Study on the Effects of Pharmacological and Physical Therapy in Delaying the Progression of Moyamoya Disease (Moyamoya Syndrome) : Randomized Controlled Study
Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease characterized by progressive stenosis or occlusion at the terminal portion of the internal carotid artery, with formation of an abnormal vascular network at the base of the brain. Moyamoya syndrome (MMS) has the same cerebrovascular imaging and clinical manifestations as moyamoya disease, but it is accompanied by other systemic comorbidities. Moyamoya disease and moyamoya syndrome are collectively referred to as moyamoya-like cerebrovascular disease. They are highly prevalent in East Asia, and China has a large patient population. In 2018, the incidence was 1.6 per 100,000 person-years, and the disease is a major cause of stroke in children, adolescents, and young adults \[1\]. This group of diseases often causes severe complications such as stroke and cognitive impairment, leading to poor prognosis and reduced ability to live independently \[2\]. Among patients who do not receive effective treatment, the risk of severe neurological deficit or death is as high as 75%, and approximately 60% of patients with moyamoya disease develop cognitive impairment \[3\]. Therefore, moyamoya disease (moyamoya syndrome) is a major health problem that seriously affects the health of the Chinese population. At present, several urgent problems remain in the clinical diagnosis and treatment of moyamoya disease (moyamoya syndrome). First, the epidemiological characteristics and disease susceptibility of this condition in the Chinese population are not yet fully clear. Second, reliable clinical assessment tools and standardized risk prediction models for moyamoya disease are lacking, and there is still no clear basis for identifying which patients need timely intervention. Third, a systematic precision treatment pathway for moyamoya disease has not yet been established, and high-quality evidence is still lacking regarding the role of pharmacological and physical therapy in delaying disease progression. Therefore, systematic research to clarify the efficacy of different treatment approaches in moyamoya disease is of great significance for promoting the establishment of an integrated diagnostic and therapeutic system for this disease. \[Add a paragraph introducing ischemic conditioning and its role in stroke and MMD.\] Systematic treatment is an important means to improve the prognosis of moyamoya disease. Current major treatment options include revascularization surgery and pharmacological therapy. Previous studies have shown that revascularization surgery can improve cerebral blood flow and reduce the risk of stroke; however, for asymptomatic or early-stage patients, surgery is not the only option \[4\]. In terms of pharmacological therapy, nonsurgical treatments such as antiplatelet therapy and intensive lipid-lowering therapy may delay disease progression, but high-quality clinical evidence remains lacking. In addition, emerging physical therapies such as ischemic conditioning have been shown to improve the tolerance of brain tissue to ischemia and have demonstrated potential therapeutic value in patients with stroke \[5\]. However, the safety and efficacy of these treatment approaches in patients with moyamoya disease require further study and validation. Therefore, this study proposes to conduct a multicenter, prospective randomized controlled clinical trial to systematically evaluate the efficacy and safety of aspirin therapy and ischemic conditioning therapy in delaying the progression of moyamoya disease, and to provide evidence-based support for nonsurgical treatment strategies for patients with moyamoya disease. \[The following content was moved from the study rationale section and should be integrated with the research background.\] Even when patients with moyamoya disease (moyamoya syndrome) have not yet developed definite symptoms of cerebral infarction, their cerebral hemodynamics may already be in a compensated or critical state. They are often prone to nonspecific symptoms such as headache and dizziness, subjective cognitive decline, and TIA attacks, and they have a potential risk of progression to symptomatic stroke. Microembolus formation and vascular endothelial dysfunction may further reduce flow reserve and aggravate hypoperfusion, thereby leading to adverse events. For such mildly affected patients, early intervention has important clinical value for delaying disease progression and preventing cerebrovascular events. Aspirin irreversibly inhibits cyclooxygenase-1 and blocks thromboxane A2 production, thereby inhibiting platelet aggregation. In the pathological process of moyamoya disease (moyamoya syndrome), microcirculatory changes and vascular intimal injury may activate platelets and promote microthrombus formation, which may aggravate ischemia-induced stroke. Therefore, aspirin may reduce the risk of ischemic events by inhibiting platelet aggregation. Ischemic conditioning is a noninvasive physical therapy that activates systemic endogenous protect
History of any form of intracranial hemorrhage, including subarachnoid hemorrhage, intracerebral hemorrhage, intraventricular hemorrhage, etc.; history of symptomatic ischemic stroke; frequent transient ischemic attacks (TIAs) before enrollment, defined as ≥3 episodes within 7 days; or history of epileptic seizures. Concomitant cerebrovascular diseases that may significantly affect perioperative risk or outcome assessment, such as intracranial aneurysms requiring concomitant treatment, cerebral arteriovenous malformations, arteriovenous fistulas, or other relevant cerebrovascular lesions. History of severe traumatic brain injury, brain tumor, encephalitis, meningitis, or other inflammatory diseases of the central nervous system; other major intracranial diseases; any prior invasive intracranial treatment; or history of cranial radiotherapy. Planned cerebral revascularization surgery within 3 months. Severe cardiac dysfunction (left ventricular ejection fraction \<50% or New York Heart Association \[NYHA\] class III-IV), hepatic dysfunction (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \>2 times the upper limit of normal), or renal dysfunction (serum creatinine \>1.5 times the upper limit of normal); major systemic diseases such as unstable angina, acute coronary syndrome, asthma, or chronic obstructive pulmonary disease (COPD); severe noncardiovascular comorbidities with an expected survival of \<1 year; or any other serious comorbidity considered by the investigator to significantly increase study-related risk. Contraindications to aspirin, including: 1. Known allergy to aspirin; 2. Severe renal dysfunction (serum creatinine \>1.5 times the upper limit of normal) or severe hepatic dysfunction (ALT or AST \>2 times the upper limit of normal); 3. Severe heart failure (NYHA class III-IV); 4. Coagulation disorders or a history of systemic bleeding; 5. History of thrombocytopenia or neutropenia; 6. History of drug-induced hematologic disorders or hepatic injury; 7. White blood cell count \<2×10⁹/L or platelet count \<100×10⁹/L; 8. History of gastrointestinal bleeding within 3 months before enrollment, or a documented history of gastric ulcer or gastritis; 9. Any other contraindication to aspirin. Contraindications to remote ischemic conditioning (RIC), including: 1. Peripheral vascular disease of the upper or lower extremities, particularly significant stenosis or occlusion of the brachial, ulnar, or radial arteries, or any condition considered by the investigator to make upper-arm cuff inflation for RIC unsuitable; 2. Conditions that may affect the safety of upper-limb RIC, including but not limited to severe skin or soft-tissue infection or injury, marked lymphedema, arteriovenous fistula or dialysis fistula, recent deep venous thrombosis, or inability to tolerate upper-arm cuff inflation as judged by the investigator, such as severe pain or recurrent subcutaneous bleeding; 3. Known allergy to the RIC device or any of its component materials. Requirement for aspirin and/or other antiplatelet therapy because of diseases other than moyamoya disease, such as systemic, circulatory, or hematologic disorders; or continuous use of other antiplatelet agents for ≥5 days before enrollment, with the last dose administered within 10 days before enrollment. Requirement for anticoagulant therapy, including conditions such as atrial fibrillation, prosthetic heart valves, known or suspected endocarditis, venous thrombosis, or other diseases requiring anticoagulation; or use of heparin or oral anticoagulants within 10 days before enrollment. Pregnancy, suspected pregnancy (defined as a positive pregnancy test in a woman of childbearing potential who has not used effective contraception), or breastfeeding. Conditions that may interfere with completion of key follow-up assessments, such as severe cognitive impairment or psychiatric disorders resulting in inability to cooperate with study evaluations, or a clear expectation that follow-up cannot be completed. Current participation in another interventional clinical trial that, in the investigator's judgment, may interfere with assessment of the study outcomes
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