Retrospective study of the effects of inpatient rehabilitation on improving and maintaining functional independence in people with Friedreich ataxia.

OBJECTIVES: To determine the effects of inpatient intervention for people with Friedreich ataxia (FRDA), and to identify whether improvements gained were sustained postdischarge. DESIGN: This retrospective observational cohort study comprised people with FRDA admitted to inpatient rehabilitation. SETTING: All participants in the study were referred by a specialist multidisciplinary FRDA clinic to inpatient rehabilitation. PARTICIPANTS: From 2003 until 2010, people (N=29; men, n=17; women, n=12) with FRDA were admitted to rehabilitation, representing 42 admissions. On admission, 9 participants were ambulant and 33 participants were nonambulant. INTERVENTIONS: Each participant was prescribed goal-related therapy on an individual basis by the multidisciplinary team, and this consisted of a range of treatment approaches. MAIN OUTCOME MEASURE: The FIM was used to determine the efficacy of inpatient rehabilitation. RESULTS: Consistent with the progressive nature of the condition, FIM scores, as measured on an annual basis preintervention, declined over time. However, FIM scores increased by a mean of 8.5 points during periods of inpatient rehabilitation and continued to increase by a mean of 2.0 points during the period immediately after rehabilitation. Results demonstrate these increases during and immediately after inpatient rehabilitation were significant (P<.001). CONCLUSIONS: To the best of our knowledge, this study provides the first evidence that a period of inpatient rehabilitation reverses or halts the downward decline in function for people with FRDA. The benefits from this intervention continued during the period immediately after inpatient rehabilitation, indicating that these gains are more than just short-term achievements. Further exploration of intensity, type, and length of rehabilitation is required to ensure that the most appropriate rehabilitation is provided.

Characterising the neuropathology and neurobehavioural phenotype in Friedreich ataxia: a systematic review.

Friedreich ataxia (FRDA), the most common of the hereditary ataxias, is an autosomal recessive, multisystem disorder characterised by progressive ataxia, sensory symptoms, weakness, scoliosis and cardiomyopathy. FRDA is caused by a GAA expansion in intron one of the FXN gene, leading to reduced levels of the encoded protein frataxin, which is thought to regulate cellular iron homeostasis. The cerebellar and spinocerebellar dysfunction seen in FRDA has known effects on motor function; however until recently slowed information processing has been the main feature consistently reported by the limited studies addressing cognitive function in FRDA. This chapter will systematically review the current literature regarding the neuropathological and neurobehavioural phenotype associated with FRDA. It will evaluate more recent evidence adopting systematic experimental methodologies that postulate that the neurobehavioural phenotype associated with FRDA is likely to involve impairment in cerebello-cortico connectivity.

Utilisation of advance motor information is impaired in Friedreich ataxia.

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We sought to examine motor planning ability in 13 individuals with FRDA and 13 age- and sex-matched control participants using two experimental paradigms that examined the ability to incorporate different levels of advance information to plan sequential movements. Individuals with FRDA demonstrated a differential pattern of motor response to advance information and were significantly disadvantaged by conditions requiring initiation of movement without a direct visual cue. There was also a significant negative correlation with age of disease onset and differing levels of advance information, suggesting an impact of FRDA on the development of motor cognition, independent of the effect of disease duration. We suggest that deficits are due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology or a possible combination of the two.

A longitudinal diffusion tensor imaging study in symptomatic Huntington's disease.

OBJECTIVE: The striatum and its projections are thought to be the earliest sites of Huntington's disease (HD) pathology. This study aimed to investigate progression of striatal pathology in symptomatic HD using diffusion tensor imaging. METHOD: Diffusion weighted images were acquired in 18 HD patients and in 17 healthy controls twice, 1 year apart. Mean diffusivity (MD) was calculated in the caudate, putamen, thalamus and corpus callosum, and compared between groups. In addition, caudate width was measured using T1 high resolution images and correlated with caudate MD. Correlation analyses were also performed in HD between caudate/putamen MD and clinical measures. RESULTS: MD was significantly higher in the caudate and putamen bilaterally for patients compared with controls at both time points although there were no significant MD differences in the thalamus or corpus callosum. For both groups, MD did not change significantly in any region from baseline to year 1. There was a significant negative correlation between caudate width and MD in patients at baseline but no correlation between these parameters in controls. There was also a significant negative correlation between Mini-Mental State Examination scores and caudate MD and putamen MD at both time points in HD. CONCLUSIONS: It appears that microstructural changes influence cognitive status in HD. Although MD was significantly higher in HD compared with controls at both time points, there were no longitudinal changes in either group. This finding does not rule out the possibility that MD could be a sensitive biomarker for detecting early change in preclinical HD.

Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia.

Friedreich ataxia (FRDA), the commonest of the inherited ataxias, is a multisystem neurodegenerative condition that affects ocular motor function. We assessed eye movement abnormalities in 20 individuals with genetically confirmed FRDA and compared these results to clinical measures. All subjects were assessed with infrared oculography. Fifteen individuals underwent a full protocol of eye movement recordings. Ten subjects were analysed using two-dimensional scleral coil equipment and five using three-dimensional scleral coil recording equipment. We also recorded visual quality of life, Sloan low contrast letter acuity and Friedreich Ataxia Rating Scale scores to compare to the visual measures. Whilst saccadic velocity was essentially normal, saccadic latency was prolonged. The latency correlated with clinical measures of disease severity, including the scores for the Friedreich Ataxia Rating Scale and the Sloan low contrast letter acuity tests. Fixation abnormalities consisting of square wave jerks and ocular flutter were common, and included rare examples of vertical square wave jerks. Vestibular abnormalities were also evident in the group, with markedly reduced vestibulo-ocular reflex gain and prolonged latency. The range of eye movement abnormalities suggest that neurological dysfunction in FRDA includes brainstem, cortical and vestibular pathways. Severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FRDA and differentiate it from a number of the dominant spinocerebellar ataxias. The correlation of saccadic latency with FARS score raises the possibility of its use as a biomarker for FRDA clinical trials.

Speech acoustic markers of early stage and prodromal Huntington's disease: a marker of disease onset?

Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis.

Impairment in motor reprogramming in Friedreich ataxia reflecting possible cerebellar dysfunction.

The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three "oddball" stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto-cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two.

Friedreich ataxia: from genes to therapies?

Most cases are caused by a single mutation, paving the way for therapeutic advances for this fatal disease.