Clinical Research Directory

Neurorehabilitation in Patients With Disorders of Consciousness: Multidimensional Ambispective Study on the Impact of Single and Combined Approaches

Sponsor: IRCCS Centro Neurolesi Bonino Pulejo

Summary

Disorders of consciousness (DOC), such as the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and the minimally conscious state (MCS), represent severe clinical conditions arising from acquired brain injury (ABI), exerting a profound impact on patients, caregivers, and healthcare systems. The clinical heterogeneity, diagnostic challenges, and paucity of robust evidence on the comparative efficacy of rehabilitation interventions underscore the need for a deeper understanding of the underlying neurophysiological, cognitive, and biological mechanisms involved in consciousness recovery. This monocentric ambispective observational study aims to investigate the effects of advanced neurorehabilitation treatments-including multimodal sensory stimulation, non-invasive neuromodulation via transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS), and the use of augmentative and alternative communication (AAC) devices with eye-tracking-on various facets of residual consciousness in patients diagnosed with DOC admitted to the Neurorehabilitation Unit of the IRCCS Centro Neurolesi "Bonino Pulejo" in Messina. The study design encompasses the collection of clinical and rehabilitation data from hospitalized patients undergoing treatment, both retrospectively and prospectively. Specifically, data from patients admitted and treated in the 36 months preceding study initiation, as well as those admitted and treated in the subsequent 36 months, will be included. Upon data collection, participants will be classified a posteriori as "responders" or "non-responders" based on whether they meet at least one of the following criteria: (I) an increase of ≥3 points on the Coma Recovery Scale-Revised (CRS-R) from baseline or a clinically relevant state transition (e.g., VS/UWS → MCS; MCS → emergence from MCS \[EMCS\]); (II) an increase of ≥10 points on the Functional Independence Measure (FIM) or ≥0.5 standard deviations (SD) from baseline; (III) an increase of ≥10 points on the Barthel Index or ≥0.5 SD from baseline. The primary objective is to estimate the proportion of responders and non-responders at the end of training or hospitalization. Secondary objectives include identifying variables predictive of treatment response at the end of intervention (training type/modality, aetiology, demographic factors, comorbidities), quantifying the dose-response gradient (number of sessions/session duration versus response probability), and assessing changes in neurophysiological, physiological, and biological parameters collected during hospitalization (neuroimaging examinations, neurofilament light chain \[NfL\] assays, EEG/event-related potentials \[ERP\], skin conductance response, heart rate frequency and variability, and oculomotor activity). Data will be analysed using descriptive statistics appropriate to variable distributions. The primary endpoint, defined as the proportion of responders at the end of training/hospitalization, will be evaluated using logistic regression models in an as-treated approach, reporting odds ratios and marginal estimates (risk ratios and absolute risk differences) with 95% confidence intervals (CI). Confounding will be addressed through multivariable adjustment and propensity score-based methods (inverse probability of treatment weighting \[IPTW\]/overlap weighting). Continuous secondary outcomes will be analysed with linear models or linear mixed-effects models for repeated measures. Dose-response relationships will be explored, alongside sensitivity and subgroup analyses. All analyses will be performed using R software (version 4.4.2), employing two-sided tests with a significance level of α=0.05. The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

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