Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases.

This report describes unique presentations of inclusion body myositis (IBM) in two unrelated patients, one male and one female, with genetically and histologically confirmed fragile X-associated tremor/ataxia syndrome (FXTAS). We summarize overlapping symptoms between two disorders, clinical course, and histopathological analyses of the two patients with FXTAS and sporadic IBM, clinically defined per diagnostic criteria of the European Neuromuscular Centre. In case 1, a post-mortem analysis of available brain and muscle tissues is also described. Histopathological features (rimmed vacuoles) consistent with clinically defined IBM were detected in both presented cases. Postmortem testing in case 1 revealed the presence of an FMR1 premutation allele of 60 CGG repeats in both brain and skeletal muscle samples. Case 2 was a premutation carrier with 71 CGG repeats who had a son with FXS. Given that FXTAS is associated with immune-mediated disorders among premutation carriers, it is likely that the pathogeneses of IBM and FXTAS are linked. This is, to our knowledge, the first report of these two conditions presenting together, which expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS. Following detection of a premutation allele of the FMR1 gene, FXTAS patients with severe muscle pain should be assessed for IBM

Objective measurement of daytime napping, cognitive dysfunction and subjective sleepiness in Parkinson's disease.

INTRODUCTION: Sleep-wake disturbances and concomitant cognitive dysfunction in Parkinson's disease (PD) contribute significantly to morbidity in patients and their carers. Subjectively reported daytime sleep disturbance is observed in over half of all patients with PD and has been linked to executive cognitive dysfunction. The current study used daytime actigraphy, a novel objective measure of napping and related this to neuropsychological performance in a sample of PD patients and healthy, age and gender-matched controls. Furthermore this study aimed to identify patients with PD who may benefit from pharmacologic and behavioural intervention to improve these symptoms. METHODS: Eighty-five PD patients and 21 healthy, age-matched controls completed 14 days of wrist actigraphy within two weeks of neuropsychological testing. Objective napping measures were derived from actigraphy using a standardised protocol and subjective daytime sleepiness was recorded by the previously validated Epworth Sleepiness Scale. RESULTS: Patients with PD had a 225% increase in the mean nap time per day (minutes) as recorded by actigraphy compared to age matched controls (39.2 ± 35.2 vs. 11.5 ± 11.0 minutes respectively, p < 0.001). Significantly, differences in napping duration between patients, as recorded by actigraphy were not distinguished by their ratings on the subjective measurement of excessive daytime sleepiness. Finally, those patients with excessive daytime napping showed greater cognitive deficits in the domains of attention, semantic verbal fluency and processing speed. CONCLUSION: This study confirms increased levels of napping in PD, a finding that is concordant with subjective reports. However, subjective self-report measures of excessive daytime sleepiness do not robustly identify excessive napping in PD. Fronto-subcortical cognitive dysfunction was observed in those patients who napped excessively. Furthermore, this study suggests that daytime actigraphy, a non-invasive and inexpensive objective measure of daytime sleep, can identify patients with PD who may benefit from pharmacologic and behavioural interventions to improve these symptoms

Cognitive performance of excessive nappers within the Parkinson’s disease cohort.

<p>A chart comparing the cognitive performance (mean ± standard error) of patients with Parkinson’s disease (PD) divided into those with excessive daytime napping vs. those with normal daytime napping. Set shifting was measured with the Trailmaking task part B (TMT B; z score). Semantic verbal fluency (VF) was tested via the Controlled Oral Word Associated Test (COWAT animals; z score) and processing speed was measured with the choice reaction time (RT) test from the Cambridge Neuropsychological Test Automated Battery (CANTAB; z score).</p

Average nap time per day (minutes).

<p>A chart depicting the average nap time per day (± standard error) calculated by summing the daytime napping periods identified by actigraphy and averaging this over the 14 day measurement period. Panel A - Parkinson’s disease vs. Controls. Panel B - Parkinson’s disease patients divided into those who are Epworth Sleepiness Scale positive (score ≥ to 10 indicative of sleepiness) vs. Parkinson’s Disease patients who are Epworth Sleepiness Scale negative.</p

Mood and disease specific variables within the Parkinson’s disease cohort based on subjective sleepiness scores.

<p>A chart that reports depression scores, disease stage and Levodopa dose equivalents (mean ± standard error) when patients with Parkinson’s Disease are divided into those who are Epworth Sleepiness Scale positive (score ≥ to 10 indicative of a positive tendency to sleep during the day) vs. those who are Epworth Sleepiness Scale negative. </p

Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases

This report describes unique presentations of inclusion body myositis (IBM) in two unrelated patients, one male and one female, with genetically and histologically confirmed fragile X-associated tremor/ataxia syndrome (FXTAS). We summarize overlapping symptoms between two disorders, clinical course, and histopathological analyses of the two patients with FXTAS and sporadic IBM, clinically defined per diagnostic criteria of the European Neuromuscular Centre. In case 1, a post-mortem analysis of available brain and muscle tissues is also described. Histopathological features (rimmed vacuoles) consistent with clinically defined IBM were detected in both presented cases. Postmortem testing in case 1 revealed the presence of an FMR1 premutation allele of 60 CGG repeats in both brain and skeletal muscle samples. Case 2 was a premutation carrier with 71 CGG repeats who had a son with FXS. Given that FXTAS is associated with immune-mediated disorders among premutation carriers, it is likely that the pathogeneses of IBM and FXTAS are linked. This is, to our knowledge, the first report of these two conditions presenting together, which expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS. Following detection of a premutation allele of the FMR1 gene, FXTAS patients with severe muscle pain should be assessed for IBM

Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases.

This report describes unique presentations of inclusion body myositis (IBM) in two unrelated patients, one male and one female, with genetically and histologically confirmed fragile X-associated tremor/ataxia syndrome (FXTAS). We summarize overlapping symptoms between two disorders, clinical course, and histopathological analyses of the two patients with FXTAS and sporadic IBM, clinically defined per diagnostic criteria of the European Neuromuscular Centre. In case 1, a post-mortem analysis of available brain and muscle tissues is also described. Histopathological features (rimmed vacuoles) consistent with clinically defined IBM were detected in both presented cases. Postmortem testing in case 1 revealed the presence of an FMR1 premutation allele of 60 CGG repeats in both brain and skeletal muscle samples. Case 2 was a premutation carrier with 71 CGG repeats who had a son with FXS. Given that FXTAS is associated with immune-mediated disorders among premutation carriers, it is likely that the pathogeneses of IBM and FXTAS are linked. This is, to our knowledge, the first report of these two conditions presenting together, which expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS. Following detection of a premutation allele of the FMR1 gene, FXTAS patients with severe muscle pain should be assessed for IBM

Experimental Paradigm.

<p>A graphical depiction of the experimental paradigm. Patients used a set of footpedals to navigate a virtual corridor while lying on their back in a 3T MRI scanner. During the navigation of the corridor, either Direct (e.g. the word ‘WALK’) or Indirect (e.g. the word ‘RED’ written in the colour <i>red</i>) cues were presented on the bottom 1/3 of a computer screen. Patients were asked to interpret these cues and determine whether to continue walking or to stop and await the next cue based on a pre-learned rule. The experiment was designed with interspersed blocks of low cognitive load (left block) and high cognitive load (right block), in which Indirect and Direct cues were presented, respectively.</p

Results of the Region-of-Interest Analysis when viewing an Indirect > Direct cue (patients without FOG > patients with FOG).

<p>Results from the direct comparison of the contrast values from regions-of-interest between patients without FOG and patients with FOG. Error bars represent the estimated standard error for each value. Key: L  =  left; R  =  right; pSMA  =  presupplementary motor area; STN  =  subthalamic nucleus; AI  =  anterior insula; VS  =  ventral striatum. Significance levels: * – p<0.05; ** – p<0.01.</p

Within-group similarities.

<p>Cortical surface rendering of the major areas of increased and decreased BOLD response during the comparison of the Indirect WALK cue and the Direct WALK cue. A similar pattern was seen when comparing PD patients with and without FOG. Colour intensity on the graph represents the t-value obtained from the 2nd-level analysis of each group (corrected with a false detection rate of p<0.05).</p