Brainstem involvement as a cause of central sleep apnea: pattern of microstructural cerebral damage in patients with cerebral microangiopathy

Abstract

Background: The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea.

Patients and methods: Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis.

Results: In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem.

Conclusion: Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities.

Figure 1. SPM "glass brain" representations (upper row) and statistical FA maps that were superimposed on a normalized T1-weighted template (lower row) showing clusters of microstructural damage of the FD patient group compared to healthy controls (ANCOVA, modelling age as a co-variate; p<0.001, corrected for multiple comparison; minimum of 50 contiguous voxels).

Coloured bars represent t-values; display threshold is set at t value >3.16. A: FA values of the complete FD patients group (n = 23) were significantly reduced in WM areas covering widespread parts of the brain, indicating structural WM changes extending beyond the WM lesions that showed up on conventional MRI. B and C: Subgroup analyses of both patient groups (without (1B; n = 18) and with (1C; n = 5) CSA-CSR), relative to the healthy controls (n = 44). Clusters of FA changes in patients with CSA-CSR were most pronounced in the brainstem. By contrast, FD patients without CSA-CSR revealed more widespread FA decreases in supratentorial areas, but only subtle brainstem involvement. SPM  =  Statistical Parametric Mapping; FD = Fabry Disease; FA = Fractional Anisotropy; WM = White Matter; MRI = Magnetic Resonance Imaging; CSA-CSR = Central sleep apnea with Cheyne-Stokes respiration.

Figure 2. Brain regions in which microstructural lesions were associated with the severity of CSR in patients with CSA.

SPM “glass brain” presentation (left) and statistical FA maps that were superimposed on a normalized T1-weigthed template (middle and right) showing symmetric clusters of correlation between relative CSR length and decreased FA values in the upper brainstem and in frontal WM as well as in connecting fibres between both areas (p<0.001, minimum of 50 continuous voxels; corrected for multiple comparisons). Coloured bars represent t-values; display threshold is set at t-value >3.71. CSR = Cheyne-Stokes Respiration; CSA = Central Sleep Apnea; SPM = Statistical Parametric Mapping; FA = Fractional Anisotropy.