Aiming for a Better Understanding and Improvement of the Diagnosis and Prognosis of Patients With Disorders of Consciousness Through Multimodal Observations

Study Overview
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Brief Summary
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Improved treatment of severe brain injuries has resulted in increased survival rates. While some of these patients regain consciousness after a transient state of coma, others may develop a disorder of consciousness (DoC). Diagnosis of DoC currently relies on standardized behavioral assessment. The importance of accuracy in such diagnosis cannot be overstated, as it guides critical decisions on treatment (including pain management), and could underlie end-of-life decisions. Despite this importance, current behavioral diagnosis often fails, if because of the major sensory and motor deficits associated with DoC, or because of the heterogeneous etiology and pathophysiology associated with the condition. Finally, the need for accurate diagnosis and prognosis transcends the needs of the patients alone: caregiving of these patients is very stressful, principally for the large uncertainty associated with them. Thus, more accurate diagnosis and prognosis provide major relief for caregivers, and paradoxically, even if the news is not good. For all these reasons it is critical to developing personalized diagnosis and prognosis prediction tools that permit a stratified analysis at the single-patient level. The PerBrain Project will benefit from the multidisciplinary partners' expertise, and the unique opportunity to perform longitudinal assessments in four clinical sites through both established and novel electrophysiological, neuroimaging, and physiological techniques. Based on the collected data, the investigators will develop a multimodal personalized diagnostic tool for DoC patients using state-of-the-art computational tools, such as machine learning, in order to better determine the current state (diagnosis) and future outcome (prognosis). The overall aim of this project will provide for a better understanding of the pathophysiological mechanisms in DoC, which will, in turn, allow personalized rehabilitation strategies, and improved single-patient predictions of state and prognosis.

Official Title
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A Multimodal Approach to Personalized Tracking of Evolving State-Of-Consciousness in Brain- Injured Patients

Conditions
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Disorders of Consciousness, Minimally Conscious State, Unresponsive Wakefulness Syndrome, Caregivers

Intervention / Treatment
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* Behavioral: Coma scales
* Diagnostic Test: Imaging, electrophysiology, body signals, and brain stimulation
* Behavioral: Questionnaires


Participation Criteria
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Eligibility Criteria
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Recruitment is taking place in: France, Paris, Pitie-Salpetriere Hospital; Italy, Milan, Dipartimento di Cura e Riabilitazione delle Gravi Cerebrolesioni Acquisite (GCA); Israel, Raanana, Loewenstein Hospital; Germany, Munich: intensive care units of the University Clinic LMU Munich and Therapiezentrum Burgau Inclusion criteria: Disorder of consciousness (UWS and MCS) patients and their caregiver/legal guardian Patient age: 18-85 years Informed consent signed by legal guardian Exclusion criteria: Pregnancy Pre-existing coma/VS/MCS Continuous medical sedation (induced coma) Use of barbiturates for sedation Terminal malignant disease, as it increases the likelihood of not being alive for the 12-month follow-up Prediction of a highly unlikely survival until the time of the 12-month follow-up due to conditions such as multi-organ failure based on the judgement of a critical care physician Withdrawal of life-support Palliative care setting Epileptic seizures (TMS contraindication) MRI contraindications (magnetic material in or on person such as pacemakers, cochlear implants, shell splinters, metal plates, certain prosthetic joints/limbs, copper-based intrauterine device, magnetic clips or stents, some large tattoos)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with DoC<br> | Behavioral: Coma scales<br>* CRS-R and GOSE<br>Diagnostic Test: Imaging, electrophysiology, body signals, and brain stimulation<br>* MRI, fMRI, EEG, TMS-EEG, Olfaction, Respiration, EKG<br>|
| Caregivers/ legal guardian of patients with DoC<br> | Behavioral: Questionnaires<br>* several questionnaires and an interview with the caregiver<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients: Implementation of a hierarchical multi-modal personalized procedure to diagnose and track the change of the state of consciousness in brain-injured patients | Coma Recovery Scale Revised (CRS-R) [0-23] Higher score better outcome | Changes from T1: 1-2 Months from injury; T2: 4-7 Months from injury; T3: 9-12 months from injury | 
| Patients: Implementation of a hierarchical multi-modal personalized procedure to diagnose and track the change of the state of consciousness in brain-injured patients | Extended Glasgow Outcome Scale (GOSE) [1-8] Higher score better outcome | Changes from T1: 1-2 Months from injury; T2: 4-7 Months from injury; T3: 9-12 months from injury | 
| Patients: Implementation of a hierarchical multi-modal personalized procedure to diagnose and track the change of the state of consciousness in brain-injured patients | Quantitative high density EEG (64 Electrodes) | Changes from T1: 1-2 Months from injury; T2: 4-7 Months from injury; T3: 9-12 months from injury | 
| Patients: Implementation of a hierarchical multi-modal personalized procedure to diagnose and track the change of the state of consciousness in brain-injured patients | Standard EEG and transcranial magnetic stimulation (TMS-EEG) | Changes from T1: 1-2 Months from injury; T2: 4-7 Months from injury; T3: 9-12 months from injury | 
| Patients: Implementation of a hierarchical multi-modal personalized procedure to diagnose and track the change of the state of consciousness in brain-injured patients | Structural MRI and functional MRI (without contrast agent) | Changes from T1: 1-2 Months from injury; T2: 4-7 Months from injury; T3: 9-12 months from injury | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Sociodemographic characteristics | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Brief Illness Perception Questionnaire (BIPQ) [0-80] Higher score more positive illness representation | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Euro-Qol 5 (EQ-5D61) [0-15] higher values indicating better perceived quality of life. | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Adult Carer Quality of Life Questionnaire (ACQoL24) [0-120] higher values better quality of life | Changes from 0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Hospital Anxiety and Depression Scale (HADS) [0-52] higher scores indicating higher levels of anxiety and depression. | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Resilience (RS14) [14-98] higher scores relate to higher resilience levels. | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Sense of coherence (SOCS) [13-91] higher scores indicate higher sense of coherence. | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Treatment choices survey [28-140] higher score indicates a stronger agreement with the treatment and higher reason to take a given treatment decision | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 
| Caregivers: use of questionnaires to asses change in factors that impact well-being and treatment decisions of informal caregivers/family members confronted with multimodal technology-based tests for DoC patients | Semi-structured qualitative Interview based on a thematic grid for brochure development | Changes from C0: before T1 (1-2 Months from injury); C1: between T1(1-2 Months from injury) and T2 (4-7 Months from injury); C2: between T2 (4-7 Months from injury) and T3 (9-12 Months from injury); C3: after T3 (9-12 Months from injury) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caregivers: develop a brochure/guide to be applied in clinical practice for the effective communication of technology-based results | Working closely with Patient organizations/ patient representatives: Representatives of organizations (Schädel- Hirnpatienten in Not e.V. in Germany) will be consulted in focus groups to jointly discuss the met and unmet needs and communication problems reported by caregivers in the study. Additionally, we will conduct a semi-structures interview with the caregivers. This information will help to devise with the research team effective communication strategies to be implemented in a brochure for the presentation of multimodal technology-based DOC testing. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multimodal precision diagnosis, Machine Learning, Caregivers well-being, Unresponsive wakefulness syndrome, Minimally conscious state, Clinical Neuroscience, Disorders of Consciousness, Neuroimaging, Brain-Body interactions