Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance

Abstract

Although the vestibular complex represents an important component of the neural circuits crucial for the maintenance of truncal and postural stability, and it is integrated into specialized oculomotor circuits, knowledge regarding the extent of the involvement of its nuclei and associated fibre tracts in cases with spinocerebellar ataxia type 3 (SCA3) is incomplete. Accordingly, we performed a pathoanatomical analysis of the vestibular complex and its associated fibre tracts in four clinically diagnosed and genetically confirmed SCA3 patients with the aim of providing more exact information as to the involvement of the vestibular system in this disorder. By means of unconventionally thick serial sections through the vestibular nuclei stained for lipofuscin pigment and Nissl material, we could show that all five nuclei of this complex (interstitial, lateral, medial, spinal, and superior vestibular nuclei) are subject to neurodegenerative processes in SCA3, whereby examination of thick serial sections stained for myelin revealed that all associated fibre tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the eighth cranial nerve) underwent atrophy and demyelinization in all four of the patients studied. The reported lesions can help to explain the truncal and postural instability as well as the impaired optokinetic nystagmus, vestibulo-ocular reaction, and horizontal gaze-holding present in SCA3 cases.

SCA3: Neurological features, pathogenesis and animal models

“…In spite of its severe degeneration, most of the SCA3 patients with a degenerated substantia nigra never presented with parkinsonian features (2). In contrast to previous conventional neuropathological studies, recent pathoanatomical studies involving unconventional serial thick tissue sections demonstrated widespread damage to the cerebellum, thalamus, midbrain, pons, medulla oblongata, and spinal cord in SCA3 ( Figure 3) (63,64,(66)(67)(68)(69)(70)(71). This clearly exceeds the proposed 'olivopontocerebellar' pattern of neurodegeneration (2), is comparable to that commonly seen in terminal SCA2 and SCA7 patients (2,63,64,(66)(67)(68)70,(72)(73)(74) and provides suitable explanations for a variety of less understood clinical SCA3 symptoms.…”

Brain pathology of spinocerebellar ataxias

“…6) [15]. Microscopic analyses reveal widespread neuronal loss in the cerebral cortex, basal ganglia, thalamus, midbrain, pons, medulla oblongata and cerebellum ( 98,134,135,137,138,140,141,[143][144][145].…”

Electronystagmography findings in spinocerebellar ataxia type 3 (SCA3) and type 2 (SCA2)

“…Anatomopathologic studies of the vestibular complex and its association of fibre bundles in four patients with SCA type 3, revealed that the five nuclei of the complex (interstitial, lateral, medial, inferior and superior vestibular nuclei) undergo neurodegenerative processes owing to the disease, thus demonstrating that all the associated fibre bundles (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the VIII cranial nerve) undergo disseminated neuronal loss causing atrophy and demyelination of its structures 29 . These lesions may explain the alterations in the brainstem, postural instability with imbalance, oculomotor deficits (impaired optokinetic nystagmus, slow saccadic eye movements and absent caloric response) and the presence of a pathological vestibulo-ocular reflex 18,29 . Molecular genetic tests are the most important complementary exam to make the diagnosis of SCAs.…”