Early Neuropsychological Rehabilitation and Family Psychoeducation After Ischemic Stroke

Background and rationale

Cognitive deficits are frequent after ischemic stroke, predict functional recovery and may interfere with the rehabilitation process itself. They are also associated with lower quality of life and with depression. Despite this, most trials of cognitive rehabilitation begin three to four months after the acute event, and evidence regarding intervention during the early phase of recovery is limited.

Stroke also affects the family. The main caregiver typically assumes the role abruptly and without preparation, which is associated with burden, anxiety and depressive symptoms, and with a reduced quality of life for the caregiver. A frequently reported need is the lack of accessible information about the consequences of stroke and about how to manage them.

This trial addresses both dimensions simultaneously. It evaluates whether a structured neuropsychological rehabilitation program for the patient and a psychoeducational program for the main caregiver, both initiated during the early phase of recovery, improve the patient's quality of life, cognitive performance, functional status and emotional state at three months post-stroke.

Study design

Randomized, controlled, parallel-group clinical trial with a 2×2 factorial design and blinded outcome assessment, conducted at a single centre. The two factors are neuropsychological rehabilitation (present or absent) and family psychoeducation (present or absent), yielding four groups: control, neuropsychological rehabilitation only, family psychoeducation only, and combined intervention.

The factorial design allows the main effect of each intervention to be estimated within a single sample, and permits an exploratory assessment of their interaction.

Procedures

Participants are recruited during the acute phase of ischemic stroke, within 96 hours of symptom onset. Baseline assessment of the primary outcome is performed 20 days after admission, before any intervention begins. Randomization is carried out after this baseline assessment, ensuring that baseline measures are genuinely pre-intervention and that groups are comparable at the outset.

Allocation is stratified according to receipt of acute reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy), the principal prognostic confounder in functional and cognitive recovery. Randomization is performed through the electronic data capture system, so that the allocation sequence is not accessible to the personnel responsible for recruitment or eligibility assessment and the next allocation cannot be anticipated.

Both interventions begin after randomization and extend over approximately twelve weeks. The primary efficacy assessment is performed at three months post-stroke. An optional observational extension at twelve months is analysed descriptively only, as participation in this extension is voluntary and therefore subject to selection bias.

Interventions

Participants allocated to neuropsychological rehabilitation receive 24 sessions of 45 minutes of computerized cognitive training, twice weekly over 12 weeks, on an adaptive telerehabilitation platform. The sequence of exercises, their allocation to each session and the session duration are fixed and identical for all participants; task difficulty is adjusted individually by the platform algorithm according to prior performance. The program covers attention and processing speed, working and recent memory, executive functions, language and visuospatial functions, and functional transfer.

Participants not allocated to this factor receive non-specific recreational digital activities, matched in duration and frequency, without adaptive difficulty, performance feedback or structured progression. This active control condition equates exposure time and professional contact between arms, isolating the specific effect of the rehabilitative content.

Family members allocated to psychoeducation receive six individual 45-minute sessions delivered fortnightly by videoconference. Session content covers information about stroke, the role of the family in recovery, management of the patient's emotional state, behavioural difficulties, cognitive therapy and relaxation techniques, and behavioural activation. The program explicitly excludes training caregivers in cognitive rehabilitation techniques, in order to preserve the independence of the two factors of the design.

Family members not allocated to this factor receive an informational leaflet at hospital discharge, covering the definition and consequences of stroke, recommended reading and contact details of patient associations. The leaflet contains no intervention strategies, behavioural management guidance or cognitive rehabilitation techniques.

All participants receive usual clinical care, including medical stabilisation and, according to clinical indication, referral to convalescence or complementary rehabilitation services.

Outcomes and analysis

The primary outcome is the total direct score of the CAVIDACE scale at three months post-stroke, reported by the reference family member. The scale is administered at item level, which allows internal consistency in the study sample to be reported, since the instrument has not previously been validated in patients with acute stroke.

Secondary outcomes are organised into two pre-specified families, each linked to one factor of the design and tested through a fixed-sequence gatekeeping procedure. The family associated with neuropsychological rehabilitation comprises the global neuropsychological composite, the modified Rankin Scale, the Barthel Index and the Lawton Scale. The family associated with family psychoeducation comprises caregiver burden, the two subscales of the Hospital Anxiety and Depression Scale, and the Beck Depression Inventory-II.

The primary analysis follows the intention-to-treat principle and uses an analysis of covariance model with main effects, adjusting for the baseline value and for the randomization stratum. The interaction between factors is estimated in a separate model and is considered exploratory, as the study is not powered to detect it.

Molecular biomarkers of plasticity, inflammation and glial damage, and structural neuroimaging variables obtained during the acute phase, are examined as exploratory prognostic factors and potential moderators of treatment response.

A statistical analysis plan specifying the estimand, the analysis models, the handling of missing data and the pre-specified sensitivity analyses was signed and dated prior to the introduction of any outcome data into the study database.

Inclusion criteria

• First-ever ischemic stroke (transient ischemic attack excluded)
• Age 18 years or older
• Inclusion within 96 hours of symptom onset
• Prior functional independence (modified Rankin Scale ≤ 1)
• Diagnostic criteria for ischemic stroke (TACI, PACI, LACI, POCI)
• Capacity to provide informed consent, or availability of a legal representative

Exclusion criteria

• Previous neurological or psychiatric disease associated with cognitive impairment
• Severe systemic disease
• Life expectancy under one year
• Severe stroke (NIHSS score above 19 at admission)
• Alcohol or substance abuse (tobacco excluded)
• Clinically relevant aphasia preventing comprehension of test instructions Sensory impairment preventing neuropsychological assessment
• Functional illiteracy