Abstract :
[en] Managing pain and promoting recovery in patients with disorders of consciousness (DOC) is a real clinical challenge. The first aim of my thesis was to improve pain management by improving our knowledge of (i) potential pain assessment tools and (ii) spasticity, a potential source of pain that may also prevent further recovery in this population. The second aim of my work was to investigate potential pharmacological and non-pharmacological treatments for promoting recovery in patients with DOC.1.Symptomatic treatments: pain and spasticityPain management in non-communicative patients is a real challenge. Clinically, it is difficult to adapt treatment, since it is not possible to obtain feedback from the patients. Previous studies have shown that the Nociception Coma Scale-Revised (NCS-R), a scale to assess pain and nociception in patients with DOC, is a sensitive tool to assess responses to noxious stimulation. To further investigate the neural correlates of the scale, we assessed whether NCS-R scores could reflect nociceptive brain processing in this population. We investigated the correlation between NCS-R total scores and cerebral metabolism in areas involved in pain processing. Results showed a positive correlation between NCS-R total scores and brain metabolism in the posterior part of the anterior cingulate cortex - an area known to be involved in the cognitive and affective aspects of pain processing. This result supports the hypothesis that the NCS-R is related to cortical processing of pain and may constitute an appropriate behavioural tool to assess the efficacy of treatment and monitor nociception and pain in non-communicative patients. Apart from detecting pain in this population, there is also the challenge of identifying and treating the possible sources of pain. One potential source of discomfort is spasticity, which may even reduce the patients’ ability to show signs of consciousness at the bedside. Though spasticity is known to be very common in patients following a stroke or acquired brain damage, we know very little about its driving mechanisms and prevalence in DOC. As a result, there is also a lack of guidelines regarding pharmacological treatment and rehabilitation. In a cross-sectional study involving 65 patients in unresponsive wakefulness syndrome/vegetative state (UWS/VS) and minimally conscious state (MCS), we reported that 89% of the patients showed spasticity in at least one limb and 62% of the patients had severe invalidating spasticity based on the Modified Ashworth Scale. Interestingly, we also observed a positive correlation between the severity of spasticity and pain scores observed during care (as measured by the NCS-R), highlighting the importance of standardized management of pain and spasticity in this population. Finally, we identified a linear positive correlation between the severity of spasticity and time since injury, emphasizing the importance of prolonged and revised treatments in chronic stages. Recently, we conducted a single-blind randomized sham-controlled trial aiming to assess the efficacy of soft splints on upper limb spasticity in chronic patients with DOC. A positive effect of the splints on intrinsic hand muscle spasticity (as assessed by the Modified Ashworth Scale) and hand opening was observed after wearing the splints for 30 minutes. These findings suggest that soft splints, through their positive effects on muscle hypertonia, their comfort and simple application, could be easily and efficiently added to the patient’s daily management to decrease spasticity.2.Curative treatments: zolpidem and transcranial direct current stimulationZolpidem, a short-acting non-benzodiazepine hypnotic drug, has been shown to induce paradoxical effect in some rare cases of patients in DOC, promoting recovery of behavioural signs of consciousness. Using Positron Emission Tomography (PET), we assessed zolpidem-induced changes in regional brain metabolism in three chronic MCS patients with known zolpidem response (i.e. temporary emergence from MCS). The aim of this study was to better understand the neural mechanisms underlying such a recovery. Our results highlighted increased metabolism within the prefrontal areas following zolpidem intake as compared with placebo. This finding corroborates the key role of the prefrontal cortices in the recovery of consciousness. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has been previously reported to transiently improve working memory and attention by stimulating the left dorsolateral prefrontal cortex (DLPF) in patients with stroke as well as Parkinson’s and Alzheimer’s disease. However, no studies have investigated its ability to promote recovery in patients with DOC. We performed the first double-blind randomized placebo-controlled clinical trial in patients in UWS/VS and MCS and assessed the effect on the level of consciousness (as measured by the Coma Recovery Scale-Revised) of a single session of anodal tDCS over the left DLPF cortex. This crossover trial showed that, at the group level, tDCS could promote recovery of behavioural signs of consciousness in patients in MCS but not in UWS/VS. Forty three percent of patients in MCS (13/30) responded to the stimulation – i.e. showed a new sign of consciousness (e.g. visual pursuit, object localization or recognition, localisation to pain or command following) after the real tDCS that was not present before, nor after the sham tDCS. Out of these 13 patients, 5 were in this state for more than one year, suggesting that tDCS could still be effective after long time periods in a MCS. In order to improve our understanding of the underlying mechanisms of tDCS, we then retrospectively investigated why some patients showed tDCS-induced improvement (i.e. responders), while others did not. Neuroimaging data (PET and structural magnetic resonance imaging – MRI) allowed us to compare residual brain metabolism and grey matter volume in responders versus non-responders. We found that the transient recovery of signs of consciousness following tDCS in patients with chronic MCS (> 3 months) seems to require residual metabolic activity and residual grey matter in (i) the presumed stimulated area (i.e. left DLPFC), (ii) distant cortical areas (i.e. precuneus), and (iii) subcortical brain regions (i.e. thalamus) known to be involved in awareness and arousal. These findings suggest that tDCS is a feasible treatment that may promote recovery of new signs of consciousness in patients with DOC, although it also suggests that some patients may be more suited to benefit from tDCS than others. We therefore need to deepen our understanding of the neuronal correlates underlying its effect, especially in patients with brain lesions, in order to provide guidelines for clinicians.In this work, we highlighted several potential pharmacological and non-pharmacological treatments that may be helpful for improving patients’ quality of life and promoting recovery in DOC. Future studies should provide guidelines for standardized management and treatment in DOC in order to improve both motor and cognitive rehabilitation in this population.
