Clinical and neuroimaging improvements after apomorphine treatment in a patient with chronic disorders of consciousness following brain hemorrhage

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; Clinicaltrials.gov NCT0362382