Congenital central hypoventilation disorder (CCHS) is a clinically complex disorder characterized by ventilatory failure to respond to hypercapnia during sleep, autonomic dysfunction, and affective abnormalities (1,2). A major advance in our understanding of CCHS is the discovery that mutations in the PHOX2B gene, important in autonomic development, cause the majority of the cases (3). Yet, further advances in our understanding of CCHS and how the gene defect specifically results in respiratory, autonomic, and emotional dysfunction will depend on determination of the underlying neuropathology. This goal has been elusive in large part because of the rarity of clinically well-characterized cases that come to autopsy, and the lack of analysis of autopsied CCHS brains with modern quantitative and neurochemical techniques. In the few instances of examination of autopsied CCHS brains, abnormalities of the ventral medullary surface, i.e., absence or hypoplasia of the arcuate nucleus, have been reported (4). The arcuate nucleus is postulated to contain neurons and/or glia which are the human homologue of the respiratory chemosensitive fields for carbon dioxide monitoring in cats and rodents (5,6). In addition, neuronal loss and gliosis in the reticular formation of the medulla oblongata has been described in autopsied CCHS infants (7). A major strategy to elucidate brain abnormalities in CCHS is the use of magnetic resonance imaging (MRI), but its standard (nonfunctional) application fails to demonstrate subtle or structural brainstem and/or forebrain differences between children with CCHS and controls (1). The application of hypoxic, ischemic, and cold pressor challenges in CCHS patients by Dr. Harper's group in the past, however, indicated functional MRI changes, notably within limbic, cerebellar, and midbrain regions, the latter broadly defined (8,9). T2 relaxometry procedures suggested damaged regions in limbic and cerebellar regions (8). The application of MRI techniques with homeostatic challenges was also an important step in the definition of CCHS neuropathology but it begged the question of why these methods failed to demonstrate putative long-standing pathology throughout the brainstem—a structure that the clinical presentation strongly suggested was at fault. Dr. Harper's group has repeatedly emphasized the crucial role of forebrain structures in the modulation of brainstem-mediated respiratory and autonomic control; nevertheless, the seemingly lack of structural pathology in brainstem sites critical to chemosensitivity to carbon dioxide, e.g., ventral medullary surface (5,6,10), arousal to carbon dioxide, e.g., rostral raphé (11,12), and autonomic regulation, e.g., ventrolateral medulla, in CCHS was puzzling. Dr. Harper's group, however, was aware of the technical limitations in imaging the human brainstem with its well-recognized problems in spatial resolution and sensitivity (1). This group is to be applauded for keeping abreast of the technical advances in human brainstem neuroimaging and now providing us novel and important insight in the role of brainstem pathology in CCHS with the use of today's state-of-the-art technology, i.e., diffusion tensor imaging (DTI) with comparison of axial and radial diffusivity maps (1).

In a study of 25 adolescent cases of CCHS (15.2 ± 2.4 y) compared with 26 controls (15.5 ± 2.4 y), Kumar et al. (1) report major structural abnormalities in the brainstem and cerebellum of the CCHS cases based on the superimposition of axial and radial diffusivity maps. Both of these maps depend on the directional diffusivity of water molecules, with their relationship to cellular structural injury established in experimental models, as reviewed in-depth by Kumar et al. (1). Axial diffusitivity, whereby water molecules diffuse parallel to fibers, is considered sensitive to axonal injury; radial diffusitivity, on the other hand, measures the diffusion of water molecules parallel to fibers, and is considered sensitivity to myelin injury (1). Of critical importance to understanding structural pathology in CCHS (and potentially multiple other neurologic disorders) is that DTI reveals abnormalities that are not apparent by conventional MRI. In CCHS, Kumar et al. now report with DTI a composite of neuropathologic brainstem changes that involve the lateral medulla, basis pontis, dorsal midbrain, oculomotor nuclei, periaqueductal gray, rostral raphé, and decussation of the superior cerebellar peduncle in the caudal midbrain (1). They also report injury in cerebellar structures, i.e., cerebellar cortex and deep (roof) nuclei and superior and inferior cerebellar peduncles (1). Although this group has reported certain forebrain and limited brainstem regions involved in CCHS with the use of MRI in patients with hypoxic, hypercapnic, or cold pressor stressors (1,8,9), the sophisticated DTI analysis implicates previously unrecognized and specific structures with “chronic” injury, as opposed to dysfunction only, in the pathogenesis of CCHS.

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