The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease)

The nucleus raphe interpositus (RIP) plays an important role in the premotor network for saccades. Its omnipause neurons gate the activity of the burst neurons for vertical saccades lying within the rostral interstitial nucleus of the medial longitudinal fascicle and that for horizontal saccades residing in the caudal subnucleus of the pontine reticular formation. In the present study we investigated the RIP in five patients with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease. Polyethylene glycol-embedded 100 microm serial sections stained for lipofuscin pigment and Nissl material as well as paraffin-embedded Nissl stained thin sections revealed the hitherto overlooked involvement of this pontine nucleus in the degenerative process underlying SCA3, whereby in four of our SCA3 patients the RIP underwent a conspicuous loss of presumed omnipause neurons. As observed in other affected brain structures, the RIP of all our SCA3 patients displayed reactive astrocytes and activated microglial cells, while some of the few of its surviving neurons harbored an ataxin-3-immunopositive intranuclear inclusion body. The findings of the present pathoanatomical study suggest that (1) neurodegeneration in the brain stem of terminal SCA3 patients is more widespread than previously thought and is not confined to cranial nerve nuclei involved in the generation of saccades but likewise involves the premotor network for saccades and (2) damage to the RIP may contribute to slowing of horizontal saccades in SCA3 patients but is not associated with saccadic oscillations as occasionally speculated.