Response to Fernagut et al . : The ambiguous nucleus ambiguus

Sir, we are grateful for the opportunity to respond to the correspondence from Fernagut et al. (2011) on the ambiguity of dysphagia in multiple system atrophy. We thank the authors for their comments and their interest in our article on the human pre-Bötzinger complex (Schwarzacher et al., 2011). As they point out, the main focus of our study was the localization and characterization of the pre-Bötzinger complex in health and in two diseases of severe brainstem degeneration, multiple system atrophy and spinocerebellar ataxia 3 (SCA3). We characterized putative pre-Bötzinger complex neurons using immunostaining for neurokinin-1 receptor (NK-1) and somatostatin (SOM), two reliable markers of pre-Bötzinger complex neurons in experimental animals (Gray et al., 1999; Stornetta et al., 2003). Furthermore, the population of pre-Bötzinger complex neurons showed a characteristic somatic shape on conventional pigment Nissl-stained sections, making neuropathological investigations of pre-Bötzinger complex neurons in human brains feasible. Interestingly, neurons of the presumed pre-Bötzinger complex were not affected in patients with SCA3, and these findings correlated well with the absence of respiratory deficits in the clinical reports of these patients. In contrast, putative pre-Bötzinger complex neurons were severely reduced in the brains of patients with multiple system atrophy. This reduction was in accordance with the respiratory dysfunctions often reported in this disease (Nogués and Benarroch, 2008). We used the selective vulnerability of the pre-Bötzinger complex neurons as indirect, but yet to some extent functional evidence for the identification of pre-Bötzinger complex neurons in human. This view is supported by the large body of experimental evidence that indicates that the pre-Bötzinger complex is essential for breathing, as stated by Ramirez’s scientific commentary on our study (Ramirez, 2011). We further examined the distribution of motoneurons forming the ambigual complex in control, SCA3 and patients with multiple system atrophy. Neurons of the ventral portion of the ambigual nucleus were reduced in both SCA and patients with multiple system atrophy. In addition, the dorsal portion of the ambigual complex, that innervates swallowing muscles, was strongly reduced in SCA3 brains, consistent with the clinical picture of severe and ultimately lethal dysphagia, observed in patients with SCA3 (Rüb et al., 2008). Interestingly, the dorsal portion of the ambigual complex was unaffected in the brains of patients with multiple system atrophy. Fernagut et al. (2011) now present interesting clinical data from a prospective cohort of patients with multiple system atrophy who were followed by the French multiple system atrophy reference centre. Twenty-five per cent of 12 patients with multiple system atrophy, who died in 2010, received gastrostomy feeding at the end of life, in line with prior reports of dysphagia in patients with multiple system atrophy, cited by the authors (Muller et al., 2001; O’Sullivan et al., 2008). A majority of 64.1% of patients with multiple system atrophy examined by Fernagut et al. (2011) using the Unified Multiple System Atrophy Rating Scale (UMSARS) displayed at least some degree of dysphagia, and these authors reported dysphagia as a typical sign of multiple system atrophy in a recent study (Meissner et al., 2010). Although the dorsal portion of the ambigual complex was unaffected in the brains of the patients with multiple system atrophy in our study, we cannot exclude disturbances of the upper alimentary system in these patients, since the central control of doi:10.1093/brain/awr188 Brain 2012: 135; 1–2 | e206