2*GE examinations should be used together with SWI to establish both hemorrhagic and nonhemorrhagic Behçet lesions. No remnant of hemorrhage was found in 2 NBD cases with advanced brain atrophy and extensive infiltration. This outcome may suggest that previous remnants of hemorrhage may be resorbed subsequently in chronic BD or that there is possibly a different nonhemorrhagic pathophysiologic mechanism. Calcification cannot be definitively identified by MR imaging because its signals are variable on conventional spin-echo T1- or T2-weighted images and cannot be differentiated from hemorrhage by gradient-echo images because both will cause local magnetic field changes and appear as hypointensities. However, phase images on SWI can help differentiate calcification from hemorrhage because calcification is diamagnetic, whereas hemorrhage is paramagnetic, resulting in opposite signal intensities.^13,28

Some studies have suggested that venous involvement may be the primary cause of parenchymal injury. However, arterial involvement was suggested by Hirohata.²³ We consider all neuropathologic studies because both arterial and venous perivascular infiltration constitute NBD involvement. Indeed, arterial ischemia may cause white infarcts without hemorrhaging. In contrast, obvious venous ischemia is generally hemorrhagic in pathology. Cerebral venous ischemia leads to parenchymal injury because of locally increased venous pressure, which exceeds the pressure generated by the arteries. Because of leaking of blood into the damaged area, infarcts are more likely to encounter hemorrhagic transformation than arterial types of ischemic stroke.³⁹ Previous neuropathologic studies generally did not examine lesions for iron accumulation, hemorrhage, or remnants of hemorrhage. Landeyro et al⁴⁰ presented a case of an autopsy of an NBD patient in whom multiple hemorrhagic infarctions were found in the brain stem. Microscopic examination revealed generalized perivascular lymphocytic and neutrophilic inflammation in small and medium vessels with intense diapedesis bleeding. This phenomenon was predominant in the brain stem. Similarly, for this case, parenchymal NBD lesions with SWI were found to be hemorrhagic. Thus, parenchymal lesions in NBD are probably associated with venous structures. In our study, almost all hemorrhagic findings resulted from venous lesions, though in pathologic studies, both arterial and venous vascular structures generally are infiltrated, which requires clarification. Because the arterial wall is thicker and more elastic than the venous wall and the luminal pressure is higher in arteries, we believe that veins are more frequently affected, because of the external mechanical effects and inflammatory chemical substances, which have a higher potential impact on the thinner venous wall and lower venous luminal pressure.⁴¹ In our study, 1 of 23 patients demonstrated arterial infiltration, whereas we believe that the others probably showed venous infiltration. Importantly, in our study, because our approach is supported, 42 of 52 lesions were hemorrhagic, venous occlusions were shown in deep venous structures in some cases, irregularities of venous contours were observed, and venous collateral structures were revealed.

In patients with prior large cerebral hemorrhage or chronic hypertension, the prevalence of microhemorrhages were reported to be between 57% and 78%.⁴² Similarly, in patients with traumatic brain injury, it is known that microhemorrhages may occur.²⁸ Therefore, patients with neurologic or other diseases involving the central nervous system, traumatic brain injury, and hypertension were excluded from this study.

An important limitation of our study is the lack of sufficient cases, which prevented the classification of acute, subacute, and chronic lesions into separate groups. The interpretation of acute, subacute, and chronic lesions could be beneficial for understanding pathogenesis and the prognostic process. The present study was performed by using a 1.5T MR device. Comparing 1.5T with 3T and 7T high-field devices, the high-field SWI technique may provide a more detailed description about venous structures. Thus, using high Tesla devices could be advantageous for revealing venous pathologies in future studies. In the present study, the data were collected prospectively from patients who visited our tertiary outpatient clinics for a relatively short time, and further examinations were not performed. Future studies by using SWI in a larger number of NBD cases and for longer times such as 5 or 10 years may provide further information about the generation and evolution of the lesions.