Yu Jiaxing Hong Tao 2024-05-19 19:01 Beijing

Developed by

National Medical Center for Neurological Diseases

Neurological Intervention Committee of Chinese Physicians Association

Radiation Neurosurgery Expert Committee of the World Association of Chinese Neurosurgeons

Brain arteriovenous malformation (BAVM) is a class of cerebrovascular structural abnormalities caused by genetic mutations, which is one of the major causes of hemorrhagic stroke and has a high risk of death and disability.

BAVM is considered to be the most challenging disease in the diagnosis and treatment of cerebrovascular disease. Currently, well-established therapeutic measures include surgical resection, interventional embolization, and stereotactic radiotherapy. Due to the complex vascular architecture of the lesion and its close anatomical relationship with the brain tissue, no single therapeutic measure can safely and effectively treat all cases of BAVM. Therefore, in the therapeutic decision-making of cerebral arteriovenous malformations, fully understanding the characteristics of each treatment modality, selecting appropriate therapeutic measures according to the vascular architecture of the lesion, organically integrating multiple measures, and conducting multidisciplinary, multi-stage, and multi-timed treatments are the keys to obtaining ideal treatment results and prognosis.

For this reason, the National Medical Center for Neurological Diseases, the Neurointerventional Professional Committee of the Chinese Physicians Association, and the Radiation Neurosurgery Expert Committee of the World Association of Chinese Neurosurgeons have taken the lead in organizing 45 experts from the fields of neurosurgery, neurointervention, and stereotactic radiosurgery across the country to screen a total of 295 studies with high-quality evidence-based medical evidence from more than 3,000 BAVM-related literatures, and to combine them with the the Expert Consensus on Multidisciplinary Diagnosis and Treatment of Brain Arteriovenous Malformation ormulated based on the specific situation of China. For the first time, this consensus integrates three BAVM treatments, namely, surgery, intervention, and gamma knife, with a distinctive multidisciplinary perspective. 33 recommendations are given for specific clinical diagnostic and treatment issues, such as predictive factors for bleeding, clinical risks in pregnancy, diagnostic imaging measures, and clinical treatment strategies, with the aim of providing guidance for the diagnosis and treatment of BAVM nationwide.

The expert consensus has been published in the Chinese Medical Journal and released to peers on April 27, 2024 at the 21st China Cerebrovascular Disease Forum (CFCVD). We invited Prof. Hong Tao from Xuanwu Hospital of Capital Medical University, Prof. Zhu Wei from Huashan Hospital of Fudan University, Prof. Sun Shibin from Beijing Tiantan Hospital of Capital Medical University, and Prof. Chen Guangzhong from Guangdong Provincial People's Hospital, the corresponding authors of the Consensus, to interpret the essence of the Expert Consensus on the Multidisciplinary Diagnosis and Treatment of Brain Arteriovenous Malformation.

(Note: This expert consensus uses the American Heart Association scoring system for the level of recommendation and evidence)

1、Epidemiology and etiology

The mean age at diagnosis of BAVM is 31 years old, with a male-to-female patient ratio of approximately 5:4. Bulk autopsy studies have shown a detection rate of approximately (1 to 1.8)/100,000 people.

The cause of most BAVMs is mutations in the vascular endothelial cell gene. Depending on the mutation pattern, BAVM cases can be categorized into familial BAVM and sporadic BAVM, with sporadic BAVM accounting for approximately 95% of cases.

Currently, the most common hereditary diseases associated with familial BAVM are hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation (CMAVM) syndromes.

In the last decade, a series of important breakthroughs have been made in the genetics of sporadic BAVM  and it is now clear that the cause of nearly 90% of sporadic BAVM is vascular endothelial cell function-acquired KRAS or BRAF somatic mutations.

2、Clinical presentation and natural history

The mean age at diagnosis of BAVM is 31 years old, with a male-to-female patient ratio of approximately 5:4. Bulk autopsy studies have shown a detection rate of approximately (1 to 1.8)/100,000 people.

The cause of most BAVMs is mutations in the vascular endothelial cell gene. Depending on the mutation pattern, BAVM cases can be categorized into familial BAVM and sporadic BAVM, with sporadic BAVM accounting for approximately 95% of cases.

Currently, the most common hereditary diseases associated with familial BAVM are hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation (CMAVM) syndromes.

In the last decade, a series of important breakthroughs have been made in the genetics of sporadic BAVM  and it is now clear that the cause of nearly 90% of sporadic BAVM is vascular endothelial cell function-acquired KRAS or BRAF somatic mutations.

Recommendations

1). Defining the risk of bleeding in BAVM helps to develop a rational treatment strategy, and a history of bleeding is the strongest predictor of bleeding events in BAVM. Relevant risk factors, such as vascular architecture, should also be considered to comprehensively determine a patient's clinical risk. (Level B evidence, Level I recommendation)

2). Pregnant patients with BAVM need to be informed of the clinical risks associated with pregnancy and the puerperium. (Level B evidence, Level IIa recommendation)

3). Patients with new-onset focal neurologic deficits, severe headaches, or seizures during pregnancy and puerperium need to undergo cranial MRI. (Level C evidence, Level IIa recommendation)

4). Surgical intervention for BAVM in pregnant and puerperal patients needs to be individualized with the participation of relevant specialties such as neurosurgery, obstetrics and gynecology, neonatology, and anesthesiology, weighing the clinical risks of the lesion itself as well as the impact of therapeutic measures on the pregnant woman and the fetus. (Level C evidence, Level IIa recommendation)

3、Imaging diagnostic

Imaging plays an important role in the diagnosis of BAVM, the development of treatment strategies, and follow-up. Commonly used imaging tools include CT, MRI, and DSA, and the combination of all three is often needed to provide more information about the lesion.

CT scanning has a sensitivity of more than 90% for acute subarachnoid hemorrhage and intra-parenchymal hemorrhage, while CT can detect some potential signs of vascular abnormalities, such as dilated or calcified vessels. CT perfusion images can indirectly suggest the impact of BAVM on intracranial hemodynamics. CTA has good spatial resolution and has the important advantage of a short imaging time, which allows for rapid diagnosis directly from CTA when signs of suspected cerebrovascular disease are detected on CT plain images.

MRI has ideal spatial resolution and provides more information about the brain tissue, so it is more advantageous than CT in screening for BAVM. The lesion shows a typical dilated vascular flow-air signal on T2-weighted image, which is the preferred imaging modality for screening for BAVM. Currently, the spatial resolution of MRA is slightly lower than that of CTA, but its noninvasive and radiation-free characteristics make it more advantageous in the review of BAVM patients and the screening of special populations (e.g., children, pregnant women).

DSA is the gold standard for the diagnosis of BAVM, with the most optimal temporal and spatial resolution currently available, providing accurate information on BAVM vascular architecture and hemodynamics.

Recommendations

5). It is reasonable to perform cerebrovascular imaging (CTA, MRA, or DSA) in patients with suspected cerebral hemorrhage. (Level B evidence, Level IIa recommendation)

6). MRI screening is recommended for patients with recurrent headaches, seizures, or focal neurologic deficits without a clear etiology. (Level C evidence, Level IIa recommendation)

7). DSA is the gold standard for the diagnosis of BAVM and should be performed in cases where other imaging confirms or is suspicious. (Level B evidence, Level I recommendation)

8). Patients with atypical site cerebral hemorrhage with negative DSA in the acute phase are recommended to review DSA or other cerebrovascular imaging after hematoma resorption. (Level C evidence, Level IIa recommendation)

4、Genetic diagnosis

It is now clear that almost all BAVM occurrences are associated with genetic mutations, so the need for genetic screening of patients and relatives with BAVM is a current concern. The following clinical features suggest a high likelihood of familial BAVM:

(1). Multiple AVM lesions, including patients with multiple independent AVM lesions within the skull, and patients with a combination of other visceral AVMs (e.g., AVMs in organs such as the spinal cord, lungs, and liver) in addition to BAVM. Note that cerebrofacial arteriovenous metameric syndromes (CAMS) are caused by somatic mutations in the somatic somatic cells and are therefore not considered to be familial cases of BAVM;

(2). The presence of a blood relative with a confirmed diagnosis of cerebral or other AVM;

(3). The patient has a combination of multiple erythematous skin and/or mucosal (oropharyngeal and nasal) foci of capillary dilatation;

(4). A history of recurrent rhinorrhea and/or gastrointestinal bleeding in both the patient and a consanguineous relative.

Recommendations

9). Genetic testing should be considered in patients with suspected familial BAVM. (Level C evidence, level IIa recommendation)

5、Treatment

No medications have been shown to be therapeutically effective in occluding or stabilizing BAVM. Treatment of the disease remains largely dependent on surgical techniques, including microsurgery, interventional embolization, and stereotactic radiation therapy.

Microsurgery is the intervention with the highest cure rate, with a 95% to 99% cure rate. However, the invasive nature of the surgery determines that microsurgery requires strict indications to ensure the safety of the treatment. Currently, Spetzler-Martin (SM) Level I-II cases are considered to be reasonable indications for surgical treatment; SM Level IV-V cases have higher surgical risk and surgical resection should be performed with caution; SM Level III cases need to be judged based on the patient's specific clinical characteristics and vascular structure.

The difficulties in BAVM surgery mainly lie in the blood supplying arteries from the deep side of the malformation mass and the high flow arteriovenous fistula structures within the malformation mass. Therefore, a therapeutic strategy of targeted preoperative embolization of these structures has emerged and is widely used in the management of complex BAVM cases.

Various assistive techniques surrounding BAVM surgery are dominated by imaging techniques such as functional MR, diffusion tensor imaging (DTI), and neuronavigation. The use of composite operating rooms has enabled intraoperative DSA, which has further improved the surgical cure rate of BAVM.

Recommendations

10). SM Level I-II patients can be treated by microsurgery. (Level A evidence, Level IIa recommendation)

11). SM Level III patients are more heterogeneous, with cases scoring of S1V1E1 being more suitable for surgical treatment. (Level B evidence, level IIa recommendation)

12). Preoperative embolization targets blood supply from the deep side of the malformation mass, high-flow arteriovenous fistulas, aneurysm-like structures, and blood-supplying arteries from the dura mater, thereby reducing the risk of intraoperative and perioperative bleeding. Preoperative partial embolization of the malformation mass is based on individualized vascular architecture and operator experience. (Level C evidence, Level IIa recommendation)

13). Surgical management of high-Level BAVM requires caution with preoperative functional MRI as well as DTI scanning and following preoperative embolization and gamma knife. (Level C evidence, Level IIa recommendation)

14). The composite operating room helps in the surgical treatment of complex BAVM. (Level C evidence, Level IIa recommendation)

Stereotactic radiosurgery is indicated for medium- and small-volume BAVMs, especially in cases located in deep (brainstem, thalamus, and basal ganglia, etc.) or functional areas (e.g., motor-sensory, language, and visual cortices, etc.); BAVMs remaining after microsurgery or endovascular embolization; and salvage treatment of large-scale, symptomatic BAVMs that are not amenable to other treatments. The occlusion rate of aberrant clusters 3 to 5 years after gamma knife surgery generally ranges from 60% to 90%.

For small and medium-sized BAVMs, a single treatment with a peripheral prescription dose of 16 to 22 Gy is generally adopted; for larger volumes (volume >10cm3) of vascular malformations located in or adjacent to important neurological function areas, brainstem, thalamus, etc., a staged treatment protocol is mostly adopted, which includes volumetric and metrological staging. A combined strategy of Gamma Knife and endovascular intervention may be adopted for larger lesions and the presence of dangerous structures.

Recommendations

15). Gamma Knife is indicated for small and medium volume BAVMs and is particularly suitable for BAVMs located in deep or functional areas. (Level B evidence, Level IIa recommendation)

16). Residual BAVM after surgery or endovascular embolization can also be treated with Gamma Knife. (Level B evidence, Level IIa recommendation)

17). There is a long waiting period after BAVM is treated with Gamma Knife until complete occlusion, typically 2 to 3 years or even longer, during which there is still a risk of bleeding. (Level B evidence, Level I recommendation)

18). For large-volume BAVM, staged treatment is needed, either volume staging or dose staging, and the specific treatment strategy needs to be individualized according to the location and volume of the malformation mass, history of bleeding, and patient symptoms. (Level B evidence, Level IIa recommendation)

19). Regular clinical and imaging follow-up is required after gamma knife treatment, and thin-layer MRI, including T1, T2, enhanced T1, and 3D TOF sequences, should be performed every six months to one year to promptly evaluate the changes in the near- and far-future deformity clusters as well as the occurrence of ARE. DSA should be performed when complete disappearance of the vascular malformation mass is demonstrated on MRI and at 3 years after radiosurgical treatment; DSA is recommended to clarify specific changes in vascular architecture before secondary treatment when a staged treatment strategy is adopted. (Level B evidence, Level IIa recommendation)

Interventional therapy is an indispensable tool in the multidisciplinary treatment of BAVM. It consists of the following five categories according to the therapeutic strategy:

(1). Curative embolization;

(2). Targeted embolization;

(3). Palliative embolization;

(4). Surgical preoperative embolization;

(5). Stereotactic radiation therapy combined with embolization.

The strategy of curative embolization is applicable in highly selected cases. Clinical studies have shown a higher percentage of curative embolization in BAVMs ≤3 cm in diameter, with a superficial location, a single feeder artery, and a single draining vein. Thus embolization is advantageous for lesions with deeper locations (e.g., basal ganglia, thalamus, midbrain, etc.) and simple vascular constructs.

Transvenous embolization has a cure rate of approximately 90%, and is particularly suitable for deep, small, single draining veins with tortuous arterial supply or small safe distances (e.g., transitory supply, perforating supply, etc.) in BAVM.

Targeted embolization refers specifically to a therapeutic strategy that targets the aneurysmal structure of the BAVM as well as high-flow arteriovenous fistulas to reduce the risk of bleeding. Targeted embolization should not be the end point of treatment for BAVM, especially in cases with a history of bleeding, and should be considered in conjunction with stereotactic radiotherapy or microsurgery after effective debridement of the structures at risk to increase the likelihood of curing the lesion. However, in elderly patients, the risk of bleeding and the risk of treatment need to be weighed comprehensively, and long-term observation after targeted embolization is also reasonable.

Recommendations

(20). It is reasonable for curative embolization of SM Level I-II BAVM lesions when access is ideal. (Level B evidence, Level IIa recommendation)

(21). In cases where curative embolization is proposed, complete embolization can be achieved with 1 treatment for small volumes and in separate sessions for larger volumes. (Level C evidence, Level IIa recommendation)

(22). Transvenous access embolization may be attempted in BAVMs with single-branch drainage and a tortuous arterial route of supply or a small safe distance. (Level C evidence, Level IIa recommendation)

(23). Nonadherent embolic agents have higher passage of malformed vascular clusters and are ideal embolic agents for curative embolization. (Level C evidence, Level IIa recommendation)

(24). Targeted embolization is justified in cases with well-defined risk structures. (Level C evidence, Level IIa recommendation)

(25). Palliative partial embolization is feasible in cases of BAVM with clinical symptoms due to abnormal hemodynamics. (Level C evidence, Level IIa recommendation)

Each of the three therapeutic techniques, microsurgery, stereotactic radiotherapy, and interventional therapy, has independent advantages but is not in a fully complementary relationship. For cases with simple structures and shallow locations (e.g., SM Level Ⅰ to Ⅱ), all three can achieve relatively satisfactory treatment results. However, for cases with larger volumes and diffuse structure of the malformation mass, they face greater challenges regardless of the method used. Therefore, for relatively complex BAVM cases, it is necessary for the operator to rationally select or combine various treatment approaches based on the specific vascular structure of the lesion with a full understanding of the various treatment techniques in order to obtain ideal treatment results.

Recommendations

(26). BAVM requires rational choice of treatment based on individualized vascular architecture and clinical features. For low-level cases, an overall treatment strategy should be formulated with the goal of cure; for complex high-level lesions, for which all current treatment methods are unsatisfactory, conservative observation can be adopted for unruptured cases, while ruptured cases require multidisciplinary combined treatment to achieve a cure as much as possible. (Level C evidence, Level IIa recommendation)

Patients in the acute phase of BAVM hemorrhage are recommended to be treated in an intensive care unit with continuous monitoring of general vital signs and intracranial pressure. Since swelling of brain tissue after hemorrhage will increase the risk of BAVM resection, and the compression of hematoma will cause part of the malformation mass not to show up on angiography leading to underestimation of surgical risk. Therefore, elective treatment of BAVM lesions has been suggested. Clinical data show that early and delayed resection of ruptured BAVM have similar long-term functional prognosis. Delayed resection leads to higher cure rates, but the risk of re-rupture of the lesion during the waiting period should be guarded against.

Recommendations

(27). The acute phase of BAVM hemorrhage can be treated by targeting the hematoma alone, and the malformed mass can be treated with surgical intervention after hematoma resorption. (Level C evidence, Level IIa recommendation)

(28). SM Level I-II and superficial located BAVMs can undergo BAVM resection in the acute phase of hemorrhage. Adequate preoperative assessment of vascular constructs is required, and treatment in a composite operating room helps to avoid lesion remnants. (Level C evidence, Level IIa recommendation)

(29). BAVMs with a chance of curative embolization and small hematoma size can be treated with embolization on an emergency basis. (Level C evidence, Level IIa recommendation)

(30). High-Level BAVM can be treated with targeted embolization of structures at risk in the acute phase to set the stage for subsequent microsurgery or stereotactic radiosurgery. (Level C evidence, Level IIa recommendation)

BAVM-related epilepsy can be effectively controlled after complete occlusion of the malformed vessel mass. Clinical data showed that the epilepsy control rates in the microsurgery, stereotactic radiosurgery, and interventional embolization groups were 78%, 66%, and 50%, respectively. However, in unruptured BAVM, high-quality clinical data showed that surgical intervention was not superior to pharmacologic therapy alone in terms of seizure control.

Recommendations

(31). Complete occlusion of the lesion is effective in controlling BAVM-related epilepsy. (Level B evidence, Level I recommendation)

(32). Preoperative EEG and intraoperative cortical EEG monitoring are reasonable options for patients with medically refractory epilepsy. (Level C evidence, Level IIa recommendation)

(33). For patients with unruptured refractory BAVM epilepsy, antiepileptic drug therapy alone is an option. (Level B evidence, Level IIa recommendation)Conclusion

This consensus was developed with reference to the latest research advances in the clinical diagnosis and treatment of BAVM, and was finalized after discussion and feedback from 45 experts in the committee and several revisions. However, BAVM has a complex vascular architecture and strong lesion heterogeneity, and its clinical diagnosis and treatment strategy still has many key points that should be explored. This consensus only represents the viewpoints of the authoring expert group and has no legal effect. In the future, as we continue to increase the number of clinical studies related to central nervous system vascular malformations, we will provide higher value clinical evidence and guidance for the subsequent improvement of this consensus.

Corresponding author

Hong Tao, Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Email: Hongtao.edu@gmail.com;

Zhu Wei, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China, Email: drzhuwei@fudan.edu.cn;

Sun Shibin, Department of Stereotactic Radiosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China, Email: gksssb@163.com;

Chen Guangzhong  Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Provincial Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China, Email: chengz5413@126.com.

Author

Yu Jiaxing (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China);

Zhu Wei (Department of Neurosurgery, Huashan Hospital, Fudan University);

Sun Shibin (Department of Stereotactic Radiosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China);

Chen Guangzhong (Department of Neurosurgery, Guangdong Provincial People's Hospital);

Hong Tao (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University)

Consensus Development Experts

(ranked in alphabetical order of surname)

Bai Satellite (Department of Neurosurgery, Henan Provincial People's Hospital);

Chen Fenghua (Department of Neurosurgery, Xiangya Hospital, Central South University)

Chen Guangzhong (Department of Neurosurgery, Guangdong Provincial People's Hospital)

Chen Hua (Department of Neurosurgery, Jiangsu Provincial People's Hospital);

Chen Jincao (Department of Neurosurgery, Zhongnan Hospital, Wuhan University);

Chen Xiaolin (Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University);

Chen Zuoquan (Department of Neurosurgery, Shanghai Tenth People's Hospital);

Deng Jianping (Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University);

Duan Chuanzhi (Department of Neurosurgery, Zhujiang Hospital, Southern Medical University);

Fang Bing (Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine);

Feng Wenfeng (Department of Neurosurgery, Nanfang Hospital, Southern Medical University);

Gao Ge (Department of Neurosurgery, Anhui Provincial Hospital);

Gu Zhen (Department of Neurosurgery, Yunnan University Hospital);

Guo Geng (Department of Neurosurgery, The First Hospital of Shanxi Medical University);

Guo Zongduo (Department of Neurosurgery, The First Hospital of Chongqing Medical University, Chongqing, China);

Hang Chunhua (Department of Neurosurgery, Nanjing Gulou Hospital, Nanjing, China);

He Xuying (Neurological Medicine Center, The Second People's Hospital of Guangdong Province);

Hong Tao (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University);

Huang Qinghai (Center for Cerebrovascular Disease, Changhai Hospital, Naval Military Medical University);

Li Conghui (Department of Neurosurgery, The First Hospital of Hebei Medical University);

Li Qiang (Center for Cerebrovascular Disease, The First Affiliated Hospital of Naval Medical University);

Lin Yuanxiang (Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University);

Liu Yi (Department of Neurosurgery, West China Hospital, Sichuan University);

Lu Hua (Department of Neurosurgery, Jiangsu Provincial People's Hospital);

Baimaitili (Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University);

Pan Li (Radio Wave Knife Center, Huashan Hospital, Fudan University, Gamma Knife Center, Shanghai Gamma Hospital);

Ren Jun (Department of Neurosurgery, The Second Hospital of Lanzhou Medical University);

Shi Huaizhang (Department of Neurosurgery, The First Hospital of Harbin Medical University);

Sun Shibin (Department of Stereotactic Radiosurgery, Beijing Tiantan Hospital, Capital Medical University);

Wang Daming (Department of Neurosurgery, Beijing Hospital, Beijing, China);

Wang Donghai (Department of Neurosurgery, Qilu Hospital, Shandong University);

Wang Jun (Department of Neurology, PLA General Hospital);

Xu Kan (Department of Neurosurgery, The First Hospital of Jilin University);

Yang Hua (Department of Neurosurgery, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine);

Ye Ming (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University);

Yu Jia (Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China);

Yu Jiaxing (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China);

Yu Bo (Department of Neurosurgery, Shengjing Hospital, China Medical University);

Zhang Dong (Department of Neurosurgery, Beijing Hospital);

Zhang Hongqi (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University);

Zhang Huaqiu (Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China);

Zhang Peng (Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China);

Zhao Yuanli (Department of Neurosurgery, Peking Union Medical College Hospital);

Zhong Shu (Department of Neurosurgery, Guangxi Hospital, The First Affiliated Hospital of Sun Yat-sen University);

Zhu Wei (Department of Neurosurgery, Huashan Hospital, Fudan University).

Conflict of interest: All authors declare no conflict of interest.

© Copyright

It is strictly prohibited for any media, website or individual to reprint or otherwise copy publish/publish the text, pictures, videos and other materials in this article without authorization. Media, websites or individuals who have been authorized by the agreement must indicate the source of the use, and violators will be held liable in accordance with the law.

△ Special Note

The text, pictures, audio and video contained in this page are for medical professionals only. The content contained on this page is only the personal opinion of experts and cannot replace the judgment of medical professionals. This page is not open to non-medical professionals, please understand.