Abstract
Introduction
The most appropriate method to manage adult patients with ischemic-onset moyamoya disease (MMD) without hemodynamic compromise remains undetermined. This study aimed to elucidate the long-term (5- to 10-year) clinical, angiographic, and cognitive outcomes of nonsurgical management alone (including a reduction in atherosclerotic burden by medical treatments and antiplatelet therapy) for adult patients with ischemic MMD without cerebral misery perfusion through combined analyses of two prospective cohorts with the same inclusion criteria.
Methods
The first cohort (71 patients) achieved the 10-year follow-up. The second cohort (55 patients) was followed for ≥5 and ≤10 years. Whether further cerebrovascular events had developed was determined during follow-up. To determine the development of angiographic disease progression and cognitive decline, patients underwent magnetic resonance angiography (MRA) and neuropsychological testing, respectively, at inclusion as well as at last follow-up during or at the end of the 10-year follow-up. Additional MRA was performed if any further cerebrovascular events had developed.
Results
In a combination of the two cohorts, the 10-year cumulative further cerebrovascular event rate was 9.5%, the incidence of angiographic disease progression was significantly higher in patients with further cerebrovascular events (100%) than in patients without (7%; p < 0.001), and the incidence of clopidogrel administration at last follow-up during or at the end of the 10-year follow-up was significantly higher in patients with declined cognition (100%) than in those without (21%; p < 0.001). Due to the small number of patients with further cerebrovascular events or declined cognition, multivariate statistical analysis was not performed.
Conclusion
The 10-year cumulative further cerebrovascular event rate was <10% and angiographic disease progression may cause further cerebrovascular events in adult patients with ischemic MMD without cerebral misery perfusion who received nonsurgical management alone, including a reduction in atherosclerotic burden by medical treatment and antiplatelet therapy. Cognitive declines may develop in such patients without further cerebrovascular events.
Keywords: Adult, Cognition, Ischemia, Moyamoya disease, Outcome
Introduction
Adult patients with ischemic-onset moyamoya disease (MMD) who show hemodynamic compromise (e.g., cerebral misery perfusion, defined as increased oxygen extraction fraction (OEF) on positron emission tomography [PET]) are typically advised to undergo surgical revascularization to prevent the development of further cerebrovascular events [1–3]. However, the most appropriate methods to manage such patients without hemodynamic compromise remain unclear.
We conducted a prospective cohort study of 71 adult patients with ischemic-onset MMD without cerebral misery perfusion on PET who were treated with nonsurgical management alone, including reduction of atherosclerotic burden by medical treatments and antiplatelet therapy [4–6]. The results of 2- and 5-year follow-ups revealed that the incidence of further cerebrovascular events at 5 years was only 6%, and symptoms at the time of further cerebrovascular events were observed only in the form of transient ischemic attack (TIA) or minor stroke [4, 5]. In addition, cognitive function had not deteriorated at 5 years after the last ischemic event among patients without further cerebrovascular events [5]. Finally, the incidence of angiographic disease progression at 5 years was 12% and angiographic disease progression was always exhibited by patients who showed further cerebrovascular events [6]. These findings suggested that patients without misery perfusion should initially receive nonsurgical management alone and that revascularization surgery should be performed only if ischemic symptoms recur [4, 5]. However, the follow-up period of 5 years was considered to represent a possible limitation in evaluating the clinical course of adult MMD.
Two additional studies involving more than 100 participants have reported long-term outcomes for nonsurgically managed patients with adult-onset MMD who presented with ischemia and stable hemodynamics [7, 8]. One study reported 5- and 10-year cumulative further cerebrovascular event rates of 20% and 30%, respectively [7], whereas the other revealed rates of 8.5% and 20%, respectively [8]. Five-year cumulative further cerebrovascular event rates in these two reports were relatively high compared with those from our prospective cohort study (6%) [5]. Both of those previous reports retrospectively reviewed medical records and defined outcomes of nonsurgically managed patients with MMD as “controls” or “natural clinical courses” [7, 8]. Given such study concepts and designs, the specific type of nonsurgical management (e.g., medication) and the severity of further cerebrovascular events (e.g., modified Rankin Scale [mRS] score after such events) were unclear [7, 8].
Given this background, we prospectively followed patients who had already been followed for 5 years with nonsurgical management alone [4, 5] for another 5 years (i.e., a total of 10 years of follow-up). Further, we conducted another cohort study consisting of patients with the same inclusion criteria as the first cohort and prospectively followed these patients for ≥5 years with nonsurgical management alone (i.e., the same as the first cohort). This study therefore aimed to elucidate long-term (5- to 10-year) clinical, angiographic, and cognitive outcomes of nonsurgical management alone, including a reduction in atherosclerotic burden by medical treatments and antiplatelet therapy, for adult patients with ischemic MMD without cerebral misery perfusion through combined analyses of the two prospective cohorts.
Methods
Study Design
The design for this prospective observational study was reviewed and approved by our institutional research committee (approval No. H20-45). Written, informed consent was obtained from all patients before study enrollment.
Patient Selection
Patients who visited our department from May 2008 to December 2020 and met the following inclusion criteria [4, 5] were prospectively enrolled: (1) presence of MMD according to the diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health, Labour and Welfare of Japan (including Guidelines for Diagnostic Imaging by magnetic resonance imaging [MRI] and magnetic resonance angiography [MRA] and only bilateral lesions) [9]; (2) presence of episodes displaying carotid territory ischemic symptoms occurring ≤3 months before presentation to our department; (3) age between 30 and 60 years at last ischemic episode; (4) mRS score of 0 or 1 at presentation to our department; and (5) absence of misery perfusion (defined as abnormally elevated OEF) in the symptomatic cerebral hemispheres on brain 15O gas PET performed according to the reported previously method [4] (see online suppl. material, Methods, Brain15O Gas PET and Definition of the Absence of Cerebral Misery Perfusion; for all online suppl. material, see https://doi.org/10.1159/000553483). Briefly, in the five regions perfused by the middle cerebral artery of each patient, when OEF was greater than the upper limit of the 95% confidence interval for control values obtained from 10 healthy subjects (51.8% for precentral region; 52.1% for central region; 52.2% for parietal region; 51.3% for angular region; 51.3 for temporal region), this region was defined as having abnormally elevated OEF [4]. Further, when one or more region in the symptomatic hemisphere exhibited abnormally elevated OEF, the patient was defined as having misery perfusion in that hemisphere [4]. The patients enrolled in the present study were prospectively divided into the following two groups: patients included from May 2008 to September 2015 (first cohort) [4, 5] and those included from October 2015 to December 2020 (second cohort).
Patient Management and Follow-Up
In the initial 2 years after inclusion in the first cohort, patients received an antiplatelet drug as follows: clopidogrel at 75 mg/day for patients ≥50 years old, and cilostazol at 200 mg/day for patients <50 years old [10, 11]. If a patient experienced side effects from cilostazol, pharmacotherapy was changed to clopidogrel by the clinician. Based on results of the 2-year follow-up [10, 11], clinicians intentionally administered cilostazol (200 mg/day) as a first choice to patients at the beginning of the third year of follow-up in the first cohort and from the start of the second cohort.
In accordance with previous reports [12–16], the presence of a daily smoking habit, hypertension, diabetes mellitus, and dyslipidemia was determined at the patient’s first visit to our hospital after their last ischemic event. After inclusion to the study, all patients visited our outpatient clinic at 8-week intervals. During this time, clinicians checked their clinical condition, including blood pressure, and collected data through blood biochemistry tests. Based on the findings, each patient received medical treatment [12]. Increased systolic/diastolic blood pressure, glycated hemoglobin (HbA1c), and low-density lipoprotein cholesterol (LDL-C), as well as atherosclerotic burden, were defined in reference to previous reports [12–16].
At each visit, clinicians also determined whether any further cerebrovascular events had developed and whether the modified Rankin Scale (mRS) score had deteriorated. If any further cerebrovascular events had developed, additional evaluations using mRS scores and brain 15O gas PET were performed 3–4 weeks thereafter.
Assessment of Angiographic Disease Progression
Each patient underwent axial three-dimensional time-of-flight MRA at inclusion, at the end of the 5-year follow-up, and at the last follow-up. When further cerebrovascular event developed, an additional MRA was also performed at that time. Angiographic disease progression was determined according to the previously reported definition [6] by comparing MRA findings at the time of the further cerebrovascular event, at the end of the 5-year follow-up, or at the last follow-up with those at inclusion.
Assessment of Increase in Cerebral Microbleeds
For each patient, three-dimensional T2*-weighted MRI (T2*-weighted imaging [WI]) was performed at inclusion and at the end of or the last follow-up during the subsequent 5-year follow-up. Cerebral microbleeds (CMBs) were defined as round, homogeneous, low-signal-intensity regions (diameter >2 and <10 mm) on T2*WI [17, 18]. The increase in CMBs in each cerebral hemisphere was assessed by comparing T2*WI among inclusion and each follow-up [19].
Neuropsychological Testing and Definition of Declined Cognition
Neuropsychological testing to assess cognitive decline was performed as described previously [4, 5] (see online suppl. material, Methods, Evidence for Selection of Neuropsychological Tests and Definition of Declined Cognition). Briefly, the following neuropsychological tests were conducted to assess cognitive function at inclusion, at the end of the 5-year follow-up, and at the last follow-up: the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to measure verbal and performance intelligence quotients (IQs) [20], the Wechsler Memory Scale (WMS) to measure memory quotient (MQ) [21], and the Rey-Osterrieth Complex Figure test (Rey test) [22], in which patients have to copy and recall a complex figure. Cognitive ability was evaluated based on the scores from these five tests (WAIS-R verbal IQ, WAIS-R performance IQ, WMS MQ, Rey copy, and Rey recall). All tests were performed by a trained neuropsychologist blinded to the medical data of patients.
An interval change of each neuropsychological test score was calculated for each patient according to the following equation: score at the end of the 5-year or last follow-up – score at inclusion [4, 5]. Declined cognition at the end of the 5-year or last follow-up was indicated by significant decreases in one or more of the interval changes in the five following neuropsychological test scores: WAIS-R verbal IQ ≤−6, WAIS-R performance IQ ≤−6, WMS MQ ≤−8, Rey copy ≤−2, or Rey recall ≤−5 [4, 5].
Statistical Analysis
All data are expressed as the mean ± standard deviation. Variables were compared between patient groups using the Mann-Whitney U test or Fisher’s exact test. The cumulative further cerebrovascular event rate was evaluated using the Kaplan-Meier method. Interval changes in atherosclerotic risk factors between inclusion and last follow-up were compared using Fisher’s exact test. When the number of target events such as further cerebrovascular event or declined cognition during follow-up was ≥10 × the number of variables showing a value of p < 0.2 in univariate analyses, multivariate statistical analysis of factors related to each target event was performed using logistic regression modeling by entering these variables into the final model. For all assessments, values of p < 0.05 were considered to indicate statistical significance.
Results
Over the 151-month study period, a total of 133 patients met the inclusion criteria for the present study. Of these 133 patients, 7 declined to participate. The remaining 126 patients were included in the present study, comprising 71 patients in the first cohort [4, 5] and 55 patients in the second cohort. Patients included in the two cohorts were followed-up until December 2025. As a result, the 10-year follow-up for patients in the first cohort was achieved. The 5-year follow-up for patients included in the second cohort was also achieved, but only 3 patients in this cohort achieved the 10-year follow-up; the remaining 45 patients, except those who withdrew or developed further cerebrovascular events, were followed close to the end of the 10-year follow-up.
Thirty-five (28%) of the 126 patients in the two cohorts experienced side effects from cilostazol. For these patients, cilostazol was changed to clopidogrel within 4 weeks after the initial administration. No significant differences in the basic characteristics of patients were found between the two cohorts (Table 1) (see online suppl. material, Results, Comparison of15O Gas PET Values in Each Middle Cerebral Artery Region of Interest in the Symptomatic Cerebral Hemisphere between First and Second Cohorts).
Table 1.
Comparisons of basic characteristics of patients between first and second cohorts
| Variables | 1st cohort (n = 71) [4] | 2nd cohort (n = 55) | p value |
|---|---|---|---|
| Age at inclusion (mean±SD), years | 43.0±8.4 | 42.4±8.6 | 0.562 |
| Female sex | 59 (83%) | 46 (84%) | >0.999 |
| Familial MMD | 3 (4%) | 3 (5%) | >0.999 |
| Daily smoking at inclusion | 16 (23%) | 11 (20%) | 0.828 |
| Hypertension at inclusion | 15 (21%) | 10 (18%) | 0.823 |
| Diabetes mellitus at inclusion | 10 (14%) | 7 (13%) | >0.999 |
| Dyslipidemia at inclusion | 17 (24%) | 14 (25%) | >0.999 |
| Thyroid disease at inclusion | 2 (3%) | 1 (2%) | >0.999 |
| TIAs alone before inclusion | 53 (75%) | 44 (80%) | 0.528 |
| Time from last event to PET (mean±SD), weeks | 7.2±2.7 | 6.7±2.3 | 0.307 |
| Administration of cilostazol at further cerebrovascular events or last follow-up | 52 (73%) | 39 (71%) | 0.842 |
Further Cerebrovascular Events and Clinical Outcomes
Mean ± standard deviation for follow-up duration in each cohort, including those patients who died, withdrew, or developed further cerebrovascular events, was 110 ± 27 months in the first cohort and 84 ± 27 months in the second cohort (mean ± standard deviation of follow-up duration for the combined cohort: 98 ± 30 months). During follow-up, 2 patients in the first cohort died of cancer and 4 other patients (2 in the first cohort and 2 in the second) withdrew. Eleven patients developed further cerebrovascular events, all of which were ischemic events with hemiparesis ipsilateral to the last symptom before inclusion. These events comprised TIAs (defined as a transient episode of neurological symptom due to the focal brain dysfunction without acute infarction or tissue injury) in 7 patients and minor stroke (defined as score ≤1 on every National Institutes of Health Stroke Scale (NIHSS) item, NIHSS score ≤3, and normal consciousness with acute infarction or tissue injury) in 4. All patients in the latter group showed acute infarction in the watershed area. No patients developed hemorrhagic stroke during follow-up.
Combining the two cohorts, 5- and 10-year cumulative further cerebrovascular event rates were 6.4% (4.1% for TIAs, 2.3% for minor stroke) and 9.5% (6.0% for TIAs, 3.5% for minor stroke), respectively, and ratios of the numbers of patients at risk at the end of the 5- and 10-year follow-ups plus the numbers of patients with further cerebrovascular events during 5- and 10-year follow-ups to the number at risk at inclusion were 0.96 (121/126) and 0.59 (74/126), respectively (Fig. 1) (see online suppl. material, Results, Further Cerebrovascular Event Rate in First and Second Cohorts).
Fig. 1.
Kaplan-Meier curve for further cerebrovascular events during the 10-year follow-up in a combination of the first and second cohorts.
In the 11 patients who developed further cerebrovascular events, mRS score in the 7 patients with further TIAs did not change between before and after such events. However, mRS score in 3 of the 4 patients with further minor stroke deteriorated from 0 to 1, while that in the remaining patient deteriorated from 0 to 2, with only clumsy motor skills in the affected hand. Brain 15O gas PET performed between 3 and 4 weeks after further cerebrovascular events revealed newly developed misery perfusion in the affected middle cerebral artery territory in all 11 of these patients (Fig. 2).
Fig. 2.
Patient in their 40 s with TIAs presenting as left hemiparesis before inclusion in the first cohort. Asymptomatic progression of stenosis in the horizontal portion of the right middle cerebral artery is seen, and signals in the right M2 and its distal arteries are decreased on MRA at the end of the 5-year follow-up (middle, lower) when compared with that at inclusion (left, lower). The patient experienced further minor stroke presenting as left hemiparesis at 79 months after inclusion. Signals in the whole right middle cerebral arteries are further decreased on MRA at the further minor stroke (right, lower) when compared with that at the end of the 5-year follow-up (middle, lower). Three weeks after the further minor stroke, 15O gas PET shows an increase in OEF in the right cerebral hemisphere (right, upper).
Atherosclerotic risk factors at inclusion and at further cerebrovascular events or last follow-up were compared in 121 patients (excluding 5 patients who died or withdrew within the 5-year follow-up) (Table 2). Incidences of all atherosclerotic risk factors at further cerebrovascular event or last follow-up were significantly reduced compared with those at inclusion.
Table 2.
Comparison of atherosclerotic risk factors at inclusion and at further cerebrovascular event or last follow-up
| Variables | At inclusion (n = 121) | At further cerebrovascular event or last follow-up (n = 121) | p value |
|---|---|---|---|
| Daily smoking habita | 25 (21%) | 4 (3%) | 0.002 |
| Increased systolic blood pressureb | 57 (47%) | 8 (7%) | 0.002 |
| Increased diastolic blood pressurec | 51 (42%) | 16 (13%) | <0.001 |
| Increased HbA1cd | 33 (27%) | 18 (15%) | <0.001 |
| Increased LDL-Ce | 64 (53%) | 27 (22%) | <0.001 |
| Atherosclerotic burdenf | 90 (74%) | 47 (39%) | <0.001 |
Hb, hemoglobin; SD, standard deviation; LDL-C, low-density lipoprotein cholesterol.
aLifetime history of smoking ≥100 cigarettes or smoking for 6 months in addition to smoking within 1 month preceding the last ischemic event.
bSystolic blood pressure >130 mm Hg.
cDiastolic blood pressure >80 mm Hg.
dHbA1c ≥ 5.6%.
eLDL-C ≥120 mg/dL.
fPresence of a daily smoking habit, increased systolic blood pressure, increased diastolic blood pressure, increased HbA1c, or increased LDL-C.
Angiographic Disease Progression
In the first cohort, 68 patients underwent MRA at the time of further cerebrovascular event during or at the end of the 5-year follow-up [6], and 63 patients underwent MRA at the time of further cerebrovascular event during or at the end of the subsequent 5-year follow-up (Fig. 3). In the second cohort, 53 patients underwent MRA at the time of further cerebrovascular events during or at the end of the 5-year follow-up, and 4 underwent MRA at the time of further cerebrovascular event during or at the end of the subsequent 5-year follow-up and the other 45 patients underwent MRA at last follow-up during the subsequent 5-year follow-up.
Fig. 3.
Flowcharts of relationships among angiographic disease progression (ADP) on MRI and further cerebrovascular events (FCEs) during follow-up in the first and second cohorts. *, patients with asymptomatic angiographic disease progression at the end of the 5-year follow-up who developed further cerebrovascular events with further angiographic disease progression during the subsequent 5-year follow-up. [5], patients who had been already published in reference [5].
Based on a combined analysis of the two cohorts, the 5-year angiographic disease progression rate was 11.6% (14/121) and the further cerebrovascular event rate of patients with angiographic disease progression during the 5-year follow-up was 57.1% (8/14). By contrast, none of the patients without angiographic disease progression during the 5-year follow-up experienced any further cerebrovascular events. In the first cohort, 2 (50.0%) of 4 patients with asymptomatic angiographic disease progression at the end of the 5-year follow-up developed further cerebrovascular events with further angiographic disease progression during the subsequent 5-year follow-up (Fig. 2), and 3 (5.0%) of 60 patients without angiographic disease progression at the end of the 5-year follow-up newly developed asymptomatic angiographic disease progression at the end of the subsequent 5-year follow-up. Finally, the 10-year angiographic disease progression rate was 16.2% (11/68) and the further cerebrovascular event rate of patients with angiographic disease progression during the 10-year follow-up was 54.5% (6/11). In the second cohort, while 2 patients with asymptomatic angiographic disease progression at the end of the 5-year follow-up did not have further angiographic disease progression during subsequent 5-year follow-up, 3 (6.4%) of 47 patients without angiographic disease progression at the end of the 5-year follow-up showed new development of angiographic disease progression during the subsequent 5-year follow-up and 1 of these 3 patients developed a further cerebrovascular event.
Among the 120 patients who did not die or withdraw during follow-up in the two cohorts, the incidence of angiographic disease progression was significantly higher in those patients with further cerebrovascular events than in those without (Table 3). Whereas all 11 patients with further cerebrovascular events showed angiographic disease progression, none of the patients without angiographic disease progression experienced further cerebrovascular events (Fig. 3). No other variables differed between patients with and without further cerebrovascular events. Although two variables (hypertension at inclusion and angiographic disease progression) displayed values of p < 0.2 in univariate analyses, the number of further cerebrovascular events was insufficient (<20) and multivariate statistical analysis of factors related to further cerebrovascular events was therefore not performed.
Table 3.
Factors related to further cerebrovascular events during follow-up
| Variables | Further cerebrovascular events | p value | |
|---|---|---|---|
| yes (n = 11) | no (n = 109) | ||
| Age at inclusion (mean±SD), years | 39.1±6.0 | 42.5±8.3 | 0.207 |
| Female sex | 9 (82%) | 91 (83%) | >0.999 |
| Familial MMD | 1 (9%) | 5 (5%) | 0.446 |
| Hypertension at inclusion | 0 (0%) | 23 (21%) | 0.121 |
| Diabetes mellitus at inclusion | 0 (0%) | 15 (14%) | 0.355 |
| Dyslipidemia at inclusion | 2 (18%) | 27 (25%) | >0.999 |
| Thyroid disease at inclusion | 1 (9%) | 2 (2%) | 0.253 |
| TIAs alone before inclusion | 9 (82%) | 86 (79%) | >0.999 |
| Time from last event to PET (mean±SD), weeks | 7.2±2.7 | 6.9±2.5 | 0.677 |
| Daily smoking at further cerebrovascular events or last follow-up | 0 (0%) | 4 (4%) | >0.999 |
| Increased systolic blood pressure at further cerebrovascular events or last follow-up | 0 (0%) | 8 (7%) | >0.999 |
| Increased diastolic blood pressure at further cerebrovascular events or last follow-up | 0 (0%) | 15 (14%) | 0.355 |
| Increased HbA1c at further cerebrovascular events or last follow-up | 1 (9%) | 17 (16%) | >0.999 |
| Increased LDL-C at further cerebrovascular events or last follow-up | 2 (18%) | 24 (22%) | >0.999 |
| Atherosclerotic burden at further cerebrovascular events or last follow-up | 2 (18%) | 44 (40%) | 0.201 |
| Administration of cilostazol at further cerebrovascular events or last follow-up | 7 (64%) | 78 (72%) | 0.729 |
| Angiographic disease progression at further cerebrovascular events or last follow-up | 11 (100%) | 8 (7%) | <0.001 |
FCEs, further cerebrovascular events; SD, standard deviation; MMD, moyamoya disease; TIA, transient ischemic attack; PET, positron emission tomography; LDL-C, low-density lipoprotein cholesterol.
Cognitive Outcomes
In the first cohort, 63 patients underwent neuropsychological testing at the end of the 5-year follow-up [5] and 59 patients underwent neuropsychological testing at the end of the subsequent 5-year follow-up. In the second cohort, 47 patients underwent neuropsychological testing at the end of the 5-year follow-up and 46 underwent neuropsychological testing at the last follow-up during or at the end of the subsequent 5-year follow-up.
No patients in the first [5] or second cohorts were found to show declined cognition at the end of the 5-year follow-up. However, 5 patients (8.4%) in the first cohort and 4 patients (8.7%) in the second cohort showed declined cognition at last follow-up during or at the end of the subsequent 5-year follow-up.
Regarding the 105 patients in the two cohorts who underwent neuropsychological testing at the last follow-up during or at the end of the subsequent 5-year follow-up, incidences of clopidogrel administration and increase in CMBs at last follow-up during or at the end of the 10-year follow-up were significantly higher among patients with declined cognition than among those without (Table 4). All 9 patients with declined cognition received clopidogrel for more than 90 months and exhibited an increase in CMBs in the symptomatic and/or asymptomatic cerebral hemispheres (Fig. 4). No other variables differed between patients with and without declined cognition. Although four variables (familial MMD, thyroid disease at inclusion, clopidogrel administration, and increase in CMBs at last follow-up during or at the end of the 10-year follow-up) showed values of p < 0.2 in univariate analyses, the number with the declined cognition was insufficient (<40) and multivariate statistical analysis of factors related to declined cognition was therefore not performed.
Table 4.
Factors related to declined cognition during follow-up
| Variables | Declined cognition | p value | |
|---|---|---|---|
| yes (n = 9) | no (n = 98) | ||
| Age at inclusion (mean±SD), years | 39.4±6.9 | 42.6±8.5 | 0.418 |
| Female sex | 8 (89%) | 79 (82%) | >0.999 |
| Years of schooling (mean±SD) | 13.2±1.5 | 13.1±1.7 | >0.999 |
| Right handed | 8 (89%) | 86 (88%) | >0.999 |
| Familial MMD | 2 (22%) | 3 (3%) | 0.057 |
| Hypertension at inclusion | 0 (0%) | 23 (24%) | 0.201 |
| Diabetes mellitus at inclusion | 0 (0%) | 15 (16%) | 0.352 |
| Dyslipidemia at inclusion | 2 (22%) | 24 (25%) | >0.999 |
| Thyroid disease at inclusion | 1 (11%) | 1 (1%) | 0.165 |
| TIAs alone before inclusion | 7 (78%) | 76 (79%) | >0.999 |
| Symptomatic left hemisphere | 5 (56%) | 57 (58%) | >0.999 |
| Daily smoking at last follow-up | 0 (0%) | 4 (4%) | >0.999 |
| Increased systolic blood pressure at last follow-up | 1 (11%) | 7 (7%) | 0.524 |
| Increased diastolic blood pressure at last follow-up | 2 (22%) | 12 (13%) | 0.342 |
| Increased HbA1c at last follow-up | 1 (11%) | 14 (15%) | >0.999 |
| Increased LDL-C at last follow-up | 1 (11%) | 21 (22%) | 0.681 |
| Atherosclerotic burden at last follow-up | 5 (56%) | 36 (38%) | 0.308 |
| Administration of clopidogrel at last follow-up | 9 (100%) | 20 (21%) | <0.001 |
| Increase in CMBs at last follow-up | 9 (100%) | 11 (11%) | <0.001 |
| Angiographic disease progression at last follow-up | 0 (0%) | 7 (7%) | >0.999 |
SD, standard deviation; MMD, moyamoya disease; TIAs, transient ischemic attacks; LDL-C, low-density lipoprotein cholesterol; CMBs, cerebral microbleeds.
Fig. 4.
T2*-weighted magnetic resonance images in a patient in their 40 s with a minor stroke presenting as right hemiparesis before inclusion in the second cohort. The patient initially received cilostazol but side effects developed, and cilostazol was changed to clopidogrel. This patient received clopidogrel for 93 months after this change. A new microbleed is seen in the left thalamus at the last follow-up (right) when compared with an image at inclusion (left). The patient exhibited declined cognition at the last follow-up.
Discussion
Combined analyses of the two prospective cohorts showed that the 10-year cumulative further cerebrovascular event rate was <10% and angiographic disease progression may cause further cerebrovascular events in adult patients with ischemic MMD without cerebral misery perfusion who received nonsurgical management alone, including a reduction in atherosclerotic burden by medical treatment and antiplatelet therapy. They also suggested that cognitive decline may develop in such patients without further cerebrovascular events.
The 5-year cumulative further cerebrovascular event rate in the present study (6.4%) was low when compared with two previous studies of more than 100 participants each (9% and 17%) [7, 8]. Further, differences in 10-year cumulative further cerebrovascular event rates among the present (9.5%) and two previous studies (20% and 33%) [7, 8] increased when compared with differences in 5-year cumulative further cerebrovascular event rates. These discrepancies may be explained by differences in study design (i.e., prospective follow-up vs. retrospective data collection). Actually, although the longest duration of follow-up in the previous studies was more than 180 months, the mean duration of follow-up in the present study (98 months) was 21 months longer than that of participants in the previous studies (77 months each) [7, 8]. Further, the ratio of the number at risk at the end of the 5- and 10-year follow-up periods plus the numbers of patients with further cerebrovascular events during the 5- and 10-year follow-up periods to the numbers at risk at inclusion was considerably higher in our cohorts when compared with that in the previous retrospective study (0.96 versus 0.63 for 5-year follow-up; 0.59 versus 0.33 for the 10-year follow-up) [7]. In addition, while previous retrospective studies have lacked descriptions of the specific type of nonsurgical management [7, 8], we intentionally reduced atherosclerotic burden with medical treatment for all patients in our cohorts. Because such atherosclerotic burden causes further cerebrovascular events in patients who experience cerebrovascular events and a reduction in atherosclerotic burden helps prevent the development of further cerebrovascular events [23–27], the low further cerebrovascular event rate in our cohorts may also be attributed to this reduction. In addition, we intentionally administered cilostazol instead of clopidogrel. As suggested by data from a previous study, cilostazol might improve cerebral perfusion more effectively than clopidogrel [10]. In another study, hemodynamic failure (including reduced cerebral perfusion) was reported as an independent predictor of subsequent hemorrhage among patients with hemorrhagic MMD [28]. Moreover, comparisons of the effects of cilostazol and thienopyridine derivatives such as clopidogrel have indicated that these drugs can inhibit platelet aggregation [29]. However, cilostazol treatment had no effect on bleeding time, whereas oral administration of thienopyridine derivatives prolonged bleeding time, suggesting that cilostazol inhibits platelet aggregation without prolonging bleeding time [29]. Such findings suggest that cilostazol administration may inhibit the development of not only new hemorrhagic events but also further ischemic events in adult patients with ischemic MMD. A large cohort study in Korea reported that among patients with MMD, cilostazol was associated with a greater survival benefit than other antiplatelet regimens [30]. In 2023, the American Heart Association/American Stroke Association reported that in patients with MMD, cilostazol may improve survival more effectively than other antiplatelet drugs [31]. These effects of cilostazol plus the reduction in atherosclerotic burden might explain the absence of hemorrhagic stroke and the low rates of further ischemic events in our cohorts (see online suppl. material, Discussion, Comparison with Outcomes of Surgically Treated Adults with Ischemic-Type MMD, using Previous Articles).
In the present study, among patients who developed further cerebrovascular events, mRS score remained ≤1 after further cerebrovascular events, except in 1 patient with a post-event mRS score of 2 with minor sequelae. This suggests the possibility that patients without hemodynamic compromise should initially receive medical management alone after the first ischemic event, with revascularization surgery if any further cerebrovascular events occur.
In our institute, patients with misery perfusion (defined as an increased OEF) in the symptomatic cerebral hemispheres on brain 15O gas PET were considered as candidates for revascularization surgery and were advised to undergo such surgery [32, 33]. However, during the present first and second study periods, 3 patients declined revascularization surgery [3]. These patients received nonsurgical management alone in the same fashion as the present study and were prospectively followed up [3]. All 3 patients suffered further cerebrovascular events within 1 year after inclusion, after which the modified Rankin disability scale scores deteriorated to ≥3, suggesting that unlike adult patients without cerebral misery perfusion due to ischemic MMD, receiving nonsurgical management alone is associated with considerably poor outcomes for such patients with cerebral misery perfusion [3].
Kuroda et al. [34] reported that the incidence of angiographic disease progression in adult MMD is 2.4% per year and that angiographic disease progression may be related to the development of further cerebrovascular events. The data from the present study are comparable with those of that study, even though that study included patients who presented with a variety of events (e.g., ischemia, hemorrhage, other symptoms), showed a variety of cerebral hemodynamics, and underwent revascularization surgery [34]. In the present cohorts, patients with further cerebrovascular events always exhibited angiographic disease progression with the development of misery perfusion on brain 15O gas PET, but no patients without angiographic disease progression experienced any further cerebrovascular events. The former finding represents the nature of MMD itself, that is, “disease still progressing even in adulthood.” The latter finding suggests that further cerebrovascular events can be prevented in patients with “progression-arrested MMD” by medical management alone, including a reduction in atherosclerotic burden and administration of cilostazol. Notably, in the first cohort, half of the patients with asymptomatic angiographic disease progression at the end of the 5-year follow-up developed further cerebrovascular events with further angiographic disease progression during the subsequent 5-year follow-up, and 5% of patients without angiographic disease progression at the end of the 5-year follow-up newly developed asymptomatic angiographic disease progression at the end of the subsequent 5-year follow-up. In the second cohort, a patient without angiographic disease progression at the end of the 5-year follow-up developed further cerebrovascular events with new occurrence of angiographic disease progression during the subsequent 5-year follow-up. These findings suggest that although the timing of angiographic disease progression varies among patients, angiographic disease progression may be a high risk factor for the development of further cerebrovascular events.
No patients in the second cohort exhibited declined cognition at the end of the 5-year follow-up, corresponding with our previous data from the first cohort [5]. However, 8–9% of patients exhibited declined cognition at last follow-up during or at the end of the subsequent 5-year follow-up. All these patients with declined cognition received clopidogrel for more than 90 months and exhibited an increase in CMBs in the symptomatic and/or asymptomatic cerebral hemispheres on T2*-weighted MRI. Previous analyses of data obtained at the end of the 5-year follow-up in the first cohort revealed clopidogrel administration as an independent predictor of an interval increase in CMBs, and such increases were associated with reductions in neuropsychological test scores [19]. However, these reductions did not meet the criteria for the patient to show declined cognition at the end of the 5-year follow-up [19]. Histopathologically, CMBs suggest the presence of surrounding gliosis and necrosis, in addition to hemosiderin deposition [17]. As the presence of even a single CMB has been associated with global disruptions to the microstructural integrity of white matter [18], CMBs are considered to indicate probable widespread injury to the brain [35] and to damage the structure of the adjacent neural tissue directly, thereby resulting in cognitive decline [36]. In the present cohorts, an increase in CMBs may have also led to declined cognition.
This study has several limitations. First, whereas patients in the first cohort had been prospectively followed for 10 years, most patients in the second cohort did not complete the 10-year follow-up. For these patients, more accurate long-term outcomes for nonsurgical management alone among adult patients with ischemic-onset MMD without cerebral misery perfusion will be considered complete at the end of the 10-year follow-up. Second, because the number of target events such as further cerebrovascular events or declined cognition during follow-up was <10× the number of variables showing values of p < 0.2 in univariate analyses, multivariate statistical analysis of factors related to each target event was not performed using logistic regression modeling. We therefore could not confirm the relationship among further cerebrovascular events and angiographic disease progression or among cognitive decline and clopidogrel administration. Considering the low incidences of further cerebrovascular events and cognitive decline, a larger prospective cohort of 300–500 participants appears warranted. Further, all patients in the present two cohorts received cilostazol or clopidgrel and were not compared to controls without administration of any antiplatelet drugs. The choice of antiplatelet therapy (cilostazol or clopidgrel) was not also randomized. These findings introduce potential confounding by indication, and the observed association between clopidogrel use and cognitive decline should be interpreted with caution. Third, genes for MMD such as ring finger protein 213 may be related to differences between the two categories such as “disease still progressing even in adulthood” and “progression-arrested MMD” [37, 38]. Further studies to elucidate the relationships between genomic factors and these two categories may prove beneficial. Fourth, recent studies have shown that periventricular anastomoses are important to predict the subsequent occurrence of hemorrhagic stroke [39, 40]. Although no patients developed hemorrhagic stroke during follow-up in the present two cohorts, we did not assess the presence or absence of periventricular anastomoses. Lastly, when clinicians determined at the outpatient visit whether any further cerebrovascular events had developed, subtle or transient cerebrovascular events might have been underestimated because non-disabling neurological symptoms due to such events might not have been recognized or reported by the patient. The “true” cumulative further cerebrovascular event rate may thus be higher than the present result.
Conclusion
The 10-year cumulative further cerebrovascular event rate was <10% and angiographic disease progression may cause further cerebrovascular events in adult patients with ischemic MMD without cerebral misery perfusion who received nonsurgical management alone, including a reduction in atherosclerotic burden by medical treatment and antiplatelet therapy. Cognitive decline may develop in such patients without further cerebrovascular events.
Statement of Ethics
This prospective observational study was carried out in accordance with the guidelines of the World Medical Association and the Declaration of Helsinki, and the protocol was reviewed and approved by the institutional Ethics Committee at Iwate Medical University School of Medicine (Approval No. H20-45). Written informed consent was obtained from all patients or their next of kin before the study began.
Conflict of Interest Statement
The corresponding author (Kuniaki Ogasawara) declares the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: consigned research funds from Nihon Medi-Physics Co., Ltd. The corresponding author (Kuniaki Ogasawara) is an Editorial Board Member of Cerebrovascular Diseases. The corresponding author (Kuniaki Ogasawara) does not have other conflicts of interest to declare. The other authors (Toshinari Misaki, Kenya Miyoshia, Shunrou Fujiwara, Hiroaki Saura, and Yosuke Akamatsu) have no conflicts of interest to declare.
Funding Sources
This study was supported in part by a Grant-in-Aid from the National Hospital Organization Kamaishi Hospital KENKYUHI (0001).
Author Contributions
Kuniaki Ogasawara, Toshinari Misaki, and Yosuke Akamatsu: conception and design, acquisition of data, analysis and interpretation of data; drafting the article critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Kenya Miyoshi and Hiroaki Saura: acquisition of data; critical revision of the article for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Shunrou Fujiwara: conception and design; critical revision of the article for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding Statement
This study was supported in part by a Grant-in-Aid from the National Hospital Organization Kamaishi Hospital KENKYUHI (0001).
Data Availability Statement
The data generated and analyzed during this study are not publicly available on ethical grounds. However, inquiries regarding these data can be directed to the corresponding author.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data generated and analyzed during this study are not publicly available on ethical grounds. However, inquiries regarding these data can be directed to the corresponding author.
