Moyamoya disease (MMD), characterized by progressive stenosis or occlusion of the bilateral intracranial internal carotid arteries, is associated with abnormal vascular networks at the base of the brain, termed the "moyamoya" vessels.13)15) "Probable MMD" is characterized by unilateral hemispheric involvement and exclusion of the following basic diseases (arteriosclerosis, autoimmune disease, meningitis, brain neoplasm, down syndrome, Recklinghausen's disease, head trauma, irradiation to the head.1) MMD generally peaks at two different ages, the second and fifth decades.8) A number of studies have reported that surgical revascularization for symptomatic MMD is effective in pediatric patients.2)12)14) Owing to disease progression, early surgical interventions in pediatric patients can reduce morbidity resulting from stroke even in the absence of symptoms.7)10) However, evidence regarding the incidence and natural course of asymptomatic MMD in adults is limited.

The prevalence of asymptomatic adult MMD has recently increased due to development of noninvasive diagnostic techniques and the increase in regular medical checkups.11) Given the lack of guidance regarding treatment in these patients, the aim of this study was to document the natural course of asymptomatic adult MMD to aid in treatment decisions.

We reviewed data from May 2003 to December 2012 in the clinical database of our institute for identification of patients who were diagnosed with MMD or probable MMD according to published guidelines.1) We included probable MMD in this study because we think that MMD and probable MMD are inseparable diseases. Of the 587 MMD patients identified, 459 patients were adults (aged ≥ 20 years) at the time of diagnosis. Patients were considered to have asymptomatic MMD when it was detected without the presence of an ischemic event, a hemorrhagic event, or a focal neurological deficit. As a result, 42 patients were included in this retrospective cohort study. Clinical records were reviewed retrospectively, and follow-up data from September 2013 were evaluated.

All of the patients had complained of a simple headache and underwent subsequent brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Diagnosis of MMD was based on MRI and MRA findings, and 21 patients underwent conventional angiography to confirm the diagnosis. Cerebral perfusion was measured in 41 patients using 99mTc-hexamethylpropylene amine oxime single photon emission computed tomography (SPECT), xenon computed tomography (CT), or positron emission tomography (PET), and cerebral reserve capacity was assessed after an intravenous injection of acetazolamide. Cerebral perfusion and reserve capacity images were interpreted as normal or decreased status, respectively, by the same competent professor of nuclear medicine.

Analysis of the relationships between disease progression and associated factors was performed using χ² tests. The progression free survival rate was estimated by Kaplan-Meier analysis. The significance of the differences was assessed using the log-rank test. IBM SPSS V. 21 (IBM Corp., Armonk, NY, United States) was used in performance of statistical analyses.

Of the 42 patients included in this study, MMD progression was evident in 12 patients (13 of 75 hemispheres), representing almost a third of the sample. Symptomatic progression, associated with cerebrovascular events, occurred in four of these patients. Three of the four patients suffered an intracerebral hemorrhage, while the fourth experienced a transient ischemic stroke.

In general, child MMD is considered to be progressive while adult MMD is relatively stable.15) However, the current results and those of a previous study that reported disease progression in 15 of 120 adult patients (12.5%) suggest otherwise.9) Further, higher rate of hemorrhagic stroke in adult MMD than that in children has been well documented.3)13) There are differences in disease presentation and features between adults and children with moyamoya.13) In addition, in children, disease diagnosis can be delayed and symptoms classified inaccurately owing to an inability to communicate.5)

Suzuki and Takaku proposed an angiographic staging system for MMD.15) However, the stages are not correlated with disease severity. Instead, CVRC has been known to be more effective for monitoring the progression of the disease; the patients are often in a chronic state of cerebral vasodilation, and maintenance of cerebral blood flow is necessary.4) Therefore, we evaluated the CVRC of the patients. Despite a lack of differences in the majority of factors between patients with and without disease progression, a relationship was observed with CVRC; decreased CVRC was evident with more progressed disease (Table 2). This was supported by the results of the Kaplan-Meier cumulative event-free survival analysis, in which a significant difference was observed between patients with progressive disease and a reduced initial CVRC and those with progressive disease and a normal initial CVRC (Fig. 1). This difference was also evident in patients with symptomatic progression (Fig. 2). Based on these results, CVRC may be an important indicator for patients with asymptomatic MMD, and closer observation or early revascularization surgery may be necessary in patients with reduced CVRC.

In our institute, symptomatic progression is an important indication for revascularization surgery in MMD patients. However, in this study, none of the patients underwent surgery during the follow-up period. Only one patient for whom an operation was recommended did not make a decision regarding surgery. Therefore, we could not assess disease progression following revascularization surgery. However, another study conducted with patients with asymptomatic MMD reported that disease progression did not occur after revascularization surgery.9) This is an interesting finding for this treatment modality; early revascularization surgery may be considered for asymptomatic MMD patients who had initial decreased CVRC.

This study is one of only a few studies conducted with adult patients with asymptomatic MMD. A multicenter survey conducted in 2007 included 40 patients with asymptomatic MMD; however, patients were all older adults.9) In a study investigating 40 patients (74 hemispheres) for a median follow-up period of 32 months, Jo et al. also reported that asymptomatic MMD in adults is not a stable disease. However, in this report, stroke rate was 0%, but in our study, three patients (3/42, 7.1%) had stroke during the follow-up period.6)

This study has certain limitations. A retrospective review of medical records was used for collection of patient data. In addition, the sample size was small; however, MMD itself, particularly in the asymptomatic state, is very rare. Therefore, we plan to conduct future multi-center studies to guide treatment in adult, asymptomatic adult MMD patients.

The aim of this study was to document the disease course and factors related to disease progression in adults with asymptomatic MMD. Based on our results and those of previous studies, we conclude that asymptomatic adult MMD can no longer be considered a permanent stable disease. Therefore, close observation with regular brain imaging study is required for asymptomatic adult MMD patients, particularly patients with reduced CVRC.