Parkinsonian Patients and Poor Awareness of Dyskinesias

Abstract

The question of whether the awareness of levodopa-induced dyskinesias (LID) is reduced, or altogether missing, in patients with Parkinson’s disease (PD) has been attracting growing interest. Why is this topic important? Firstly, as studies addressing the efficacy of drugs on LID employ patients’ motor diaries as an outcome measure, poor LID self-awareness might interfere with data collection in clinical trials; secondly, poor LID self-awareness may result in increased doses of dopaminergic drugs, which could in turn be associated with an enhanced risk of side effects such as LID. Lastly, understanding this phenomenon may shed light on some pathophysiological aspects of LID in PD. The few studies conducted so far concluded that at least a proportion of PD patients are either partially or totally unaware of the presence of LID. These studies used different methods to ascertain LID awareness as well as different patient populations. Consequently, several hypotheses have been postulated to explain poor self-awareness of LID, which suggest that several possible mechanisms may be implicated. An impairment in the experience of moving abnormally was suggested by Vitale et al. (1) in a pilot study conducted on PD patients (and on patients with Huntington disease). The authors found that poor LID self-awareness was more marked in PD patients with mild LID, and therefore suggested that poor LID self-awareness merely reflects the fact that when LID are mild, their interference with normal activities is limited and patients tend to underestimate them. These results, however, were not confirmed in the study conducted by Sitek et al. (2), who instead observed, by means of a video protocol, that poor selfawareness of LID was more pronounced in patients with longer symptom duration (and therefore with possibly more severe LID). This finding reported by Sitek et al. (2) thus suggests that other mechanisms are likely to play a role in the phenomenon of poor self-awareness of LID. Amanzio et al. (3) believed that factors linked to the cognitive domain might be involved. In a well planned study, they investigated whether awareness of different movement disorders in cognitively intact PD patients differs in the on and off states. The results of their study revealed a significant difference between awareness of LID measured in the on state and awareness of hypo-bradykinesia assessed in the off state. In particular, while 22 of the 25 patients enrolled in their study displayed a reduced awareness of LID, a reduced awareness of hypo-bradykinetic movement disorders was found in only 6 of the 25 patients. On the basis on these findings, the authors suggested that dopaminergic therapy may, by stimulating mesocortical–limbic pathways, exert a detrimental effect on the function of the orbitofrontal and cingulated frontal–subcortical loops, thereby contributing to a poor self-awareness of LID. Supporting this view, recent papers indeed showed that frontal cortex studied by advanced neuroimaging techniques differ between patients with or without LID. In one study, PD patients with LID had significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of motor tasks when compared with PD patients without LID (4). In addition, in another study cortical thickness analysis revealed a pronounced increase of thickness in the right inferior frontal sulcus in PD patients with LID with respect to PD patients without LID (5). The hypothesis of Amanzio et al. is not, however, supported by the observations of other authors, who found that poor self-awareness is not only associated with LID, but also with motor symptoms assessed in the off state, and that awareness of off motor symptoms improved, at least in part, during the on state following dopaminergic stimulation (1, 6, 7). Maier et al. (7) also found that the severity of impairment of motor self-awareness was unrelated to dopaminedependent executive functioning. These authors also reported that impaired awareness of abnormal movements (and therefore of LID) was significantly associated with the postural instability gait disorder phenotype of PD to a greater extent than with the hyperkinetic phenotype. Although the postural instability gait disorder phenotype is frequently associated with cognitive decline, it is noteworthy that the severity of the impaired awareness of movement in the study by Maier et al. (7) was not correlated with either disease duration or cognitive outcome. Other authors have proposed alternative or complementary hypotheses. For example, one noteworthy finding comes from the work by Jenkinson et al. (8), who highlighted the fact that normal motor awareness entails a correct comparison of intended vs. actual movement, and predicted in their work that anosognosia of LID in PD arises from a failure to detect discrepancies between intended movement and visual feedback. To test their hypothesis, they used a mirror to reverse the expected visual consequence of an executed movement. PD patients with poor self-awareness of LID did not