Central hypoventilation in progressive supranuclear palsy

Abstract

Central hypoventilation, also known as Ondine's curse, results from an impairment of the autonomic respiratory drive. It is characterized by an attenuated or absent respiratory response to hypoxemia and hypercapnia with preservation of volitional respiratory function. RJ was a 75-year-old woman with a diagnosis of probably PSP who developed central hypoventilation approximately four years after her initial onset of symptoms. Brain MRI showed no evidence of medullary lesions, one of the more common causes of adult onset central hypoventilation. The respiratory centers in the medulla, especially the ventral respiratory group (VRG) containing Botzinger and pre-Botzinger complex of neurons, appear critical for normal respiratory rhythm generation. RJ was maintained on a portable ventilator after her diagnosis of Central Hypoventilation. Ten month after being placed on ventilation she passed of unclear cause. RJ showed pathological features consistent with a diagnosis of PSP, specifically loss of neurons, secondary demyelination, and tau-positive inclusions in both astrocytes and neurons, chiefly in the globus pallidus, midbrain, and brainstem. RJ showed significant tauopathy in the region of the VRG in particular. We also examined this region in sixteen other cases of PSP and found similar tauopathy in all but one case, which had significantly less involvement of this area. We had limited clinical data on these cases but one had two episodes of unexplained hypoxia shortly before being placed on hospice. Central hypoventilation associated with tauopathy involving the VRG may be more common than often appreciated.

Keywords: Progressive Supranuclear Palsy; primary hypoventilation; tauopathy.

Figure 1

R.J. histopathologic features: formalin‐fixed, paraffin‐embedded 5‐micron sections of the globus pallidus were prepared by standard methods and stained with hematoxalin and eosin (H&E; A) or with H&E with Luxol fast blue (LFB) myelin stain (B). Myelin pallor, neuronal loss, and gliosis were widespread throughout affected brain regions. (C) An H&E/LFB‐stained section of control globus pallidus for comparison. Scale bars in (A–C) are all 100 μm. (D) A lower‐magnification view of the medulla, including the inferior olivary nucleus (ION) and the dorsal accessory olivary nucleus (DAO); dorsal to this, in the left half of the image, lie the ventral respiratory group and nucleus ambiguus, which also demonstrate architectural effacement attributed to degenerative changes similar to those observed in the globus pallidus. Scale for (D) is 500 μm.

Figure 2

R.J. taupathy: immunohistochemical stains for tau were performed on paraffin sections with the use of PHF‐1 antibody after antigen retrieval and show characteristic tau‐positive astrocytes and dystrophic neurites in the globus pallidus. Scale bar is 100 μm.

Figure 3

PHF‐1 immunohistochemistry of the VRG of representative PSP case including R.J. (3E). All cases but A show striking tauopathy. Scale bar is 40 μm for all panels.