Moyamoya Disease: Largely Unknown Pathogenesis, Diagnosis and Treatment Lian Duan Department of Neurosurgery, 307 Hospital, PLA The Center for Cerebrovascular Disease, PLA

Moyamoya Normal

Macroscopical and microscopical findings at autopsy. A ： malformation of the vascular network around the proximal MCA ； B: fine vascular network ； C: SAH in the right parieto-temporal area ； D: SAH in right parietal lobe. Lin R, Clinical and immunopathological features of moyamoya disease. PLoS One 2012

Photomicrographs of brain vessels in MMD patients. Lin R, Clinical and immunopathological features of moyamoya disease. PLoS One 2012

Immunohistochemical study of intracranial arteries. A,D:immunoreactivity indicating that a-SMA is detected in the thickened intima of MCA. B,D:S100A4 protein is detected in the thickened intima and media smooth muscle cells Lin R, Clinical and immunopathological features of moyamoya disease. PLoS One 2012

VEGF, bFGF ， MMP1-3 ， MMP9 ， MMP12 ， PDGF- BB ， TGF-β1 ， TNF-α IL-1β, IL-6, IL-8...

Up-regulated spots that were significantly and consistently changed in human sera of moyamoya patients compared to normal controls. Koh EJ: Comparative analysis of serum proteomes of MMD. J Korean Neurosurg Soc 2010

Down-regulated spots that were significantly and consistently changed in human sera of moyamoya patients compared to normal controls. Koh EJ: Comparative analysis of serum proteomes of MMD. J Korean Neurosurg Soc 2010

Mechanism of neovascularzation

Increased levels of circulating CD34+ cells in patients with angiographic evidence of moyamoya-like vessels. Yoshihara T: Increase in circulating CD34+ cells in patients with angiographic evidence of moyamoya-like vessels. J Cereb Blood Flow Metab 2008.

Increased Levels of Circulating Endothelial Progenitor Cells in Patients With Moyamoya Disease Rafat N: Increased levels of circulating endothelial progenitor cells in patients with MMD. Stroke 2009.

The EPC-CFU numbers from MMD patients. Formation of EPC-CFUs at 7 days after plating the MNCs of MMD patients at different disease stages. Advanced stage MMD patients had lower CFU numbers than early stage MMD patients or controls (D). Jung KH: Circulating EPC as a pathogenetic marker of MMD. J Cereb Blood Flow Metab 2008.

Kim JH: Decreased level and defective function of EPC in children with MMD. J Neurosci Res 2010.

Genetic Analyses: Current Concepts and Future Directions Prevalence (per ) Incidence Japan Hokkaido Nanjing US

Kraemer: Analysis of HLA genes in caucasian patients with idiopathic MMA. Acta Neurochir(wien) 2012.

Unified multipoint linkage analysis between familial MMD and markers on chromosome 17q Yamauchi T: Linkage of familial MMD to chromosome 17q25. Stroke 2000.

The vascular injury repair model. Kang HS: Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial MMD. Neurosurgery 2006.

Kamada: A genome-wide association study identifies rnf213 as the first MMD gene. J Hum Genet 2011.

Association analysis of 63 non-familial MMD cases and 45 control subjects and the structure of the RNF213 protein. Kamada F: A genome-wide association study identifies rnf213 as the first MMD gene. J Hum Genet 2011.

 Further investigations are needed to identify the underlying cause of moyamoya disease.  Data from proteomics, progenitor cell research and genetic investigations in moyamoya disease will not only be important for the development of novel therapies specific to moyamoya disease but will also have the potential to enhance treatment options for a wide variety of disorders of the CNS, including stroke, hemorrhage, vascular malformations, and CNS tumors.

Diagnosis

Increased Thyroid Function and Elevated Thyroid Autoantibodies in Pediatric Patients With MMD Patients (N=114) Controls (N=114) Elevated thyroid autoantibodies TPOAb-positive TGAb-positive

F, 5y, weakness of right extremities for 2 year. LICA RICA

M, 46y, numbness and weakness in his right extremities for 1 year

MMD Coexistence of MMD and aneurysm

The correlation between moyamoya disease and arteriosclerosis M, 45y, paralysis of right limb and speech disorders for 9 month, hypertension disease history for 7 years.

DSA also show stenosis of bilateral vertebral arteries

The portion of vasculopathy Angiograph of LVA Angiograph of LICA

Challenge to diagnosis criteria Moyamoya disease or moyamoya syndrom? PCA involvement

Treatment

F,39y,first ventricular hemorrhage in 27th May,2007 LICA RICA LVA

Angiogram after bilateral EDAS in 19th Aug,2009 Left Right

Second hemorrhage in 24th May,2012 after bilateral EDAS

Third hemorrhage the second day after EDAS using left occipital artery in 25th June,2012

In some cases, successful surgery can not prevent disease progress (infarct and hemorrhage), making us go back to the study of pathogenesis of MMD.