Primary objective.

To evaluate the incidence of ischemic stroke during the 6-month follow-up period after surgery.

Secondary objective.

To assess early postoperative haemodynamic changes, graft patency, changes in neurological and cognitive outcomes at 6 months, all-cause mortality at 6 months, perioperative complications, and the extent of cerebral revascularisation on follow-up imaging.

Study Population.

Patients with chronic ICA occlusion who underwent elective STA-MCA bypass surgery were enrolled between July 2025 and December 2027.

Study setting.

This single-centre study was conducted at the Department of Vascular and Functional Neurosurgery of the National Centre for Neurosurgery, a tertiary referral institution located in the capital city that provides neurosurgical care to the entire national population. With a capacity of 160 beds, the Centre represents the only specialized neurosurgical facility of its kind in Kazakhstan and serves as a regional referral hub for neighboring Central Asian countries [16].

Patient selection.

The study requires a multidisciplinary team comprising a neurologist, neurosurgeon, neuropsychologist, neuroradiologist, biostatistician, and research administrator.

Patients will be identified through the Department of Vascular and Functional Neurosurgery. STA-MCA bypass procedures for patients with chronic ICA occlusion will be performed by a team of neurosurgeons within the department. Neurosurgeons must have experience in vascular anastomosis and have successfully conducted STA-MCA bypass surgery on at least 10 patients. Neurological and cognitive assessments will be conducted by a consultant neurologist and neuropsychologist. All radiological imaging will be independently reviewed and interpreted by two radiologists from the Department of Radiology.

Baseline symptomatic status will be incorporated as an adjustment variable in multivariable and longitudinal analyses to account for differences in baseline risk and recovery potential. Exploratory subgroup analyses by symptom status will be performed where sample size permits.

Inclusion.

1. Chronic ICA occlusion confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), and digital subtraction angiography (DSA).
2. Evidence of cerebral hypoperfusion on magnetic resonance imaging (MRI) arterial spin labelling (ASL) within the territory of the occluded ICA, defined as a ≥ 30% reduction compared with the contralateral hemisphere.
3. Modified Rankin Scale (mRS) score of 0–3 at baseline.
4. Preserved language comprehension, with no more than mild motor aphasia and no significant cognitive impairment.
5. Adults aged 18–80 years.
6. Provision of written informed consent by the patient or a legally authorised representative.
7. Willingness and ability to comply with follow-up assessments.

Exclusion.

1. Large territorial infarction or marked cerebral atrophy on MRI.
2. Bilateral ICA occlusion or concomitant neurovascular disease (e.g., cerebral aneurysm or arteriovenous malformation).
3. Severe systemic comorbidities, life expectancy <2 years, or a mRS score >3.
4. Cardiac conditions that are associated with a high risk of cerebral embolism (e.g., prosthetic heart valves, infective endocarditis, intracardiac thrombus, sick sinus syndrome, cardiac myxoma, or cardiomyopathy with left ventricular ejection fraction <25%; atrial fibrillation, patent foramen ovale, and atrial septal aneurysm are not exclusion criteria).
5. Contraindications to MRI, CTA, DSA, iodinated contrast agents, or required perioperative antiplatelet therapy.
6. Non-functioning STA-MCA bypass.
7. Participation in another interventional or experimental study within the previous 12 months, including those involving ionizing radiation.
8. Pregnancy.

Radiological assessment.

The assessment schedule is given in Table 1. To evaluate the ICA occlusion, a three-level assessment will be conducted using CTA of the head and neck vessels, MRI ASL and Time-of-flight (TOF) sequences, and a confirmatory assessment of occlusion during DSA. All imaging studies will be performed and interpreted by neuroradiologists and neurosurgeons, with findings reviewed collaboratively.

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Table 1. Data collection schedule.

https://doi.org/10.1371/journal.pone.0354103.t001

Included patients will undergo CTA of the head and neck vessels with a slice thickness of 0.5-0.625 mm to confirm ICA occlusion and to measure the diameter of the donor STA branch at 2 mm distal to its bifurcation.

MRI perfusion studies will be conducted before surgery on 1.5 or 3 Tesla MRI to evaluate cerebral blood flow (CBF) and determine the extent of cerebrovascular insufficiency. The main perfusion method will be ASL, which will provide quantitative CBF values, assess the degree of perfusion deficit, and reveal signs of compensatory collateral circulation based on the presence of arterial transit artifacts (ATA). Imaging parameters are described in in S1 Table.

DSA will be performed using a biplane digital subtraction angiography system (Artis Zee, Siemens) with a 6F guiding catheter at a frame rate of 7.5 frames per second. The angiographic assessment will evaluate the presence of communicating arteries, the completeness of the Circle of Willis, and the extent of collateral circulation. Hemodynamic compensation will be quantified by analyzing filling times and phase delays across the arterial, parenchymal, and venous phases, expressed in frames. Image analysis will be conducted using Siemens Artis Q angiography software to ensure accurate and reproducible measurements.

Neurological assessment.

The degree of neurological deficit before and after surgery will be evaluated by neurologist using the Baseline neurological examination findings, mRS and National Institutes of Health Stroke Scale (NIHSS) scores. The consequences of prior stroke will also be assessed with the mRS [15] and the Functional Activities Questionnaire (FAQ) [17]. Preoperatively and six months after surgery, all patients will be evaluated under a unified diagnostic protocol, with results collected and recorded separately before entering them into a general database with strict personal data encoding.

Cognitive function assessment.

Changes in cognitive function before and after surgery and six months postoperatively will be assessed using the neuropsychological tests, measuring both verbal and non-verbal IQ.

A standardized battery of neuropsychological tests will be administered by a psychologist to evaluate global cognition, memory, visuospatial skills, and executive function (S2 Table). The Montreal Cognitive Assessment (MoCA) will be used as a screening tool for global cognitive function, assessing domains including attention, executive functions, memory, language, visuospatial skills, abstraction, and orientation [18]. The Rey Auditory Verbal Learning Test (RAVLT) will be employed to evaluate verbal learning and memory performance, including immediate recall, delayed recall, and recognition memory [19]. Nonverbal test of Kohs Block Design will be used to assess visuospatial reasoning, problem-solving, and perceptual-motor coordination by requiring participants to reproduce geometric patterns with colored blocks [20]. The Stroop Test will be applied to measure selective attention, processing speed, and cognitive flexibility by evaluating the ability to inhibit cognitive interference [21].

To minimize potential learning or practice effects associated with repeated testing, assessments will be conducted at predefined intervals with sufficient time between evaluations, and standardized administration procedures will be maintained across all sessions. Whenever available, alternative test versions will be used for repeated assessments.

Neuropsychological test performance will be interpreted using age- and education-adjusted normative data when available, in order to reduce the potential confounding effect of educational background on cognitive outcomes.

Perioperative management.

Perioperative management was standardized for all patients to minimize treatment variability and potential confounding effects on outcomes. General anesthesia was performed using a standardized protocol with continuous hemodynamic monitoring. Intraoperative blood pressure was strictly controlled to avoid hypotension or excessive fluctuations that could compromise cerebral perfusion or graft flow. Postoperatively, patients were monitored in a dedicated intensive care unit with close neurological interventional and continuous blood pressure control. Systolic blood pressure targets were maintained within a predefined range to ensure adequate bypass perfusion while minimizing the risk of hyperperfusion-related complications.

All patients received standardized antiplatelet therapy with aspirin 100 mg once daily, initiated preoperatively or immediately postoperatively according to the institutional protocol, and continued throughout the follow-up period unless contraindications developed.

Surgical treatment.

Eligible patients with chronic ICA occlusion will undergo standard STA-MCA bypass surgery. The procedure will be carried out using a standardized microsurgical end-to-side anastomosis technique. Intraoperative selection of the donor STA branch and recipient MCA segment will be based on vessel diameter, flow characteristics, and surgical accessibility. Intraoperative bypass patency will be assessed using the “faucet” technique” [22] in combination with microscopic indocyanine green (ICG) angiography to ensure adequate flow through the anastomosis.

Intraoperative perfusion and blood flow direction assessment.

Intraoperative perfusion and blood flow direction will be assessed using ICG fluorescent angiography with the Carl Zeiss Pentero 800 microscope equipped with FLOW 800 technology, which allows real-time visualization of cerebral vessels. All data will be processed and analyzed to create a color map depicting hemodynamic and perfusion delays. This enables comparison of perfusion parameters in the anastomosis region before and after bypass surgery, as well as assessment of blood flow direction and hyperperfusion zones in the brain. The assessment will be performed by neurosurgeons.

Postoperative study procedures.

Within 1-3 days after surgery, CTA of the head and neck will be performed to confirm bypass patency, measure the caliber of the donor STA branch, and visualize its course. At 3–5 days postoperatively, ASL-based MR perfusion imaging will be conducted to evaluate cerebral perfusion changes compared with preoperative studies. 3D segmentation and quantitative perfusion mapping will be applied to provide an objective assessment of regional perfusion improvements following surgery. Before hospital discharge, all patients will undergo a repeat evaluation of neurological status and cognitive function using the same standardised tests as preoperatively.

Follow-up assessment.

At six months after surgery, all patients will undergo follow-up assessment including CTA of the head and neck to evaluate bypass patency and measure the caliber of the donor STA branch, MR perfusion imaging with 3D segmentation to assess cerebral perfusion changes, and repeat neurological and neuropsychological evaluations using the same tests administered preoperatively and at discharge (NIHSS, mRS, MoCA, RAVLT, Kohs Block Design, and Stroop tests). The planning of the follow-up is described in Table 1.

Primary endpoint.

To evaluate the incidence of ischemic stroke during the 6-month follow-up period after surgery.

Secondary endpoints.

Early postoperative graft patency, perioperative safety, neurological and cognitive outcomes, recurrent cerebrovascular events, mortality, and radiological markers of revascularisation.

Definitions of outcomes.

The primary outcome is defined as the incidence of ischemic stroke during the 6-month follow-up period after surgery. This outcome will be assessed based on clinical evaluation and confirmed by neuroimaging (MRI or CT) in cases of suspected new neurological deficits, in accordance with standard diagnostic criteria for ischemic stroke.

Secondary outcomes included early postoperative haemodynamic change (≤7 days) assessed using the same imaging modality; graft patency was defined as uninterrupted flow through the bypass on intraoperative ICG and postoperative CTA; changes in cerebral haemodynamic status from baseline to 6 months after surgery will be assessed using ASL MRI and defined as a quantitative increase in regional CBF in the affected hemisphere and/or a reduction in interhemispheric perfusion asymmetry compared with baseline; change in neurological status from baseline to 6 months assessed using the NIHSS and the mRS; changes in cognitive function from baseline to 6 months based on standardised neuropsychological testing; all-cause mortality at 6 months; perioperative complications within 30 days (including intracranial haemorrhage, hyperperfusion syndrome, seizures, wound complications, and graft occlusion); and angiographic extent of revascularisation on follow-up imaging.

Sample size calculation.

Sample size estimation was performed in Stata (version 19.5) using the power pairedmeans command, based on a paired pre-post comparison of the primary outcome. Assuming a two-sided α of 0.05, 80% power, a standardised effect size of 0.40, and a within-subject correlation of 0.5, 52 evaluable patients were required. Allowing for potential loss to follow-up, a target sample size of 60 patients was set, providing approximately 86% power. Sensitivity analyses indicated that power ranged from 73% to 98% across plausible within-subject correlations (0.3–0.7).

Mortality analysis.

All-cause mortality will be assessed 6 months after surgery. Mortality will be reported as the number and proportion of deaths with exact 95% confidence intervals.

Time-to-event analysis will be performed using Kaplan-Meier survival curves, with survival probability reported for the follow-up period. Patients alive at the last follow-up will be censored on the date of last clinical contact. Considering the cohort of 60 patients, Cox regression will not be performed unless the number of events is sufficient.

Missing data handling.

Missing data will be evaluated for extent and pattern. Longitudinal analyses will use mixed-effects models, which account for within-subject correlation and allow inclusion of incomplete observations under a missing-at-random assumption. Where appropriate, multiple imputations by chained equations will be used, with sensitivity analyses performed to assess robustness. For time-to-event outcomes, patients will be censored at the last follow-up.