Chapter 15 - Sporadic adult-onset ataxia of unknown etiology

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Abstract

Sporadic adult-onset ataxia of unknown etiology (SAOA) denotes the non-hereditary degenerative adult-onset ataxia disorders that are distinct from multiple system atrophy (MSA). Rather than being a defined disease entity, SAOA has to be regarded as a group of disorders of unknown etiology that are defined by a common clinical syndrome and the exclusion of known disease causes. Epidemiological studies have revealed prevalence rates ranging from 2.2 to 8.4 per 100 000, which are higher than those of hereditary ataxias. Clinically, SAOA is characterized by a slowly progressive cerebellar syndrome starting around the age of 50 years. About one-third of SAOA patients have either polyneuropathy or pyramidal tract involvement accompanying cerebellar ataxia. Cognitive impairment is not the rule, and, if present, is only mild. More than half of SAOA patients have signs of mild autonomic dysfunction that do not meet the criteria of severe autonomic failure required for a diagnosis of MSA. Neuropathological and imaging studies show an isolated cerebellar cortical degeneration with no or only mild brainstem involvement. There is no established therapy for SAOA.

Section snippets

Definition

Sporadic adult-onset ataxia of unknown etiology (SAOA) is a recently introduced term that denotes the non-hereditary degenerative adult-onset ataxia disorders that are distinct from multiple system atrophy (MSA) (Abele et al., 2002). SAOA is defined by the following criteria: (1) Progressive ataxia, (2) disease onset after the age of 20 years, (3) no acute or subacute disease onset, (4) no evidence of a causative gene mutation, (5) no established symptomatic cause, (6) no possible or probable

Etiology and pathogenesis

By definition, SAOA is an adult-onset degenerative disorder of unknown etiology. Consequently, a correct diagnosis of SAOA implies that all known genetic and acquired causes of ataxia have been ruled out. Nevertheless, a number of hypotheses have been put forward to account for the etiology of SAOA.

Neuropathology

There are almost no recent neuropathological studies of SAOA. Current knowledge therefore mainly relies on old neuropathological reports, some of which appeared more than a century ago. In these studies, a clear distinction between acquired ataxias and SAOA was not made. In addition, further confusion arises in interpreting older literature in view of the modern experience that a considerable fraction of apparently sporadic ataxias are due to defined gene defects (Dürr et al., 1996, Abele et

Epidemiology

There is only very limited information on the epidemiology of SAOA. In a population-based study performed in Cantabria (Spain), Polo et al. (1991) found a prevalence of 2.2:100 000. Subsequent studies performed in the Aosta valley (Italy) and in south-east Wales (UK) found a prevalence of 6.9:100 000 and 8.4:100 000, respectively (Leone et al., 1995, Muzaimi et al., 2004). In both latter studies, the prevalence of SAOA was considerably higher than that of hereditary ataxias. This is in agreement

Sex

The early studies on IDLOCA by Harding, 1981, Klockgether et al., 1990 reported a male preponderance, with a male:female ratio of 2.3:1 and 1.3:1, respectively. As both studies included MSA patients, and a higher prevalence of MSA in males is well established, the male preponderance in these studies might be due to the admixture of MSA patients (Ben Shlomo et al., 1997, Klockgether et al., 1998b, Watanabe et al., 2002). However, a male preponderance was also found in two recent studies of

CT

As part of a larger CT study in patients with progressive ataxias, Claus and Aschoff (1980) reported CT findings of 14 patients with sporadic, adult-onset ataxia. Unfortunately, a distinction between acquired ataxias and SAOA was not made in their paper. Nevertheless, the authors found a homogeneous pattern of cerebellar atrophy mainly affecting the vermis and the dorsal and lateral aspects of the cerebellar hemispheres. In a CT study that included six SAOA patients, an almost purely cerebellar

Peripheral nerve conduction

Up to one-third of SAOA patients have clinical evidence of peripheral neuropathy. Correspondingly, a number of nerve conduction studies have provided electrophysiological evidence for sensorimotor peripheral neuropathy of mixed axonal–demyelinating type in a subgroup of SAOA patients. The prevalence of peripheral neuropathy in these studies ranged from 23% to 50% (Claus et al., 1988, Cruz et al., 1995, Pellecchia et al., 1999, Abele et al., 2007).

Somatosensory evoked potentials

Mondelli et al. (1992) provided evidence for

Therapy

As the etiology and pathogenesis of SAOA are unknown, there is no specific treatment approach for SAOA. Nevertheless, a number of compounds have been tested for their ability to temporarily improve ataxia. The respective studies of these compounds have been performed in mixed groups of ataxia patients that often included SAOA patients. Two placebo-controlled studies using the 5-HT precursor 5-hydroxtryptophan gave conflicting results. While Trouillas et al. (1988) observed a beneficial effect,

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