Summary report of the 3rd International Moyamoya Meeting held on July 12–13, 2013 in Sapporo, Japan

Summary report of the 3rd International Moyamoya Meeting held on July 12–13, 2013 in Sapporo, Japan


Honorary Chairman: Nobuo Hashimoto
Chairman: Kiyohiro Houkin, MD


Ken Kazumata, MD; Hideo Shichinohe, MD; Masaki Ito, MD

Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan


Corresponding Author: Kiyohiro Houkin, MD

Department of Neurosurgery, Hokkaido University Graduate School of Medicine,
North 15 West 7, Kita, Sapporo 060-8638, Japan
Tel: +81-11-706-5987; Fax: +81-11-708-7737; E-mail:


Disclosure of Funding:

This report and the 3rd International Moyamoya Meeting were supported by a grant from the Research Committee on Moyamoya Disease, sponsored by the Ministry of Health, Labour and Welfare of Japan.


Conflict of Interest:

The authors have no personal or institutional financial interest in the drugs or imaging modalities described herein.



On July 12–13, 2013, the 3rd International Moyamoya Meeting (IMM) was held in Sapporo, Japan. This report is a brief summary of the 3rd IMM and addresses the direction of future meetings.
IMM was originally proposed by Dr. Nadia Khan (University Children’s Hospital Zurich, Switzerland) and Dr. Gary Steinberg (Stanford University School of Medicine, Stanford, CA, USA) to share knowledge of moyamoya disease (MMD) with western medical communities with the primary aim to create closer ties between neurologists and basic medical researchers. In 2009, the first IMM was hosted by Dr. Steinberg in San Francisco, CA, USA and the second was hosted by Dr. Khan in Zurich, Switzerland. It was an honor for us to host the 3rd IMM in Sapporo, Japan on July 12–13, 2013.
As a nation that experiences the highest incidence of MMD, Japan must bear the responsibility of sharing knowledge of this disease with the global community. Recently, many neurologists, surgeons, and basic researchers from western countries have developed original approaches and arrived at novel findings regarding MMD. Asian medical professionals from South Korea, China, and India have also published many significant findings obtained from a formidable number of the patients that have enhanced our collective knowledge of MMD. Recent discoveries in both clinical and basic research of disease susceptibility have identified a single nucleotide polymorphism (RNF 213) that has promoted unforeseen developments in the diagnosis, treatment, and prognosis of MMD. The results of the Japan Adult Moyamoya (JAM) trial to investigate the efficacy of surgical revascularization was discussed at the 3rd IMM, which was attended by more than 100 experts from around the world.


3rd IMM



Subject matter of the oral presentations

I. Clinical research

The meeting began with a keynote lecture by Dr. Steinberg, titled “Insights into repeat revascularization, etiology of postoperative transient delayed neurologic deficits and the genetics of MMD.” Dr. Steinberg described a procedure using pedicled omentum after previously failed surgery15 and Dr. Steinberg also introduced a multidisciplinary approach for basic MMD research.
The second presenter was Dr. Khan who addressed the issue of diagnostic criteria and classification on the basis of her experience in Zurich on treating children with MMD using combined revascularization procedures. A modified classification system and its correlation with quantitative magnetic resonance angiography (qMRA) were demonstrated.
Next, Dr. Baltsavias (University Hospital Zurich, Zurich, Switzerland) illustrated microangiographic images to identify transchoroidal medullary anastomosis, which is a significant anatomical substrate to determine collateral circulation. Drs. Vajkoczy and Czabanka (Charité–Universitätsmedizin, Berlin, Germany) also have significant surgical experience in the treatment of MMD in Europe. Dr. Vajkoczy reported the importance of the blood–brain barrier (BBB) in MMD pathogenesis and discussed the diagnostic role of serum-derived endothelial cells from MMD patients that express angiopoietin-2 (Ang-2), which is a known antagonist of tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie-2). In addition, animal models that overexpress Ang-2/Tie-2 were used to analyze BBB function in MMD pathogenesis, indicating that a crucial role of the angiopoietin/Tie-2 signaling pathway. Dr. Wanebo (Moyamoya Center, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Scottsdale Healthcare System, Phoenix, AZ, USA) summarized his experience with 154 MMD patients, one of the largest case series in North America1. Dr. Amin-Hanjani (University of Illinois, College of Medicine, Chicago, IL, USA) reported the results of qMRA–non-invasive optimal vessel analysis, which identified decreased blood flow in a diminutive superficial temporal artery 6 months after surgery2. Postoperative improvement in blood oxygenation level-dependent responses in motor activation was also demonstrated. Dr. Young (Eulji University Hospital, Seoul, South Korea) demonstrated cognitive dysfunction in patients with MMD. Not only executive dysfunction but also visuospatial dysfunction was identified in some patients, suggesting that cognitive dysfunction may not be confined to the frontal domain, as previously thought. Dr. Ahn (University of Ulsan, Asan Medical Center, Seoul, South Korea) discussed a series of complications, thereby providing valuable information regarding the treatment of MMD in clinical practice. In the last session, Dr. Kim (Seoul National University College of Medicine, Seoul, South Korea) discussed differences in clinical features between adult and pediatric patients9. It is a matter of debate whether adult MMD is a result of late onset pediatric MMD or if the disease developed after adolescence. The impact of comorbid illness, such as thyroid dysfunction, was also discussed. Interestingly, achalasia (esophageal dysfunction) might be a clinical manifestation of MMD. Comorbid illness, as demonstrated by Prof. Kim, raised attention to the genetic research of Dr. Tournier-Lasserve, which demonstrated the value of such symposiums with different specialists.
Japanese investigators also contributed significant findings. For example, Dr. Kuroda presented the results of a multicenter study of asymptomatic MMD patients (AMORE study)12 and Dr. Miyamoto presented the results of the JAM trial for the first time in an academic meeting. The results of this random controlled study clearly indicated the importance of preventive measures to avoid hemorrhagic stroke after direct bypass surgery. These results will be incorporated into standard practice for adult MMD. Dr. Morioka demonstrated morphological changes in the middle cerebral artery that were detected using magnetic resonance imaging5. Furthermore, surgical techniques were demonstrated by Drs. Kikuta8, Kawashima7, and Inaji. Dr. Fujimura presented diagnostic methods and novel management of hyperperfusion using minocycline3. Lastly, Dr. Tominaga imparted knowledge regarding the Suzuki classification system of MMD.


II. Basic research

During the meeting, three researchers gave presentations regarding the role of the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (also known as KDR) pathway in MMD pathogenesis. Dr. Hishikawa reported results of novel gene therapy to enhance angiogenesis in an animal model of MMD. In this study, a model of occlusion of the rat bilateral common carotid artery with encephalo-myo-synangiosis (EMS) was employed. This group attempted gene transfer of VEGF and apelin, which participate in angiogenesis after ischemia, to the temporal muscle of the rat model. Their results showed that both VEGF and apelin gene transfer could enhance angiogenesis on the brain surface after EMS. Dr. Kim (Yonsei University, Seoul, South Korea) presented a paper titled “The role of VEGF and KDR polymorphisms in MMD and collateral revascularization.” Dr. Kim conducted a case-control study to investigate whether VEGF-2578, -1154, -634, and 936, and KDR-604, 1192, and 1719 polymorphisms were associated with MMD16. The results of this study suggested that the VEGF -634G allele was associated with pediatric MMD and poor collateral vessel formation. Dr. Shichinohe reported the relationship between endothelial progenitor cells (EPC) and the MMD pathogenesis and found that patients with MMD had significantly lower levels of circulating EPC than age-matched healthy controls, suggesting aggressive consumption of EPC at the stenotic carotid lesion and dilated moyamoya vessels.
Several researchers presented original works regarding genetic abnormalities in the pathogenesis of MMD, especially ring finger protein 213 (RNF213), a genetic variant that increases susceptibility to MMD. Dr. Miyawaki reported the results of a case–control study of the RNF213 c.14576G>A variant in a large population, which clarified that the genetic variant was found in 1.8% patients in the normal control group and was significantly associated with not only definite MMD [odds ratio (OR), 144.0], but also non-moyamoya intracranial occlusive lesion (OR, 16.8). This group concluded that the genetic variant was also a high-risk allele for occlusive disease in intracranial arteries13,14. Dr. Takamatsu reported an alternative method to analyze the RNF213 c.14576G>A variant. In this report, the pyrosequencing method was adopted to analyze genetic variants, which was rapid and simple as compared with direct sequencing methods that are generally used. It was concluded that the pyrosequencing method was sufficiently reliable to screen for RNF213 variants. Dr. Sonobe reported the pathogenic role of RNF213 in MMD. In this study, bilateral carotid artery ligation, which is also known as chronic cerebral hypoperfusion, was used to treat RNF213-deficient mice. Histological analysis revealed vascular fragility characterized by medial thinness in RNF213-deficient mice following cerebral hypoperfusion. This study concluded that the RNF213 variant might be involved in the pathogenesis of MMD. Dr. Tournier-Lasserve (INSERM U740; Paris Diderot University, Paris, France) reported three unrelated families affected with X-linked moyamoya syndrome characterized by the association of moyamoya angiopathy, short stature, and a stereotypical facial dysmorphism. Syndromic moyamoya was determined to be caused by a Xq28 deletion that removed the coding region of the deubiquitinating enzyme breast cancer antigen type 1 (BRCA1)/BRCA2-containing complex, subunit 3 (BRCC3), suggesting that BRCC3 is associated with angiogenesis as well as a loss-of-function in mutants. Dr. Kure presented a lecture titled “Identification of susceptibility gene for MMD” and summarized his research regarding the role of RNF213 in MMD6. Dr. Koizumi demonstrated cutting edge genetic research using induced pluripotent stem cells established from patients with MMD4,10,11. The endothelial cells produced by patients carrying the RNF213 variant R4810K indicated low angiogenic activity. The results of this study indicated that the RNF213 variant R4810K could down-regulate securing expression, which is potentially associated with MMD.
Dr. Smith (Boston Children’s Hospital, Boston, MA, USA) presented translational research to identify novel biomarkers to diagnose childhood MMD. The upper level of excreted netrin-1 in urine is considered a prospective indicator of MMD; however, their clinical trial is not yet concluded. He also discussed his substantial experience with secondary MMD.



Recent advancements in genetic research have finally revealed a clue to the pathogenesis of MMD. The correlation between clinical phenotypes and genotypes will become the main theme of future clinical studies. Regarding diagnostic criteria, we are in the realm of a transition toward more subjective methods using genomics rather than just morphological changes depicted by angiograms. We certainly need a more sophisticated method of patient stratification on the basis of disease severity. International agreements in diagnostic criteria and severity rating are indispensable to research consistency. Certainly, IMM will play an active role in organizing international corroboration in this regard.
What extent does MMD encompass as a single disease entity? Comorbid illness may shed some light on the mechanism for the development of MMD. Patients in western countries often demonstrate moyamoya phenomenon. Japanese investigators have defined “true” MMD on the basis of the bilateral involvement as demonstrated by angiography. However, the differences between MMD and moyamoya phenomenon remain unclear, except for equivocal differences in angiographic appearances. Comorbid illness may share common traits as well as pathological status, which may aggravate MDD. Therefore, secondary MMD will require further attention. Genetic research contributes to the early diagnosis as well as to identify patients at greater risk of disease onset. The term MMD indicates the end phenotype of the disease entity. The relationship between intermediate clinical phenotype (quasi-moyamoya) and genotype will be investigated further in future studies. The stratification of patients based on neuroimaging will lead to a rational treatment paradigm. Therefore, classification of the clinical stage and the symptom-imaging relationship will continue to be a principle subjects in future meetings. Direct anastomosis was employed by the majority of the participants. In the next few years, vascular reconstruction of the posterior cerebral artery as well as previous surgical sites will be our next challenges. A mechanism of hyperperfusion has not yet been fully clarified. An improved treatment paradigm for hyperperfusion will be disclosed in the next few years. Furthermore, cognitive dysfunction remains understudied and brain damage without apparent cerebral infarction may change our principal strategy, which currently heavily relies on the recurrence of stroke.
In addition to the scientific knowledge, we acquired much important information from other MMD experts, most importantly enthusiasm.” To successfully complete direct bypass procedures, elaborate training, knowledge, and tough minds are required. The basic understanding of cerebral blood flow and metabolism is indispensable to better patient management. We encourage young neurosurgeons to tackle this disease and IMM will continue to be a portal organization of international experts. The 4th IMM is scheduled to be hosted by Dr. Vajkoczy at Charité–Universitätsmedizin (Berlin, Germany). We would like to thank each participant, presenter, and all personnel for their work to make the 3rd IMM a success.



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  2. Amin-Hanjani S, Singh A, Rifai H, Thulborn KR, Alaraj A, Aletich V, et al: Combined direct and indirect bypass for moyamoya: quantitative assessment of direct bypass flow over time. Neurosurgery 73:962-968, 2013
  3. Fujimura M, Niizuma K, Inoue T, Sato K, Endo H, Shimizu H, et al: Minocycline prevents focal neurologic deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease. Neurosurgery, 2013
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