the natural clinical course of hemodynamically stable

clinical articleJ neurosurg 122:82–89, 2015

J neurosurg Volume 122 • January 2015

MoyaMoya disease (MMD) is an idiopathic steno-occlusive disease of the bilateral internal carotid arteries, with characteristic abnormal vascular

networks.36 Its presentation exhibits a bimodal distribu-tion with age: children mostly exhibit an ischemic pre-sentation, and adults usually present with hemorrhage or ischemia.6,7,9,16,19,36 Although the pathogenesis and natu-ral course are not yet known, revascularization surgery has been satisfactory for patients with ischemic symp-toms.2,3,5,7,8,18,22,24,34 For pediatric MMD, revascularization surgery is universally recommended, regardless of the se-verity of MMD, because most symptoms are ischemic, and

children’s brains are still developing.18,19,27,34,37 In adult-on-set MMD, revascularization surgery is selectively recom-mended for patients with ischemic symptoms and hemo-dynamic compromise.7,31 However, the efficacy of surgery for the hemorrhagic subtype of MMD remains inconclu-sive,1,5,11,13,21,28,40 and the clinical course in asymptomatic patients who do not undergo surgery is not known.18,19,22,23 Thus, there are still limitations to predicting the prognosis and determining the treatment strategy. We conducted this retrospective study to gain an insight into the management of MMD by investigating the clinical features and natural courses of hemodynamically stable adult MMD.

The natural clinical course of hemodynamically stable adult moyamoya diseaseWon-Sang cho, MD,1 Young Seob chung, MD, PhD,1 Jeong eun Kim, MD, PhD,1 Jin Pyeong Jeon, MD,1 Young Je Son, MD,1 Jae Seung Bang, MD,1 Hyun-Seung Kang, MD, PhD,1 chul-Ho Sohn, MD, PhD,2 and chang Wan Oh, MD, PhD1

Departments of 1Neurosurgery and 2Radiology, Seoul National University College of Medicine, Seoul, Korea

OBJect Moyamoya disease (MMD) is a rare cerebrovascular disease and its natural history is still unclear. The au-thors aimed to investigate the natural course of hemodynamically stable cases of adult MMD, with the analysis of stroke risk factors.MetHODS Two hundred forty-one patients were included in this retrospective study. One hundred sixty-six (68.9%) were female, and mean age (± SD) at first visit was 41.3 ± 12.0 years (range 18–69 years). Unilateral involvement was identified in 33 patients, and 19 patients (7.9%) had a family history of MMD. According to the clinical presentations, patients were classified into hemorrhagic (n = 62, 25.7%), ischemic (n = 144, 59.8%), and asymptomatic (n = 35, 14.5%) groups. The mean duration of follow-up was 82.5 ± 62.9 months (range 7.3–347.0 months).reSultS The annual stroke risk was 4.5%, and the annual risks of rebleeding in the hemorrhagic group and recurrent ischemic events in the ischemic group were 4.3% and 3.0%, respectively. There was no significant difference in cumula-tive stroke risk between the 3 groups (p = 0.461). Risk factors included thyroid disease for overall strokes (HR 2.56, 95% CI 1.16–5.67), initial hemorrhagic presentation for hemorrhagic strokes (HR 2.53, 95% CI 1.24–5.17), and initial ischemic presentation for ischemic strokes (HR 2.69, 95% CI 1.15–6.27). Familial MMD was a common risk factor for all types of stroke. Among the 3 clinical groups, the hemorrhagic group showed the worst clinical status at discharge and at most recent follow-up. Twenty-three patients (9.5%) eventually underwent revascularization surgery.cOncluSiOnS There was no statistically significant difference in the incidence of stroke in the different clinical groups; clinical status, however, was most severe in patients with hemorrhagic presentation. In patients who experienced stroke during the follow-up period, the stroke type tended to correspond to their initial presentation. Close follow-up is needed in patients with thyroid disease and a family history of MMD.http://thejns.org/doi/abs/10.3171/2014.9.JNS132281KEY WORDS asymptomatic; hemorrhage; ischemia; moyamoya disease; clinical course; vascular disorders

aBBreViatiOnS KPS = Karnofsky Performance Scale; MMD = moyamoya disease; mRS = modified Rankin Scale; SAH = subarachnoid hemorrhage; SPECT = single photon emission computed tomography; TIA = transient ischemic attack. SuBMitteD October 15, 2013. accePteD September 23, 2014.incluDe WHen citing Published online October 31, 2014; DOI: 10.3171/2014.9.JNS132281.DiSclOSure This study was supported partly by Seoul National University Hospital Fund (0320120310, 2012-0581) and partly by a grant of the Korea Healthcare Tech-nology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI10C2020).

82 ©AANS, 2015

Unauthenticated | Downloaded 12/24/21 09:33 AM UTC

natural course of adult MMD


MethodsPatient Selection

Under the approval of the Seoul National University Hospital Institutional Review Board, we retrospectively reviewed the medical records of 241 patients who had been diagnosed with adult MMD from July 1983 to April 2011 and who had not undergone revascularization sur-gery at the time of diagnosis. Inclusion criteria were as follows: 1) adult patients (age ≥ 18 years); 2) initial symp-toms related to hemorrhage or ischemia or asymptomatic presentation; 3) compatibility with the diagnostic guide-lines;16 4) hemodynamically stable status on single pho-ton emission computed tomography (SPECT); 5) medical records pertaining to evaluation of certain concomitant medical conditions at the first visit and during the fol-low-up period, such as hypertension, smoking, diabetes mellitus, hyperlipidemia, or cardiovascular or peripheral vascular, endocrinological, or immunological diseases; and 6) follow-up duration of 6 months or more. All pa-tients were initially evaluated with cerebral angiography, CT, and MRI, and SPECT. Patients were considered to demonstrate hemodynamically stable status on SPECT if their basal perfusion status was normal or mildly de-creased and their vascular reserve capacity after acetazol-amide challenge did not decrease by more than 50% of the basal perfusion. Patients with rare symptoms such as involuntary movement and seizure that were not second-ary to ischemia or bleeding were excluded.

The patients’ demographic and clinical characteristics are summarized in Table 1. The male to female ratio was 1:2.2, and the mean age (± SD) at the first visit was 41.3 ± 12.0 years (range 18–69 years). Of the 33 patients with unilateral involvement, 20 had left-side involvement and 13 right-side involvement. Of the patients with familial MMD, 17 (89.5%) were symptomatic and 2 were asympto-matic, with all 19 being from different families. The mean Suzuki grades for the right and left hemispheres were 3.9 ± 0.5 (n = 221, range 2–5) and 3.9 ± 0.6 (n = 228, range 2–5), respectively. Hypertension was a dominant medical problem (30.3%), and thyroid diseases were present in 1 patient with hypothyroidism from Hashimoto disease and in 11 with hyperthyroidism from Graves’ disease.

evaluation of clinical courseInitial clinical manifestations were divided into 3

groups as follows: hemorrhagic group (intracranial hem-orrhage—intracerebral, intraventricular, or subarachnoid), ischemic group (ischemic symptoms of transient ischemic attack [TIA] and cerebral infarction), and asymptomatic group (asymptomatic presentation, including true asymp-tomatic as well as nonspecific symptoms such as headache and dizziness). There were 62 patients in the hemorrhagic group (25.7%), 144 in the ischemic group (59.8%), and 35 in the asymptomatic group (14.5%). Of the 62 patients in the hemorrhagic group, 9 (14.5%) had subarachnoid hem-orrhage (SAH) with or without intracerebral or intraven-tricular hemorrhage, and 53 (85.5%) had intracerebral amd/or intraventricular hemorrhage without SAH. Of the 144 patients in the ischemic group, 70 had TIAs (48.6%) and 74 had infarctions (51.4%).

We analyzed the natural clinical course of MMD with respect to 3 different aspects during the follow-up: 1) an-nual risk of stroke, 2) risk factors for stroke event, and 3) clinical outcome. Clinical outcomes were evaluated with the modified Rankin Scale (mRS)38 and Karnofsky Per-formance Scale (KPS)14 at the initial visit (status at dis-charge) and last follow-up evaluation. The overall mean duration of follow-up was 82.5 ± 62.9 months (range 7.3–347.0 months). Stratified by clinical group, the mean values for duration of follow-up were 95.4 ± 90.3 months (range 7.3–347.0 months) in the hemorrhagic group, 77.3 ± 65.1 months (range 7.3–331.9 months) in the ischemic group, and 81.5 ± 50.6 months (range 18.4–188.4 months) in the asymptomatic group.

Statistical analysisContinuous variables were expressed as mean ± SD.

Categorical variables were compared by using Pearson’s chi-square test. The annual risk of stroke was calculated with a person-year method, and the cumulative stroke risk was evaluated using the Kaplan-Meier method. Compari-sons of risks in the different groups were performed using log-rank tests. A stroke event was defined as a symptomat-ic hemorrhage or ischemia that occurred in the pathologi-cal hemisphere, regardless of laterality, during the follow-up period. The timing of the stroke event was determined from the initial presentation to the first symptomatic stroke. The endpoints were the occurrence of stroke (uncensored), the last follow-up evaluation (censored), and surgical in-tervention (censored). Cox proportional hazard analysis was performed to evaluate risk factors for stroke during

taBle 1. clinical features of 241 patients with adult MMD*

Characteristic Value

Sex Male 75 Female 166Age (yrs) Mean 41.3 ± 12.0 Range 18–69Laterality Bilateral involvement 208 Unilateral involvement 33Familial type (%) 19 (7.9)Initial clinical manifestations (%) Hemorrhagic group 62 (25.7) Ischemic group 144 (59.8) Asymptomatic group 35 (14.5)Concomitant medical diseases (%) Hypertension 73 (30.3) Hyperlipidemia 30 (12.4) Thyroid disease 12 (5.0)Follow-up duration (mos) Mean 82.5 ± 62.9 Range 7.3–347.0

* Unless specified otherwise, values indicate the number of patients.

83


W. S. cho et al.


follow-up, and variables with significance values of p < 0.2 were selected for multivariate analysis. Included risk fac-tors were sex, age, initial clinical manifestations (hemor-rhagic, ischemic, and asymptomatic, including non specific symptoms), bilaterality (bilateral or unilateral involvement of distal internal carotid arteries), familiality (more than 1 first-degree relative with MMD), and concomitant medi-cal diseases such as hypertension, hyperlipidemia, and thyroid disease that were already known or newly detected at the first visit or during the follow-up period, all of which were medically managed after identification. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 19.0 software (IBM SPSS Inc.).

resultsincidence of Stroke

The annual risk of stroke is presented for patients in all 3 groups in Table 2. During the entire follow-up period, the rate of any stroke in all patients was 4.5%/person-year. Stroke events occurred more frequently in the hemorrhagic group than in either the ischemic or the asymptomatic group (5.7% vs 4.2% and 3.4%, respective-ly). Hemorrhagic events tended to occur at a higher rate in the hemorrhagic group than in the ischemic group (4.3% vs 1.2%), and ischemic events occurred at a higher rate in the ischemic group than in the hemorrhagic group (3.0% vs 1.4%). In the asymptomatic group, the risk of hemor-rhagic stroke was higher than the risk of ischemic stroke (2.5% vs 0.8%).

Overall, the 5- and 10-year cumulative risks of any stroke were 17% and 31%, respectively. The 5- and 10-year risks of hemorrhagic stroke were 10% and 19%, respectively, and risks of ischemic stroke were 9% and 20%, respectively, with no significant difference (p = 0.857, Fig. 1 left). By group, the 5- and 10-year risks of any stroke were 15% and 40% in the hemorrhagic group, 17% and 33% in the ischemic group, and 15% and 25% in the asymptomatic group, respectively (Fig. 1 right). There were no significant between-group differences in stroke risk (p = 0.461 in total, p = 0.288 between the hemorrhag-ic and ischemic groups, p = 0.697 between the ischemic and asymptomatic groups, p = 0.265 between the hemor-rhagic and asymptomatic groups).

The 5- and 10-year cumulative risks of recurrent hem-orrhagic and ischemic events are demonstrated in Fig. 2. In a comparison of recurrent ischemic risk between pa-tients with infarction and those with TIA alone within the ischemic group, there was no significant difference (p = 0.290). In addition, the numbers of infarction or TIA events were similar in patients with infarction and those with TIA alone within the ischemic group (infarction, p = 0.618; TIA, p = 0.631).

risk Factors for StrokeUnivariate analyses for risk factors identified 2 sig-

nificant factors for any stroke (familial MMD and thyroid disease), 4 risk factors for hemorrhagic stroke (male sex, hemorrhagic presentation, hyperlipidemia, and familial MMD), and 4 risk factors for ischemic stroke (ischemic

presentation, hypertension, familial MMD, and thyroid disease). In multivariate analyses (Table 3), familial MMD was a common significant factor in any, hemor-rhagic, and ischemic strokes. Thyroid disease was a risk factor for any stroke, and initial symptoms of either hem-orrhage or ischemia were risk factors for the same types of stroke during follow-up.

clinical OutcomesClinical states at the initial and final periods are pre-

sented in Fig. 3. The initial clinical scores for all patients were 79.8 ± 14.1 (range 30–100) on KPS and 1.9 ± 1.2 (range 0–5) on mRS. The final clinical scores were 85.8 ± 17.7 (range 0–100) and 1.3 ± 1.4 (range 0–6), respectively, on the same measures. At each period, the hemorrhagic group showed the worst clinical status in terms of both KPS and mRS scores.

A total of 23 patients (9.5%) underwent revasculariza-tion surgery because of the aggravation or occurrence of ischemic symptoms and hemodynamic instability. Among them, 17 (73.9%) were in the ischemic group and 4 (17.4%) were in the hemorrhagic group. The mean dura-tion of follow-up duration for these patients was 48.8 ± 32.6 months (range 10.9–157.2 months).

Four patients died in the hemorrhagic group (6.5%); in all 4 cases, the cause of death was recurrent hemorrhage.

DiscussionFrom this retrospective cohort study with a relatively

large number of patients, we obtained valuable information about the natural course of adult MMD. The annual risk of stroke was 4.5%/person-year, and the 5- and 10-year cumu-lative risks of any stroke were 17% and 31%, respectively. The cumulative risks of hemorrhage and ischemia were similar during the mean follow-up period of 82.5 months. Regardless of the initial clinical presentation (hemorrhag-ic, ischemic, or asymptomatic), there was no significant difference in the cumulative risk for any stroke. However, the clinical status at any period in the study was worst in patients with hemorrhagic presentation. Patients with hem-orrhagic presentation tended to show a higher incidence of recurrent hemorrhage, although patients with ischemic symptoms demonstrated a higher rate of recurrent ische-mia than the other groups. In our multivariate analyses, familial MMD and thyroid disease were risk factors for any stroke event during follow-up, and familial MMD and hemorrhagic presentation were identified as risk factors for a hemorrhagic stroke. Familial MMD and ischemic pre-sentation were significant risk factors for ischemic events.

taBle 2. annual risk of stroke*

GroupHemorrhagic

StrokeIschemic Stroke

Overall Stroke

All patients 2.3 2.2 4.5 Hemorrhagic group 4.3 1.4 5.7 Ischemic group 1.2 3.0 4.2 Asymptomatic group 2.5 0.8 3.4

* Values indicate %/person-year.

84




Fig. 1. Kaplan-Meier curves for stroke events during follow-up. left: There was no significant difference between hemorrhagic and ischemic strokes in all patients (p = 0.857). right: There was no significant difference in overall stroke events among the groups with different clinical presentations (p = 0.461). Figure is available in color online only.

Fig. 2. Kaplan-Meier curves for stroke event in each group. left: The 5- and 10-year cumulative risks of rebleeding in the hem-orrhagic group were 23% and 34%, respectively. right: The 5- and 10-year risks of recurrent ischemia in ischemic group were 13% and 28%, respectively. Figure is available in color online only.

85


W. S. cho et al.


Ischemia, including TIA and infarction, is the most frequent symptom in both pediatric and adult MMD.2,6,

7,9,10,16,18,32,36 Nonetheless, there have been few studies on the natural course of ischemia in MMD. Hallemeier et al.8 reported a cumulative 5-year risk of stroke of 82% in adult patients with ischemic presentation who were conservatively managed. In an earlier study of pediatric MMD, 50%–90% of patients were found to experience neurological deficits due to recurrent ischemia.3 In anoth-er study of pediatric MMD, 79% of the patients suffered from recurrent ischemia with intellectual impairment, and the mortality rate was 3.7% (1 of 27 patients died).24 In the present study of adult MMD, the annual risk of is-chemia was 2.2% in all patients and 3.0% in patients with ischemic presentation. In addition, the 5- and 10-year cumulative risks of ischemic events were 9% and 20%, respectively, in all patients, and 13% and 28% in patients with ischemic presentation.

Hemorrhage is the major cause of poor clinical out-

come and death in patients with MMD.21,24,30,40 Accord-ing to one report,21 mortality rates were 7% after initial bleeding and 29% after rebleeding. In this study, the in-cidences of stroke during follow-up were similar among the clinical groups of hemorrhagic, ischemic, and asymp-tomatic patients. However, the initial and final clinical outcomes were worst in patients with a hemorrhagic pre-sentation, and all of the deaths resulted from a recurrent hemorrhage. The incidence of hemorrhagic presentation is known to be higher in adult MMD than in pediatric MMD,9,16,20,23,36 and higher in Asian patients than in West-ern ones.2,6,9,10,13,20,32 As reported, the incidence rates are 46%–62.4% in Korea,9,10 52%–56% in China and Tai-wan,20 21% in Japan,13,20 13%–29% in United States,2,6,20,32 and the rate in our study was 25.7%. In our institute, surgi-cally treated patients have been more numerous than con-servatively treated patients (by a factor of approximately 2–3, unpublished data), and many of these patients have ultimately undergone surgery because of their ischemic symptoms. Thus, the actual incidence of hemorrhagic presentation seems to be less than 25.7%.

Rebleeding has been reported with an incidence rang-ing from 17% to 61% in patients with initial bleeding4,13,21,30 and an annual rebleeding rate ranging from 1.7% to 7.1% in adult MMD patients (Table 4).6,21 In this study, the an-nual bleeding rate was 2.3% in all patients and 4.3% in those with hemorrhagic presentation. In addition, 14.1% of all patients and 30.6% of patients with hemorrhagic pre-sentation experienced one or more hemorrhagic events during follow-up. Because hemorrhage is not an indication for revascularization surgery in our institute, most patients with hemorrhagic presentation were included in this study; consequently, the results pertaining to the natural course of hemorrhagic MMD are thought to be valid as presented.

There are few studies reporting on risk factors for recur-rent ischemia and hemorrhage and their clinical outcomes. Hypertension and young age at onset are significant fac-

Fig. 3. Clinical states in 3 different clinical groups at the initial and last follow-up periods as determined by KPS (left) and mRS (right). Figure is available in color online only.

TABLE 3. Significant risk factors for stroke during follow-up on multivariate analysis with cox proportional hazard method

Event & Risk Factor HR 95% CI p Value

Any stroke event Familial MMD 2.624 1.276–5.393 0.009 Thyroid disease 2.562 1.158–5.669 0.02Hemorrhagic event Initial symptoms (hemorrhage vs others)

2.527 1.236–5.166 0.011

Familial MMD 3.094 1.238–7.730 0.016Ischemic event Initial symptoms (ischemia vs others)

2.686 1.150–6.272 0.022

Familial MMD 3.108 1.260–7.665 0.014

86




tors affecting prognosis in untreated MMD,22,33 and age > 36 years at onset and microbleeds on MRI are significant risk factors for hemorrhage.15,30,35 Female sex and stroke presentation within 3 years are significant risk factors for stroke or hemorrhage.6 This study showed that familial MMD was a common risk factor for stroke, thyroid dis-ease was a risk factor for any stroke, ischemic presenta-tion was a significant factor for recurrent ischemia, and hemorrhagic presentation was a risk factor for rebleeding. Interestingly, familial MMD was a common risk factor for all types of stroke event during follow-up, which has not been reported previously. Genetic studies are actively un-derway,26 and a recent study showed that patients with a specific variant of RNF213 presented with an early onset and severe form of MMD.29 However, it is possible to miss some familial MMD patients because not all the relatives of patients in this study were screened. Further study is needed to find out whether familial MMD really exhibits an aggressive clinical course. Thyroid disease was found to be another risk factor for stroke. Although observational studies of the relationship between hyperthyroidism and MMD have been reported,17,25 the clinical impact of hy-perthyroidism on MMD has never been evaluated. Further studies are expected to elucidate the relationship between thyroid disease and MMD in terms of clinical prognosis.

Subsequent episodes of bleeding occurred at a high-er rate in patients with a hemorrhagic presentation, and subsequent ischemic events occurred at a higher rate in patients with an ischemic presentation; these correlations were also found in the analysis of risk factors. Previous reports have supported these relationships.2,30 The recur-rence of ischemia can be reduced by revascularization surgery; however, recurrence of bleeding cannot. The val-ue of revascularization surgery for the prevention of re-current bleeding remains controversial.1,4,11,13,21,28,40 In ad-dition, rebleeding sites can differ from the previous sites of hemorrhage.11,23 Effective treatment modalities should be devised, especially in patients with hemorrhagic pre-sentation, because hemorrhage itself is the most influen-tial cause of morbidity and mortality.

It is important to know the natural history of asympto-matic patients because the disease itself progresses even if its symptoms do not. Unfortunately, there is little infor-mation about asymptomatic patients. According to Kuro-da et al.,22 the annual risk of stroke was 3.2%, and clinical outcomes were satisfactory (mRS score ≤ 2) in 97.5% of patients. In this study, the annual risk of stroke in asymp-

tomatic patients was 3.4%, with no statistical difference between groups. The stroke incidence rate was somewhat higher in asymptomatic patients than was expected, and the annual risk of hemorrhage was 2.5%. One report sug-gested a 6% mortality rate from bleeding in asymptomat-ic patients.39 Although clinical status was better in asymp-tomatic patients than in the other groups, close follow-up should be considered even in asymptomatic patients.

In our study, a total of 23 patients (9.5%) underwent revascularization surgery. Eighteen of these patients ini-tially presented with ischemic symptoms, representing 11.4% of patients with ischemic presentation. The rate of delayed operation during follow-up has been report-ed to range from 15% to 42%.8,12,22 Direct comparison is not thought to be reasonable because there are some dif-ferences among studies in terms of age, clinical status, ethnicity, and indications for revascularization surgery. However, these data can be useful for counseling patients.

This study has some limitations. First, it is retrospec-tive, so selection bias may exist. Second, it is not a truly thorough natural history of MMD because patients were followed up not from the beginning of disease but rather from the initial visit to our institute. However, this situation may be more natural in the clinical setting because of the rarity of the disease and the difficulty of early diagnosis. Third, patients with ischemic presentation who were in-cluded in this study had more benign disease than those who underwent revascularization surgery for ischemia at initial presentation and were not included. Thus, our re-ported incidence of recurrent ischemic events during the follow-up might be lower than the real incidence. Fourth, the mean follow-up durations may not be long enough to evaluate the full natural history of the disease, even though the mean duration of follow-up in this study was the lon-gest to date among published reports. Fifth, only 3 con-comitant medical diseases were included in the evaluation of risk factors. Although we tried to include other factors that have been shown to be related to MMD in the previ-ous studies, the incidence of such factors was too low too analyze (< 5 cases per factor).

conclusionsIn conclusion, there were no differences in the incidence

of stroke among clinical groups of hemorrhagic, ische-mic, and asymptomatic patients. However, clinical status was the worst in patients with hemorrhagic presentation. During the follow-up period, patients tended to more fre-

taBle 4. literature review about stroke recurrence in adult MMD under conservative management

Authors & YearNo. of Patients

No. of Pediatric Patients Follow-Up Duration Stroke Recurrence

Chiu et al., 1998 35 7 40 ± 31 mos Stroke: 10.3%/person-yr (hemorrhage, 1.7%; ischemia, 8.6%)Gross & Du, 2013 42 0 Mean 2.9 yrs Stroke: 13.3%/person-yr; hemorrhage: 1.7%/person-yrHallemeier et al., 2006 34 0 Median 5.1 yrs 5-yr stroke: 65% after initial symptomsKobayashi et al., 2000 42 1 Mean 80.6 mos Hemorrhage: 7.1%/person-yrKuroda et al., 2007 40 1 Mean 43.7 mos Stroke: 3.2%/person-yr (hemorrhage, 2.4%; infarction, 0.8%)Morioka et al., 2003 36 2 or 3 12.7 ± 7.1 yrs Hemorrhage: 29 incidents of rebleeding in 21 patients (61.1%)Present study 241 0 82.5 ± 62.9 mos Stroke: 4.5%/person-yr (hemorrhage, 2.3%; ischemia, 2.2%)

87


W. S. cho et al.


quently experience the same type of stroke as their initial presentation. Further study is needed to reduce rebleeding rates in patients with the hemorrhagic type of MMD and to elucidate the clinical relationship between thyroid dis-ease and MMD and the clinical course of familial type of MMD. Close follow-up should be performed in patients with ischemic and asymptomatic presentations.

references 1. Ahn JH, Wang KC, Phi JH, Lee JY, Cho BK, Kim IO, et al:

Hemorrhagic moyamoya disease in children: clinical features and surgical outcome. Childs Nerv Syst 28:237–245, 2012

2. Chiu D, Shedden P, Bratina P, Grotta JC: Clinical features of moyamoya disease in the United States. Stroke 29:1347–1351, 1998

3. Choi JU, Kim DS, Kim EY, Lee KC: Natural history of moyamoya disease: comparison of activity of daily living in surgery and non surgery groups. Clin Neurol Neurosurg 99 (Suppl 2):S11–S18, 1997

4. Fujii K, Ikezaki K, Irikura K, Miyasaka Y, Fukui M: The efficacy of bypass surgery for the patients with hemorrhagic moyamoya disease. Clin Neurol Neurosurg 99 (Suppl 2):S194–S195, 1997

5. Fung LW, Thompson D, Ganesan V: Revascularisation sur-gery for paediatric moyamoya: a review of the literature. Childs Nerv Syst 21:358–364, 2005

6. Gross BA, Du R: The natural history of moyamoya in a North American adult cohort. J Clin Neurosci 20:44–48, 2013

7. Guzman R, Lee M, Achrol A, Bell-Stephens T, Kelly M, Do HM, et al: Clinical outcome after 450 revascularization pro-cedures for moyamoya disease. Clinical article. J Neurosurg 111:927–935, 2009

8. Hallemeier CL, Rich KM, Grubb RL Jr, Chicoine MR, Mo-ran CJ, Cross DT III, et al: Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke 37:1490–1496, 2006

9. Han DH, Kwon OK, Byun BJ, Choi BY, Choi CW, Choi JU, et al: A co-operative study: clinical characteristics of 334 Korean patients with moyamoya disease treated at neuro-surgical institutes (1976-1994). Acta Neurochir (Wien) 142:1263–1274, 2000

10. Han DH, Nam DH, Oh CW: Moyamoya disease in adults: characteristics of clinical presentation and outcome after encephalo-duro-arterio-synangiosis. Clin Neurol Neurosurg 99 (Suppl 2):S151–S155, 1997

11. Houkin K, Kamiyama H, Abe H, Takahashi A, Kuroda S: Surgical therapy for adult moyamoya disease. Can surgical revascularization prevent the recurrence of intracerebral hemorrhage? Stroke 27:1342–1346, 1996

12. Ikezaki K: Rational approach to treatment of moyamoya dis-ease in childhood. J Child Neurol 15:350–356, 2000

13. Ikezaki K, Fukui M, Inamura T, Kinukawa N, Wakai K, Ono Y: The current status of the treatment for hemorrhagic type moyamoya disease based on a 1995 nationwide survey in Ja-pan. Clin Neurol Neurosurg 99 (Suppl 2):S183–S186, 1997

14. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH: The use of nitrogen mustards in the palliative treatment of cancer. Cancer 1:634–656, 1948

15. Kikuta K, Takagi Y, Nozaki K, Sawamoto N, Fukuyama H, Hashimoto N: The presence of multiple microbleeds as a predictor of subsequent cerebral hemorrhage in patients with moyamoya disease. Neurosurgery 62:104–112, 2008

16. Kim JE, Kim KM, Kim JG, Kang HS, Bang JS, Son YJ, et al: Clinical features of adult moyamoya disease with spe-cial reference to the diagnosis. Neurol Med Chir (Tokyo) 52:311–317, 2012

17. Kim SJ, Heo KG, Shin HY, Bang OY, Kim GM, Chung CS, et al: Association of thyroid autoantibodies with moyamoya-type cerebrovascular disease: a prospective study. Stroke 41:173–176, 2010

18. Kim SK, Cho BK, Phi JH, Lee JY, Chae JH, Kim KJ, et al: Pediatric moyamoya disease: an analysis of 410 consecutive cases. Ann Neurol 68:92–101, 2010

19. Kim SK, Wang KC, Kim IO, Lee DS, Cho BK: Combined encephaloduroarteriosynangiosis and bifrontal encephaloga-leo (periosteal) synangiosis in pediatric moyamoya disease. Neurosurgery 62 (6 Suppl 3):1456–1464, 2008

20. Kleinloog R, Regli L, Rinkel GJ, Klijn CJ: Regional differ-ences in incidence and patient characteristics of moyamoya disease: a systematic review. J Neurol Neurosurg Psychia-try 83:531–536, 2012

21. Kobayashi E, Saeki N, Oishi H, Hirai S, Yamaura A: Long-term natural history of hemorrhagic moyamoya disease in 42 patients. J Neurosurg 93:976–980, 2000

22. Kuroda S, Hashimoto N, Yoshimoto T, Iwasaki Y: Radiologi-cal findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:1430–1435, 2007

23. Kuroda S, Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:1056–1066, 2008

24. Kurokawa T, Tomita S, Ueda K, Narazaki O, Hanai T, Hasuo K, et al: Prognosis of occlusive disease of the circle of Willis (moyamoya disease) in children. Pediatr Neurol 1:274–277, 1985

25. Li H, Zhang ZS, Dong ZN, Ma MJ, Yang WZ, Han C, et al: Increased thyroid function and elevated thyroid autoantibod-ies in pediatric patients with moyamoya disease: a case-con-trol study. Stroke 42:1138–1139, 2011

26. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al: Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS ONE 6:e22542, 2011

27. Matsushima Y, Aoyagi M, Masaoka H, Suzuki R, Ohno K: Mental outcome following encephaloduroarteriosynangiosis in children with moyamoya disease with the onset earlier than 5 years of age. Childs Nerv Syst 6:440–443, 1990

28. Miyamoto S: Study design for a prospective randomized trial of extracranial-intracranial bypass surgery for adults with moyamoya disease and hemorrhagic onset—the Japan Adult Moyamoya Trial Group. Neurol Med Chir (Tokyo) 44:218–219, 2004

29. Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, et al: Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 78:803–810, 2012

30. Morioka M, Hamada J, Todaka T, Yano S, Kai Y, Ushio Y: High-risk age for rebleeding in patients with hemorrhagic moyamoya disease: long-term follow-up study. Neurosur-gery 52:1049–1055, 2003

31. Narisawa A, Fujimura M, Tominaga T: Efficacy of the revas-cularization surgery for adult-onset moyamoya disease with the progression of cerebrovascular lesions. Clin Neurol Neu-rosurg 111:123–126, 2009

32. Numaguchi Y, Gonzalez CF, Davis PC, Monajati A, Afshani E, Chang J, et al: Moyamoya disease in the United States. Clin Neurol Neurosurg 99 (Suppl 2):S26–S30, 1997

33. O’Sullivan DJ, Lim GH, Darveniza P, Coffey GL: Multiple progressive intracranial arterial occlusions (‘moyamoya’ dis-ease). J Neurol Neurosurg Psychiatry 40:853–860, 1977

34. Scott RM, Smith JL, Robertson RL, Madsen JR, Soriano SG, Rockoff MA: Long-term outcome in children with moyamo-ya syndrome after cranial revascularization by pial synangio-sis. J Neurosurg 100 (2 Suppl Pediatrics):142–149, 2004

35. Sun W, Yuan C, Liu W, Li Y, Huang Z, Zhu W, et al: Asymp-tomatic cerebral microbleeds in adult patients with moy-

88




amoya disease: a prospective cohort study with 2 years of follow-up. Cerebrovasc Dis 35:469–475, 2013

36. Suzuki J, Kodama N: Moyamoya disease—a review. Stroke 14:104–109, 1983

37. Suzuki Y, Negoro M, Shibuya M, Yoshida J, Negoro T, Wata-nabe K: Surgical treatment for pediatric moyamoya disease: use of the superficial temporal artery for both areas supplied by the anterior and middle cerebral arteries. Neurosurgery 40:324–330, 1997

38. Uyttenboogaart M, Stewart RE, Vroomen PC, De Keyser J, Luijckx GJ: Optimizing cutoff scores for the Barthel index and the modified Rankin scale for defining outcome in acute stroke trials. Stroke 36:1984–1987, 2005

39. Yamada M, Fujii K, Fukui M: [Clinical features and out-comes in patients with asymptomatic moyamoya disease—from the results of nation-wide questionnaire survey.] No Shinkei Geka 33:337–342, 2005 (Jpn)

40. Yoshida Y, Yoshimoto T, Shirane R, Sakurai Y: Clinical course, surgical management, and long-term outcome of moyamoya patients with rebleeding after an episode of intra-

cerebral hemorrhage: an extensive follow-up study. Stroke 30:2272–2276, 1999

author contributionsConception and design: Kim, Cho, Chung, Oh. Acquisition of data: Kim, Cho, Jeon, Kang, Sohn. Analysis and interpretation of data: Kim, Cho, Chung. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manu-script on behalf of all authors: Kim. Statistical analysis: Cho, Chung. Study supervision: Kim, Oh.

correspondenceJeong Eun Kim, Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. email: [email protected].

89


the natural clinical course of hemodynamically stable

Documents