Clinical Characteristics, Effect Of Surgical Revascularizations And Pathophysiological Mechanisms Of Neovascularization In Adult Moyamoya Disease Associated With Type 2 Diabetes

Moyamoya disease is one of cerebral vascular diseases characterized by the progress of stenosis or occlusionat the end of bilateral internal carotid arteries with the abnormal vascular network at the cranial base. Moyamoya syndrome, also known as quasi-moyamoya disease, manifested asstenosis or occlusion at the terminal portion of theinternal carotid artery or initial portion of the anterior and/or middle cerebral arteries with an abnormal vascular network accompanied by at least one or more underlying diseases. If an adult unilateral moyamoya disease associated with one or more underlying diseases it should be considered as quasi-moyamoya disease. MMD is a cerebrovascular disorder mainly found in Asian population with the racial diversity. Compared with the healthy persons, Clinical symptoms attributed to changes in flow resulting from stenosis of the internal carotid artery can be divided into two major etiologic categories those due to brain ischemia(i.e., stroke, transient ischemic attacks [TIAs], and seizures) and those due to the deleterious consequences of the compensatory mechanisms responding to theischemia(i.e., hemorrhage from fragile collateral vessels and headache from dilated transdural collaterals). Surgical revascularizations(direct, indirect or a combination of these two types of procedures) are recommended to improve cerebral hemodynamics, reducing the frequency of ischemic attacks, the risk of cerebral infarction, and improving the postoperative ADL and long-term outcomes. Encephaloduroarteriosynangiosis(EDAS), one of the indirect procedures, is considered as a safe and effective option for both pediatric and adult moyamoya patients. Effect of the operation may be affected by the age of patients, complications and other factors during the perioperative period or postoperation. Interestingly, more development of collateral circu Iation and improvement of clinical symptoms have been observed in adult moyamoya patients complicated with type 2 diabetes mellitus after operations in our research center. However, type 2 diabetes mellitus associated with cardiovascular and cerebrovascular diseases were indicated to be more susceptible to adverse events such as stroke. Development of the coronary collateral vessels as well as in peripheral circulation in patients with DM has been confirmed to be inhibited compared to the nondiabetic group. What’s more, studies about the effects of diabetes on the cerebral angiogenesis have not been conducted extensively in the world. Limited researches about the influence of type 2 diabetes on development of angiogenesis in moyamoya patient have been conducted. No studies has been found on the analyze of differences of neovascularization after EDAS and also the characteristics of pathological and physiological on angiogenesis between moyamoya patients and moyamoya patients associated withtype 2 diabetes mellitus. A variety of vascular growth factors and cytokines, including vascular endothelial growth factor, basic fibroblast growth factor, Transforming growth factor-β, colony stimulating factor and hepatocyte growth factor, has been reported to play an important role in the promotion of angiogenesis postoperatively in moyamoya disease. It has been found that more establishment of collateral circulation and improvement of clinical outcomes in moyamoya disease patients complicated with type 2 diabetes mellitus in our study. In order to explore reasons for this phenomenon, a retrospective analysis was conducted to demonstrate the diversity of the neovasculization along with the clinical feature and prognosis as well as distribution of growth factors in serum between moyamoya patients complicated with or without type 2 diabetes mellitus in our center.Part 1 Clinical features of moyamoya disease in patients with type 2 diabetes mellitusBackground: Moyamoya disease is an unusual form of chronic and progressive cerebrovascular occlusive disease. The number of confirmed cases increases with years along with the prevalence rates due to the development of imaging technology and deeper awareness of moyamoya disease by our clinician. This cerebrovascular disorder was mainly found in Asian population with the racial diversity. The initial symptoms primarily include cerebral ischemia, cerebral hemorrhage, headache, dizziness, and asymptomatic type. Epidemiology of the bulk of moyamoya cases has been reported in Japan, South Korea and China. Differences have been observed on the clinical symptoms and effect of surgical revascularization between adult moyamoya disease patients with T2 DM or without in our department.While no system study has been carried out to explore the clinical characteristic of MMD with T2 DM. A retrospective study was performed in the first portion to obtaina better understanding on the moyamoya disease complicated with T2 DM.Objective: We aimed to investigate the clinical feature, Suzuki stages corresponding to the degree of vascular lesions and the effect of operation on improvement of clinical symptoms in adult moyamoya patients complicated with T2 DM.Methods: A consecutive surgical series of patients with MMD who underwent EDAS between April 2004 and December 2012 was reviewed to indentify all patients 18 years of age or older at the time of surgery, at the department of Neurosurgery, 307 Hospital PLA, Beijing, China. All cases accepted preoperative cerebral angiography and met the inclusion criteria of MMD. A definite diagnosis of T2 DM was made according to the guidelines for diagnosis and treatment of T2 DM in 1999. MRI and magnetic resonance angiography imaging(MRA), transcranial Doppler(TCD) examination must be completed before the surgery. EDAS was performed once DSA was finished. MRS score and improvement of clinical symptoms after the surgical intervention were evaluated during the follow-up.Result: A total of 87 consecutive moyamoya patients with T2 DM recruited were the Han nationality in the first section. Endemic distribution of this disorder is as follows: 2 in Anhui province, 10 in Beijing, 1 in Fujian, 10 cases in Hebei, 16 cases in Henan, 4 cases in Heilongjiang, 1 case in Hubei, 9 cases in Jilin, 3 cases in Jiangsu, 2 cases in Jiangxi, 4cases in Liaoning, 1 case in Inner Mongolia, 16 cases in Shandong, 4 cases in Shanxi, 2 cases in Shaanxi, 1 case in Tianjin and 1 case Xinjiang. The largest number of MMD was distributed in Shandong and Henan province. In the setting of diabetic group, 54 were male(62.1%) and 33 were female(37.9%). The averageage of diagnosis of T2 DM was 40.8±8.9 years, while the age of diagnosis of MMD was 44.8±8.7 years which was significantly higher(t=-2.997, P=0.003<0.01). That is, diagnosis of moyamoya disease could not be established until experiencing severe neurological symptoms after the diagnosis of T2 DM. Not enough attention drawn to the initial symptom lead to the delay of the diagnosis. This part classified the initial attacks into 6 types: 35 cases(40.2%) of transient ischemic attack(TIA), 34 cases(39.1%) of cerebral infarction, 6 cases(6.9%) of cerebral hemorrhage, 4 cases(4.6%) of dizzy, 7 cases(8.1%) of headache and 1(1.1%) case of asymptomatic MMD. EDAS was performed on each patient after DSA. Significant statistical differences in scores of m RS preoperatively and postoperatively were observed(Z=-7.547, p=0.000<0.01). The improvement rate of clinical symptom was up to 82.8% after operation.Conclusion: This portion showed a peak age at onset in the late 40 s to 50 s. MMD complicated with T2 DM are more prevalent in men than in women. The age of diagnosis of MMD was significantly higher than that of T2 DM. EDAS plays an important role in improving preoperative symptoms and reduce the risk of long-term stroke. But further investigations about its effect on the change of intracranial hemodynamics are needed.Part 2 Revascularization and surgical outcomes following EDAS in adult moyamoya disease associated with type 2 diabetesBackground: Surgical revascularization such as direct, indirect or combined anastomosis has been proved to be effective in improving the decreased cerebral circulation and clinical signs. EDAS is a method of indirect revascularization procedures that has been shown to be beneficial in the childhood and adult population Disadvantage caused by DM to the formation of collateral vessels has been found in other disorders except moyamoya disease. None of studies has been conducted to explore the effect of T2 DM on MMD patients and investigate the difference of the development of superficial temporal artery collateral circulation between diabetic and nondiabetic patients.Methods: A consecutive surgical series of patients with MMD who underwent EDAS between April 2004 and December 2013 was reviewed to indentify all patients 18 years of age or older at the time of surgery, at the department of Neurosurgery, 307 Hospital PLA, Beijing, China. Of the patients accepted preoperative cerebral angiography and repeated cerebral angiography 6 to 12 months after operation, 60 patients with T2DM(mean age, 42.08±8.20 years) met the criteria for the T2 DM group. By using a matched-pair case-control study design, 120 nondiabetic subjects with definite moyamoya disease(mean age, 41.33±8.42years)matched according to age and gender were included in the control group. Postoperative collateral formation(the extension of superficial temporal artery collateral circulation) observed on external carotid angiograms between the two groups were graded according to the collateral grading system originated from Suzuki staging criteria, classified into four degrees(excellent, good, fair and poor). Modified Rankin Scale(m RS) was used to evaluate the recovery of neurological functions before and after the treatment.Result: There was nostatistically significant difference in the constituent ratios of initial symptom and preoperative Suzuki stage between patients with and without type 2 diabetes. Progression of angiopathy around the circle of Willis was postoperatively observed in bilateral internal carotid arteries in both groups. Patients with type 2 diabetes had a higher postoperative Suzuki stage(p < 0.01) and more frequent development of collateral angiogenesis germinating from the external carotid after indirect revascularization procedures in the surgical cerebral hemisphere(82.7%vs 72.2%; p < 0.05). The extent of postoperative collateral formation in patients with diabetes mellitus was significantly higher(p < 0.01). Postoperative clinical improvement in the diabetes groupwas more common after revascularization procedures(p < 0.05), and the diabetes grouphad lower modified Rankin Scale scores(p < 0.05) in comparison with the nondiabetesgroup. Late postoperative stroke and posterior cerebral artery involvement were identified as predictors of unfavorable clinical outcome in both groups, while type 2 diabetes was associated with a favorable clinical outcome.Conclusion: Encephaloduroarteriosynangiosis is an efficacious treatment for adult patients with moyamoya disease. Not only the spontaneous collateral vessels preoperatively but also the collateral circulation of the STA to the operated hemispheres postoperatively show better in patients with T2 DM than in nondiabetic patients with definite MMD. We speculate diabetes may be one of the risk factors of progression in vasculopathy in MMD and a significant factor to the development of collateral vessels.Part 3 Changes of serum growth factors in patients with MMD complicated with T2DMBackground: A great quantity of collateral circulation in MMD and a large number of neovascularization developing from transplanted vascular or tissues after EDAS have been observed. These phenomena suggest that growth factors, cytokines, and their receptors may play an important role in the angiogenesis process. Previous studies have shown that certain growth factors or cytokines such as vascular endothelial growth factor(VEGF), Basic fibroblast growth factor(b FGF), transforming growth factor-β(TGF-β), hepatocyte growth factor(HGF) are elevated in theintracranial artery, extracranial artery(superficial temporal artery), serum, and CSF of patients with MMD. It has been confirmed that insulin-like growth factor-1(IGF-1) also plays a significant role in the regulation of cell growth and expression of VEGF. More collateral circulations have been found in MMD patients complicated with T2 DM in our cohort following EDAS than that in MMD patients only. Thus we speculate whether the vascular growth factors described above existed corresponding changes and a higher degree might be in MMD patients complicated with T2 DM which promote the formation of collateral circulation.Objective: Mechanism of angiogenesis can not be investigated the animal experiment in vitro due to the absence of an experimental animal model of moyamoya disease. Analyses on the serum contents of VEGF、IGF-1、TGF-β、HGF in adult MMD associated with T2 DM, patients with MMD and the health adult were performed to explore the characteristics of growth factor in serum in MMD with T2 DM. A preliminary study on the mechanism of angiogenesis in adult MMD with T2 DM and clinical application in the treatment of moyamoya disease was investigatd in our study. This part of research was approved by the Ethic Committee of Affiliated Hospital of Military Medical Science Academy of the PLA.Methods: Serum specimens were obtained from MMD sample storehouse in Department of Neurosurgery, 307 Hospital, PLA Center for Cerebral Vascular Disease, Beijing, China. A fifteen consecutive surgical series of patients with MMD possessing serum specimen who underwent EDAS between January 2012 and January 2014 was reviewed to indentify all patients 18 years of age or older at the time of surgery. 8 cases were male and 7 were female. In order to avoid statistical bias, by using a 1:2 matched-pair case-control study design, 30 nondiabetic subjects with definite moyamoya disease matched according to age and gender were included from sample storehouse. Meanwhile, 15 healthy adult were selected by using a 1:1 matched-pair case-control study design in the control group from medical examination center.Serum levels of VEGF、IGF-1、TGF-β and HGF were detected by Enzyme-Linked Immunosorbnent Assay(ELISA). EDAS was performed in the group of patients with MMD. MRS score and improvement of clinical symptoms after the surgical intervention were evaluated during the follow-up.Result: No statistically significant difference existed in the serum levels of VEGF, IGF-1 and TGF in the three groups. There was no significant difference in the levels of HGF between definite MMD group and healthy group. Compared with normal control group(P<0.05) and definite MMD group(P<0.05), level of HGF was significantly higher in MMD patients with T2 DM. The postoperative clinical improvement in T2 DM group is better after EDAS(p=0.044<0.05) compared with the definite MMD group. Significant statistical differences in scores of m RS postoperatively(Z=-2.76,p=0.006<0.05) were observed between two groups during follow-up.Conclusion: Level of serum HGF in patients with MMD complicated with T2 DM was significantly higher than that in definite MMD patients and health adults. Better improvement of postoperative clinical outcomes was observed in T2 DM group. This result suggested that HGF might play a certain role in the pathogenesis of MMD. What’s more, high level of serum HGF might promote the improvement of neurological function and development of collateral circulation postoperatively.