Clinical and neuroimaging improvements after apomorphine treatment in a patient with chronic disorders of consciousness following brain hemorrhage
Leandro R. D. Sanz1,2, Nicolas Lejeune1,2,3,4, Séverine Blandiaux1,2, Estelle Bonin1,2, Federico Raimondo1,2,5, Rajanikant Panda1,2, Helena Cassol1,2, Neal Farber6, Steven Laureys1,2, Olivia Gosseries1,2
1. GIGA Consciousness, University of Liège, Liège, Belgium
2. Coma Science Group, University Hospital of Liège, Liège, Belgium
3. CHN William Lennox, Groupe Hospitalier Saint-Luc, Ottignies, Belgium
4. Institute of Neurosciences, UCLouvain, Brussels, Belgium
5. Institut du Cerveau et de la Moelle épinière, Sorbonne Université, Paris, France
6. NeuroHealing Pharmaceuticals Inc., Waban, MA, USA
Background: There are few available therapeutic options to promote recovery among patients with disorders of consciousness (DOC)1. Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects in traumatic brain injury2,3. 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; MCS4) 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)5. 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 values6,7, a multivariate classifier integrating 68 individual hdEEG markers8,9 and hdEEG functional connectivity using debiased weighted phase lag index10.
Results: Before treatment, CRS-R scores were compatible with a diagnosis of unresponsive wakefulness syndrome (UWS)11 in 8/9 evaluations, and with a MCS-12 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.
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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 NCT03623828
Funding
We thank the University and University Hospital of Liege, the Belgian National Funds for Scientific Research (F.R.S-FNRS), NeuroHealing Pharmaceuticals Inc., the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2), the Luminous project (EU-H2020-fetopenga686764), the Center-TBI project (FP7-HEALTH- 602150), the Public Utility Foundation ‘Université Européenne du Travail’, “Fondazione Europea di Ricerca Biomedica”, the Bial Foundation, the Mind Science Foundation and the European Commission, the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 778234, European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO). LS and NL are research fellows, AT is postdoctoral researcher and SL is research director at F.R.S-FNRS. We thank Eurogenerics and Britannia Pharmaceuticals Ltd. for providing clinical trial materials. We thank the participant here described and her family, the staff of the departments of neurology, radiology and nuclear medicine at the University Hospital of Liège and the staff of the William Lennox Neurological Hospital for their precious collaboration.
References
1. Schnakers, C. & Monti, M. M. Disorders of consciousness after severe brain injury. Curr. Opin. Neurol. 30, 573–579 (2017).
2. Fridman, E. A. et al. Fast awakening from minimally conscious state with apomorphine. Brain Inj. 23, 172–177 (2009).
3. Fridman, E. A. et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 24, 636–641 (2010).
4. Giacino, J. T. et al. The minimally conscious state. Neurology 58, 349–353 (2002).
5. Giacino, J. T., Kalmar, K. & Whyte, J. The JFK Coma Recovery Scale-
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Revised: Measurement characteristics and diagnostic utility. Arch. Phys. Med. Rehabil. 85, 2020–2029 (2004).
6. Stender, J. et al. Quantitative Rates of Brain Glucose Metabolism Distinguish Minimally Conscious from Vegetative State Patients. J. Cereb. Blood Flow Metab. 35, 58–65 (2015).
7. Stender, J. et al. The Minimal Energetic Requirement of Sustained Awareness after Brain Injury. Curr. Biol. 26, 1494–1499 (2016).
8. Engemann, D. A. et al. Robust EEG-based cross-site and cross-protocol classification of states of consciousness. Brain 141, 3179–3192 (2018).
9. Sitt, J. D. et al. Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state. Brain 137, 2258–2270 (2014).
10. Chennu, S. et al. Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness. Brain 140, 2120–2132 (2017).
11. Laureys, S. et al. Unresponsive wakefulness syndrome: A new name for the vegetative state or apallic syndrome. BMC Med. 8, 2–5 (2010).
12. Bruno, M. A., Vanhaudenhuyse, A., Thibaut, A., Moonen, G. & Laureys, S. From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J Neurol 258, 1373–1384 (2011).

Apomorphine for the treatment of chronic disorders of consciousness: a case report with multimodal assessments