Rationale and Relevance:

Branch Atheromatous Disease (BAD) describes an atherosclerotic occlusion of one of the deep penetrating cerebral arteries, including the lenticulostriate artery (LSA), paramedian pontine artery (PPA), and anterior choroidal artery (ACHA). BAD is frequently associated with early neurological deterioration (END), particularly progressive motor deficits that contribute to increased disability. Despite its clinical relevance, BAD remains underrepresented in major radiomorphological classification systems such as TOAST, which has led to limited evidence and unclear treatment strategies. Previous studies suggest that the efficacy of intravenous thrombolysis (IVT) may be reduced in BAD compared to other stroke etiologies.

Objectives:

The primary objective of this study is to evaluate the efficacy and safety of IVT compared with single antiplatelet therapy (SAPT) and dual antiplatelet therapy (DAPT) in patients with BAD-related stroke. A secondary objective is to examine the impact of acute-phase blood pressure fluctuations on END and functional neurological outcomes.

Design and Methods:

This international multicenter study will be conducted retrospectively according to the STROBE guidelines. Eligible patients include those with BAD-related stroke treated at one of the participating centers between 2010 and 2025. Inclusion criteria comprise characteristic diffusion-weighted MRI patterns in predefined vascular territories (LSA, PPA, ACHA) and a symptom onset ≤24 hours before admission. Patients with typical lacunar infarcts or with other identified stroke etiologies will be excluded.

Endpoints:

Primary endpoints include functional outcome at three months, defined as a favorable outcome with a modified Rankin Scale score of 0-1; occurrence of END, defined as a ≥4-point worsening on the NIHSS within 24-48 hours; and symptomatic intracerebral hemorrhage. Collected data include clinical, imaging, and therapeutic variables, as well as blood pressure trajectories and pre-stroke treatments (as detailed in the study protocol).

Statistical Analysis:

Analyses will be performed using SPSS and R. Descriptive statistics, univariate analyses, and multivariable models (IPTW and Poisson regression) will be applied. Results will be reported as adjusted relative risks with 95% confidence intervals.

Significance:

This study will provide the first comprehensive evaluation of IVT versus SAPT/DAPT in BAD-related stroke, and will investigate the clinical impact of blood pressure changes in this specific stroke subtype. The findings aim to support evidence-based treatment recommendations for a currently underrecognized and poorly understood stroke etiology.

Background Intracranial branch atheromatous disease (BAD) describes an occlusion of deep penetrating intracranial arteries, leading to subcortical infarction. Perforating arteries include the lenticulostriate artery (LSA), paramedian pontine artery (PPA), anterior choroidal artery (ACHA), thalamoperforating artery, and Heubner's artery. This study focuses on BAD affecting the ACHA, LSA, and PPA.

In contrast to lacunar ischemia, which is caused by hypertensive lipohyalinotic degeneration of the distal segment of a perforating artery with a diameter ≤200 µm, BAD involves larger vessels (700-800 µm) affected by atherosclerosis of the parent artery. BAD has not been classified as a major cause of cerebral infarction by the National Institute of Neurological Disorders and Stroke (NINDS) or the Trial of Org 10172 in Acute Stroke Treatment (TOAST), which has contributed to a rather scarce data regarding clinical trajectories of this particular stroke etiology. According to TOAST criteria, BAD-related strokes are often categorized under small vessel occlusion or classified as an undetermined cause. Due to their vessel size, high pressure and flow, these arteries are more susceptible to endothelial damage and atherosclerosis, leading to fluctuating symptoms. At admission, BAD often presents similarly to lacunar ischemia. But in comparison, a main clinical characteristic of BAD is the frequent occurrence of early neurological deterioration (END), often manifesting as progressive motor deficits, which contribute to poorer outcomes and increased disability. Consequently, BAD has been recognized as a major vascular mechanism of progressive motor deficits in penetrating artery infarcts. Because of its unique pathophysiology and clinical progression, finding effective treatment strategies remains difficult. Intravenous thrombolysis (IVT) appears to be less effective for BAD compared to other etiologies of acute ischemic stroke. Previous studies have explored various treatment strategies, including dual antiplatelet therapy, tirofiban, and anticoagulation therapy, but results have been inconsistent. This study will assess the efficacy and safety of IVT versus antiplatelet therapy in BAD-related stroke. Furthermore, we will examine the impact of blood pressure on END and functional outcomes.

Aims The primary aim of this study is to assess the efficacy and safety of IVT compared to single (SAPT) or dual antiplatelet therapy (DAPT) in patients with BAD-related stroke. Secondary aim is to explore the impact of blood pressure fluctuations on END and functional outcomes and its potential interactions with acute therapies.

Methods This study is an international multicenter observational study recruiting patients with BAD-related stroke in the acute phase on the stroke unit up to 24 hours before admission. As of March 26, 2025, this study has recruited six institutions, led by Department of Neurology, St. John's Hospital, Vienna, Austria and sponsored by Sigmund Freud University Vienna, Austria.

Study Population All patients with a BAD-related stroke, aged over 18 years, with symptom onset no more than 24 hours before admission, who were treated in one of the stroke units of the participating institutions between 01.01.2010 and 28.02.2025, will be included based on the following inclusion criteria. All enrolled patients must have undergone a cerebral MRI for inclusion.

Inclusion criteria

1. DWI lesion: single isolated deep subcortical stroke AND
2. The affected vessel involves the LSA, PPA, or ACHA, and the infarct lesion on DWI conforms to one of the following characteristics (A, B, OR C):

A. LSA: "Comma-like" infarct lesions with "fan-shaped" extension from bottom to top in the coronary position OR ≥ 3 layers (layer thickness 5 mm) on axial DWI.

B. PPA: Infarct lesion extending from the deep pons to the ventral pons on axial DWI.

C. ACHA: Infarct within the anterior choroidal artery territory. Exclusion criteria

1. Typical recent small subcortical infarction (RSSI) (oval, <20mm in all axes).
2. ≥ 50% stenosis on the parent artery (i.e., BA, MCA, or ICA)
3. Stroke due to other clearly identified causes or possible cardioembolic etiology.

Endpoints

The primary endpoints of this study include:

1. Modified Rankin Scale (mRS) score at three months, with a favorable outcome defined as mRS 0-1 at three months.
2. Early neurological deterioration (END), defined as a worsening of the NIHSS score by ≥4 points within 24-48 hours after symptom onset.
3. Occurrence of symptomatic intracerebral hemorrhage.

Interventions Intravenous thrombolysis (IVT), single antiplatelet therapy (SAPT), dual antiplatelet therapy (DAPT)

Hypothesis

1. H0. Patients with BAD related stroke treated using IVT will not achieve better functional outcome as compared to those treated with SAPT.

   H1. Patients with BAD related stroke treated using IVT will achieve better functional outcome as compared to those treated with SAPT.

2. H0. Patients with BAD related stroke treated using IVT will not achieve better functional outcome as compared to those treated with DAPT.

   H1. Patients with BAD related stroke treated using IVT will achieve better functional outcome as compared to those treated with DAPT.

3. H3. Patients with BAD-related stroke experiencing blood pressure drop >=30 mmHg in the first 24 hours after admission will not experience worse functional outcome as compared to those without blood pressure drop. Interaction with IVT will be significant.

H3. Patients with BAD-related stroke experiencing blood pressure drop >=30 mmHg in the first 24 hours after admission will experience worse functional outcome as compared to those without blood pressure drop. Interaction with IVT will be significant.

Informed consent Due to the retrospective nature of the study and the use of anonymized data, obtaining patient informed consent is not necessary.

Study sites Institutions participating in this study, with a full list of institutions provided under collaborating institutions. The leading institution is the Department of Neurology, St. John's Hospital, Vienna, Austria.

Study design The study will be conducted as an international multicenter retrospective observational study according to the STROBE guideline.

Sample size Although the study is retrospective, a sample size calculation was conducted. Based on outcome data from lacunar stroke patients, 59% of patients treated with IVT achieved a favorable outcome (mRS 0 - 1 at 3 months). Assuming an odds ratio (OR) of 1.67 in favor of IVT, this corresponds to an estimated 46% rate of favorable functional outcome in the control group. Using a two-sided alpha of 0.05 and a power of 80%, the calculated total sample size is 462 patients, with 231 in each group. The calculation was performed using G*Power (version 3.1.9.7, Düsseldorf, Germany).

Collected data See study protocol

Data management Collected data will be entered into an electronic database at the primary study site. All data will be fully anonymized and only shared in this form with researchers. Therefore, a data monitoring committee will not be required. All datasets will be exclusively used for this study, and no third party will be granted access at any time.

Statistics The statistical analysis will be conducted using SPSS version 29.0.1.0 (IBM Corp., Armonk, NY, USA) and R version 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables will be presented as mean ± standard deviation (SD) or median with interquartile range (IQR), depending on their distribution. Categorical variables will be expressed as frequencies (n) and percentages (%). This includes variables such as baseline characteristics, medical history, and treatment modalities. For the analysis of statistical significance in outcome measures, Pearson's χ² test or Fisher's exact test will be applied for categorical data, while Wilcoxon rank-sum tests or t-tests will be used for continuous variables, as appropriate. Statistical uncertainty will be reported using 95% confidence intervals (CI). To evaluate the association between three-month mRS and clinical or therapeutic predictors, IPTW and Poisson regression models will be utilized. The results of the Poisson regression analysis will be reported as adjusted relative risks (RR) with corresponding 95% CI. A favorable functional outcome is defined as mRS ≤1 at three months post-stroke. Statistical significance will be set at p<0.05.

Ethical considerations This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines throughout the whole research process. Approval from the ethics committee will be obtained prior to data collection. As this is a retrospective, non-interventional study, there is no additional physical risk for patients. Data collection is exclusively based on previously recorded medical records. The primary ethical concern in this study relates to data transfer between institutions. To minimize this risk, only fully anonymized data will be shared with researchers. All collected data will be used solely for scientific research purposes, and no personal information will be disclosed or made accessible to third parties.

Inclusion Criteria:

• aged over 18 years, with acute ischemic stroke and symptom onset no more than 24 hours before admission, who were treated in one of the stroke units of the participating institutions.

• All enrolled patients must have undergone a cerebral MRI for inclusion:

  1. DWI lesion: single isolated deep subcortical stroke AND
  2. The affected vessel involves the LSA, PPA, or ACHA, and the infarct lesion on DWI conforms to one of the following characteristics (A, B, OR C):

A. LSA: "Comma-like" infarct lesions with "fan-shaped" extension from bottom to top in the coronary position OR ≥ 3 layers (layer thickness 5 mm) on axial DWI.

B. PPA: Infarct lesion extending from the deep pons to the ventral pons on axial DWI.

C. ACHA: Infarct within the anterior choroidal artery territory.

Exclusion Criteria:

• Typical recent small subcortical infarction (RSSI) (oval, <20mm in all axes)
• ≥ 50% stenosis on the parent artery (i.e., BA, MCA, or ICA)
• Stroke due to other clearly identified causes or possible cardioembolic etiology.

All patients with a BAD-related stroke, aged over 18 years, with symptom onset no more than 24 hours before admission, who were treated in one of the stroke units of the participating institutions.

Individual participant data that underlie the results after deidentification

Data that support the findings of this study will available from the corresponding author after academic boards review and upon reasonable request