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See detailClinical and neuroimaging improvements after apomorphine treatment in a patient with chronic disorders of consciousness following brain hemorrhage
Sanz, Leandro ULiege; Lejeune, Nicolas; Blandiaux, Séverine ULiege et al

in Brain Injury (in press)

Background: There are few available therapeutic options to promote recovery among patients with disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has ... [more ▼]

Background: There are few available therapeutic options to promote recovery among patients with disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects in traumatic brain injury. Its efficacy among patients with non-traumatic brain injury has never been documented and its action on brain activity remains unknown. We report the case of a patient with DOC following intracranial hemorrhage, who was treated with apomorphine in a prospective open-label study. Methods/design: A 47-year-old woman with chronic DOC (minimally conscious state; MCS) following spontaneous rupture of a left carotidal aneurysm (132 days since onset), was treated with apomorphine for 30 days. The drug was administered via subcutaneous infusions 12 hours per day, with escalating doses up to 6 mg/h. The patient was monitored 30 days before initiation of therapy, during treatment and 30 days after withdrawal, using the Coma Recovery Scale – Revised (CRS-R). High-density electroencephalography (hdEEG) and fluorodeoxyglucose positron emission tomography (FDG-PET) were acquired before and after treatment. Outcome measures included CRS-R diagnosis, FDG-PET standardized uptake values, a multivariate classifier integrating 68 individual hdEEG markers and hdEEG functional connectivity using debiased weighted phase lag index. Results: Before treatment, CRS-R scores were compatible with a diagnosis of unresponsive wakefulness syndrome (UWS) in 8/9 evaluations, and with a MCS- only once. During treatment, the patient was diagnosed as UWS in 2/8 evaluations, MCS- in 5/8 evaluations and MCS+ once, characterized by the presence of reproducible response to command. After treatment withdrawal, she was diagnosed UWS once and MCS- in 4/5 evaluations. Compared to 54 healthy controls, FDG-PET whole brain metabolism revealed a 59% metabolic drop before treatment and 51% after treatment, with increases in right temporal, parietal and frontal cortical areas. The multivariate classifier using resting-state hdEEG data was in favor of a UWS before treatment, while it indicated a MCS after treatment. Most of the individual markers increased after treatment, including alpha and beta spectral power, spectral entropy, Kolmogorov complexity and permutation entropy. Functional connectivity analyses also indicated an increase in network centrality predominant in the alpha frequency band after treatment compared to before treatment. Discussion: After treatment with apomorphine, this patient showed improvements both at the clinical and neuroimaging levels. While signs of consciousness were only observed once at baseline, most of the assessments performed during and after treatment led to a diagnosis of MCS. Notably, a reproducible response to command was observed once during treatment, leading to a change of diagnosis. Brain activity measures all increased after treatment compared to before treatment. These multimodal improvements suggest that apomorphine may be efficient to promote the recovery of non-traumatic DOC patients, and that its action can be measured through different changes in brain imaging markers. Clinical trial identifiers: EudraCT 2018-003144-23; NCT03623828 [less ▲]

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See detailTreating severely brain-injured patients with apomorphine: study protocol for a double blind randomized placebo-controlled trial using behavioral and neuroimaging assessments
Sanz, Leandro ULiege; Lejeune, Nicolas; Thibaut, Aurore ULiege et al

in Frontiers in Neuroscience (2018, October)

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of ... [more ▼]

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of international guidelines and scarce therapeutic options (Schnakers and Monti, 2017). Among pharmacological treatments, apomorphine, a potent direct non-specific dopamine agonist with a high affinity for D2 receptors, has exhibited promising behavioral effects and safety of use in small-sample pilot studies (Fridman et al., 2009, 2010). However, despite the improvement compared to historical data, the lack of a control group could not eliminate the possibility that the effect was a result of spontaneous recovery, and the true efficacy of apomorphine for the recovery of consciousness remains unclear (Gosseries et al., 2014). In addition, the underlying neural mechanisms of this treatment are still unknown. An upregulation of central thalamic activity through a modulation of the anterior forebrain mesocircuit has been proposed as a possible explanation (Schiff, 2010a, 2010b) but the absence of neuroimaging and neurophysiological data prevent definitive confirmation. This clinical trial aims to 1) verify and quantify the efficacy of apomorphine subcutaneous infusion in patients with disorders of consciousness, 2) better identify the rate and the phenotype of responders to treatment, 3) evaluate tolerance and side effects occurrence in this specific patient population and 4) investigate the neural networks underlying its modulating action on consciousness using multimodal outcome measurements. Methods/design: This study is a prospective double-blind randomized placebo-controlled trial. Forty-eight patients diagnosed with disorders of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state) will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo via daily 12-hour subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, followed by a two-year remote follow-up. In an initial study phase, up to six patients will be treated in an open-label fashion. Behavioral outcome measures will include weekly assessments using standardized scales such as the Coma Recovery Scale – Revised (CRS-R) (Giacino et al., 2004) and the Nociception Coma Scale – Revised (NCS-R) (Chatelle et al., 2012) during the inpatient phase. Tolerance and safety of use will be monitored using a specifically designed Adverse Events Questionnaire filled weekly by the referent physician, from treatment initiation to the end of the inpatient phase. Long-term behavioral follow-up will be performed at 6, 12 and 24 months post-treatment by telephone interview using the Glasgow Outcome Scale – Extended (GOS-E) (Levin et al., 2001) as well as phone-adapted versions of the CRS-R and the Adverse Events Questionnaire. Neurophysiological and neuroimaging measures will complement clinical evaluations and provide data on brain activity. Resting-state high-density electroencephalography (EEG) will be acquired weekly during the whole inpatient phase. In addition, participants will be assessed before and after treatment with Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), EEG during auditory paradigms and 24-hours EEG recordings. To measure changes in circadian rhythm, body core temperature (Matsumoto et al., 2013) and body movements (Cruse et al., 2013) will be recorded with non-invasive portable devices throughout the whole duration of the inpatient phase (Figure 1). Statistical analyses will be performed blindly to detect changes in behavioral status, circadian rhythmicity, brain metabolism and functional connectivity both at the individual level (comparing before and after treatment) and at the group level (comparing the apomorphine and the placebo arms). Behavioral response will be determined by changes of diagnosis using the CRS-R, and further analyses will also look at changes between the non-responding and the responding patient subgroups. Age, gender, etiology, time since injury and diagnosis will also be included as regressors. Hypotheses: Based on the mesocircuit hypothesis, we postulate a modulation in the activity of the network’s anterior forebrain structures following administration of apomorphine (Figure 2), which will translate into the following changes: 1) A behavioral improvement such that the CRS-R diagnosis and total score will improve in responding patients, while NCS-R scores may also increase, reflecting a higher perception of pain; along with long-term functional recovery measured by sustained higher GOS-E and CRS-R scores at follow-up compared to the placebo group; 2) A relative recovery of sleep-wake cycles measured by a normalization of circadian rhythmicity as well as an increase in total body movements; 3) A metabolic improvement with significant increase of whole-brain glucose uptake, with highest increase of values found in the striatum, thalamus and frontoparietal cortical areas measured with PET; 4) A modulation of dynamic connectivity in response to apomorphine measured by resting-state fMRI analyses (seed-based and whole-brain connectivity measures) and changes of resting-state EEG connectivity metrics (notably increased mean alpha spectral connectivity, participation coefficient and delta modularity). Additionally, we can expect improvements after treatment in less specific measures of recovery such as sleep cycle architecture on 24-hours EEG hypnograms and the probability of consciousness given by a machine learning multivariate classifier derived from EEG recordings during auditory paradigms (Engemann et al., 2015). While improvements can be expected as well in the placebo arm due to spontaneous recovery and placebo effect, we hypothesize that responding patients in the apomorphine arm will exhibit significantly higher increases in these different markers of recovery. Discussion: New multimodal approaches using neurophysiology and neuroimaging allow a more accurate diagnosis of patients with disorders of consciousness but the current available treatments remain inefficient. This study aims to verify the efficacy of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal measurement methods. The results will contribute to define the role of dopamine agonists in the treatment of this challenging population of patients and help identify the neural underpinnings underlying the modulation of consciousness networks by apomorphine. Notably, this trial is designed to bring objective neuroimaging and neurophysiological evidence to further assess the validity of the mesocircuit hypothesis and its modulation by pharmacological agents, which may open new therapeutic perspectives. [less ▲]

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