| Background and Purpose — The pathologic mechanism of chronic subdural hematoma(CSDH) still was not clear. The high permeability theories had been denied, and hyperfibrinolysis and capsule hemorrhage were lack of a reliable basis theory. Except the operation method there was not a valid method to treat the CSDH.Our preliminary work showed that the subdural hematoma absorption correlated with capsule neovascularization, drug intervention decreased endothelial progenitor cells(EPCs) level can make the hematoma absorption delay in rats, most CSDH patients EPC level below normal in clinical studies, which show the formation and absorption of CSDH may related with EPC mediated angiogenesis and repair. This subject intends to prove pathogenesis, find out the main factors about the CSDH formation and prognosis, and put forward the relevant control method for establishing a new clinical strategy of prevention and treatment of CSDH patients.Methods —Basic experiment part: through the rat tail collagen make a subdural hematoma model, mixed with VEGF factor, the test comparison of hematoma volume,hematoma capsular network stations, peripheral blood levels of EPC and hematoma VEGFR- 1, VEGFR- 2, Ang- 1, Ang- 2 and Tie- 2 expression changes, etc.Through the improvement of subdural building, according to different doses of oral atorvastatin, experimental animals can be divided into 3 groups: control group(saline- treated), small dose group(3 mg/kg/day), and high-dose group(8 mg/kg/day). Using nuclear magnetic resonance(MR) dynamic observation hematoma volume change in rats. HE staining and transmission electron microscopy, immunohistochemistry, flow cytometer, real time quantitative PCR and ELISA techniques were measured after building different observation points freshman hematoma capsular disease physiological structure, peripheral blood sample number, new blood vesselsendothelial progenitor cells and smooth muscle cell density, peripheral blood and hematoma capsular angiogenesis factors related to VEGF, TGF- beta, MMP- 9, and changes the expression of Ang- 1/2, and inflammation related factors(TNF alpha, IL- 6 and IL- 10). Dynamic testing rats behavior change, the relationship between the analyses related to intervention factors.Clinical trials part: collecting peripheral blood of patients with chronic subdural hematoma after drilling, doing EPC detection, parallel prognostic analysis.Intervention experiment, collecting ≧ age 18, < 90 years old, The MGS- GCS(The Markwalder Chronic Subdural Haematoma Scale Grade) class 2(including level 2)below, in a short period of time will not happen, cerebral hernia surgery without processing necessary in patients with CSDH, volunteers oral atorvastatin therapy,methods of 20 mg/night, last 1 to 12 months. Choose medication after 1 and 3 month,review images, followed up for 2 years annual review images. During the medication regularly review and outpatient follow-up the possible side effects of liver function.All patients were banned used glucocorticoid, promote blood circulation and other drugs may affect the angiogenesis. If patients with sudden deterioration of conscious state, hematoma volume increase, cerebral hernia increased risk, etc., in a timely manner to the surgical treatment. Basic epidemiological data statistics, measurement hematoma volume before and after treatment, the MGS- level GCS, Daily Life ability assessment(Activities of Daily Life- the Barthel Index scale, ADL- BI)comprehensive evaluation of curative effect on the patients and patients with statistical treatment time and cost.Results—Basic experiment part: rats after normal modeling, peripheral blood EPC after raise to decline gradually, to the modeling after 6 days or so back to normal baseline. The death after the rat peripheral blood levels of EPC mode build after short rise, quickly dropped to below the normal baseline level. VEGF intervention experiment, the different time points of VEGF group hematoma new coated on new blood vessels from the control group have more discontinuous endothelial cell layer,and the hematoma volume significantly greater than the blank group. Atorvastatin intervention experiment showed that 7 days small dose atorvastatin group rats hematoma absorption significantly faster than the control group, high-dose group, andthe control group and high dose group of hematoma volume no statistical difference;Peripheral blood levels of EPC large and small dose group was obviously higher than that of control group, and high-dose group is higher than the small dosage group;Small dose group of capsular vascular factors related to performance for VEFG, TGF- beta, MMP- 9 low expression, and Ang-1 /Ang-2 ratio is significantly higher than the control group and high dose group. Compared with the saline treatment control group, experimental group in atorvastatin group didn’t change IL- 10 level of gene and protein expression, but significantly reduced the TNF alpha and IL- 6 levels of gene and protein expression and the expression of VEGF gene.Clinical trial part: clinical trials in patients with CSDH population levels in peripheral blood EPC was significantly lower than healthy controls, and recurrence after surgery in patients with EPC significantly below did not relapse. 23 cases of atorvastatin conservative treatment in patients with CSDH, except 1 case of patients with atorvastatin conservative treatment during a significant increase was deteriorated,hematoma, to row drilling hematoma drainage, the rest of the 22 cases with oral atorvastatin 1 ~ 12 months(3.976 + /- 3.976 months). A subdural hematoma volume before taking the medicine with an average of 47.38 + /- 18.50 ml; Hematoma volume significantly shrink after 1 month was 17.05 + /- 14.05 ml, neurologic signs and the MGS- GCS grading is improved markedly before taking the medicine; After3 months, 15 cases(71.4%) patients with hematoma absorbed completely, and 6patients(28.6%) of the hematoma absorption, on average, more than 71.38% plus or minus 11.86%.Conclusions—A subdural hematoma absorption rate not only associated with hematoma capsular number of new blood vessels, more closely related to mature and stable blood vessel formation in coated; Small doses of atorvastatin by inhibiting the hematoma cavity local inflammatory reaction, promoting angiogenesis, mature and stable hematoma absorption speed. Patients with CSDH peripheral blood EPC was significantly lower than healthy people and patients with recurrence after surgery of EPC significantly below did not relapse. Peripheral blood of EPC and the patients with chronic subdural hematoma is closely related to the occurrence and recurrence.Oral atorvastatin therapy can promote chronic subdural hematoma absorption, thismethod is simple, safe, economic, has a great prospect of clinical application, but it remains to be further confirmed by experiment and the basis of prospective randomized controlled trial. |
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