Clinical Features and Treatment Outcomes in Patients in Their Twenties with Ischemic Moyamoya Disease

Moyamoya disease (MMD) tends to cause intracranial hemorrhage in adults and cerebral ischemia in children [1]. In terms of ischemic MMD, the distribution of the age at initial onset shows two peaks: a higher peak at age 5–9 years and a lower peak at age 40–49 years [2]. On the other hand, among patients with ischemic MMD aged <60 years, those in their 20s are at the bottom of the distribution regarding the age at initial onset [2].

A surgical procedure including indirect revascularization is recommended for all pediatric patients with MMD with ischemic symptoms because the brains of such patients are still developing [3, 4]. By contrast, no clear guidelines for selective revascularization surgery in adult patients with ischemic presentation and hemodynamic compromise have been established, although this procedure has been recommended by a number of investigators [5, 6]. According to two recent cohort studies of adult patients with ischemic MMD aged 30–60 years who received pharmacotherapy alone and were prospectively followed for 5 years, the annual incidence of further cerebrovascular events in patients without misery perfusion, which implies a marginally sufficient cerebral blood supply relative to the metabolic demand, on entry was only 1.2% (primarily cerebral ischemia) [7, 8]. In addition, the modified Rankin Scale (mRS) score after further cerebrovascular events in such patients remained at 0 or 1 [7, 8]. In contrast, all patients with misery perfusion upon entry experienced a major cerebrovascular event within the next year, after which, their mRS scores deteriorated to ≥3 [9]. These findings indicate that surgical revascularization should be performed in adult patients with ischemia-onset MMD who show misery perfusion, whereas medical management alone should be provided to such patients who do not show misery perfusion until the development of further events [10]. Approximately 30% of adult patients with ischemic MMD aged 30–60 years show misery perfusion in the affected cerebral hemisphere, so revascularization surgery may be recommended for only these patients [9].

Revascularization procedures for adult patients with ischemic MMD are also controversial. Several investigators have asserted that direct revascularization procedures such as superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is the preferred procedure for adult patients with MMD presenting with ischemic stroke [1, 11]; however, other investigators have suggested that direct revascularization procedures in such patients are inferior in terms of quality-adjusted life years compared with indirect revascularization alone [12]. We also demonstrated that cerebral hyperperfusion syndrome, which sometimes occurs after direct revascularization [1], leads to decreased cognitive function in adult patients with ischemic MMD aged 30–60 years [13]. This declined cognition persists until at least 5 years after surgery in one-third of such patients, resulting in a deteriorated quality of life [14, 15]. Thereafter, we performed indirect revascularization alone for adult patients with ischemic MMD aged 30–60 years [16].

The incidence of cerebral hyperperfusion syndrome after direct revascularization surgery is reported to be considerably higher in adult than in pediatric patients (30% vs. 5%, respectively) [17], and patients in their 20 s with ischemic MMD may share features with both adult and pediatric patients. However, the clinical features and treatment outcomes of patients in their 20 s with ischemic MMD remain uninvestigated because this age group is at the bottom of the distribution in terms of the age at initial onset. Given this background, the present prospective study aimed to clarify the clinical features and treatment outcomes of patients in their 20 s (younger patients) with ischemic MMD compared with patients aged 30–60 years (older patients) [9].

This prospective observational study was performed according to the guidelines of the World Medical Association and the Declaration of Helsinki. The protocol of the present study was reviewed and approved by the Institutional Ethics Committee at Iwate Medical University School of Medicine (Approval No. H23-45). All patients provided written informed consent prior to participation. For a vulnerable patient, written informed consent was obtained from the patient’s legal guardian. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

We prospectively enrolled adult patients diagnosed with MMD according to the criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health, Labour and Welfare, Japan [18] who met the following clinical inclusion criteria: age 20–60 years at initial onset; mRS score of 0 or 1; and ischemic symptoms in the carotid territory that began ≤3 months before visiting our hospital [7‒9, 13, 16]. Patients who experienced cerebral ischemic or hemorrhagic episodes before age 20 years were excluded from the present study. According to the criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis of the Ministry of Health, Labour and Welfare, Japan [18], patients with a unilateral lesion of the moyamoya vascular phenomenon were also excluded.

All enrolled patients underwent brain ¹⁵O-gas positron emission tomography (PET) as previously described [7‒9, 13, 16]. Briefly, the oxygen extraction fraction on ¹⁵O-gas PET images was measured in the five cortical regions (precentral, central, parietal, angular, and temporal) perfused by the MCA in the bilateral cerebral hemisphere [7‒9, 13, 16]. In each MCA region of each patient, when the oxygen extraction fraction exceeded the upper limit of the 95% confidence interval of normal values that region was defined as having an abnormally elevated oxygen extraction fraction [7‒9, 13, 16]. When one or more MCA regions exhibited an abnormally elevated oxygen extraction fraction, the cerebral hemisphere was defined as showing misery perfusion [7‒9, 13, 16].

Patients with misery perfusion in the symptomatic cerebral hemisphere were eligible for revascularization surgery [7‒9, 13, 16]. Combined revascularization surgery was performed in the first study period (from January 2008 to March 2016) [9, 13]. Based on outcomes of these patients undergoing combined revascularization surgery, indirect revascularization surgery alone was performed in the second study period (from April 2016 to December 2020) [9, 16]. Patients without misery perfusion in the symptomatic cerebral hemisphere received pharmacotherapy alone including antiplatelet therapy through the two study periods [7‒10].

Revascularization surgery was performed within 4 months after the last ischemic event. Combined revascularization surgery consisted of direct and indirect revascularizations. For direct revascularization, a single STA-MCA anastomosis was performed. The recipient artery was the M4 of the MCA that supplied the symptomatic MCA territory with misery perfusion on ¹⁵O-gas PET in the symptomatic cerebral hemisphere [13]. For indirect revascularization, encephalo-duro-myo-arterio-pericranial-synangiosis was performed through a large frontotemporal craniotomy so that the synangiosis covered the symptomatic MCA territory [16]. Cilostazol was administered to all patients as an antiplatelet drug until the morning of the day of surgery and from the day after surgery to 6 months postoperative [16].

For combined revascularization surgery, systolic blood pressure was maintained between 110 and 130 mm Hg as much as possible during and for 14 days after surgery [13]. To detect postoperative cerebral hyperperfusion, brain perfusion single-photon emission computed tomography (SPECT) was performed before and on the day after surgery [13]. Postoperative cerebral hyperperfusion syndrome was determined based on brain perfusion SPECT data and symptoms before and after surgery, as previously described [13]. A propofol coma was induced in patients with postoperative cerebral hyperperfusion syndrome [13].

For indirect revascularization surgery alone, systolic blood pressure was maintained more than 110 mm Hg as much as possible during and for 14 days after surgery. To help prevent the swelling of soft tissues, such as the muscles used for encephalo-duro-myo-arterio-pericranial-synangiosis, the Japanese traditional medicines, Keishi-bukuryo-Gan and Ji-daboku-Ippo, were administered from the day after surgery to the second postoperative week [16, 19].

Patients undergoing revascularization surgery underwent cerebral angiography via arterial catheterization before and at 6 months after surgery. Based on a comparison among these angiograms, the formation of new collateral flow from the external carotid artery after surgery was graded as follows using the Matsushima Scale [20]: collateral flows feeding more than two-thirds of the MCA cortical territory (grade A), between two-thirds and one-third (grade B), and less than one-third (grade C).

Patients undergoing revascularization surgery were administered neuropsychological tests before and at 2–3 months (for combined revascularization surgery) or 6 months (for indirect revascularization surgery alone) after surgery. In patients undergoing revascularization surgery for bilateral cerebral hemispheres, neuropsychological testing was performed after each surgery. Neuropsychological tests consisted of the Wechsler Adult Intelligence Scale-Revised [21], which measures verbal and performance intelligence quotient, the Wechsler Memory Scale [22], which measures memory quotient, and the Rey-Osterrieth Complex Figure test [23], in which patients copy and recall a complex figure. For each revascularization surgery in each patient, a determination of postoperatively improved, unchanged, or declined cognition was made based on postoperative changes in the five neuropsychological test scores and previously described definitions [24].

After revascularization surgery or introduction of pharmacotherapy, patients visited our outpatient clinic at 8-week intervals for 3 years. A clinician determined whether neurological symptoms had recurred or newly developed and whether patients had returned to their original educational institution or job.

All data are expressed as the mean ± standard deviation. Differences in values between groups were evaluated using the Mann-Whitney U test or Fisher’s exact test. Significance was set at the p < 0.05 level for all statistical analyses.

Between January 2008 and December 2020, 12 consecutive patients in the younger group met the clinical inclusion criteria and participated in the present study (written informed consent was obtained from all these 12 patients). All these patients reported unilateral carotid territory ischemic symptoms that were present ≤3 months before visiting our hospital. During the same study period, 182 patients in the older group met the same clinical inclusion criteria and participated in the present study [9]. Therefore, the patients in the younger group comprised 6% of all adult patients with MMD with ischemic symptoms.

Tables 1 and 2 show the younger patients’ baseline characteristics at inclusion and a comparison with those of the older patients, respectively. The incidences of familial MMD and misery perfusion in the affected hemisphere were significantly higher in younger than in older patients. No other differences in baseline characteristics at inclusion were found between the 2 patient groups.

All 12 younger patients who were enrolled in the present study exhibited misery perfusion in the affected hemisphere on ¹⁵O-gas PET and underwent revascularization surgery. Of these 12 patients, three also had misery perfusion in the asymptomatic contralateral hemisphere at inclusion and newly experienced ischemic episodes in the contralateral hemisphere within 12 months after the first revascularization surgery (Table 3; Fig. 1, 2). These 3 patients also underwent revascularization surgery for the symptomatic contralateral hemisphere.

Five cerebral hemispheres in 4 patients in the first study period received combined revascularization surgery: three hemispheres in two patients had an uneventful postoperative course, whereas postoperative cerebral hyperperfusion syndrome developed in two hemispheres in two patients (Table 3). In the latter two patients, cerebral hyperperfusion on brain perfusion SPECT performed on the day after surgery was observed in the cortical region where the STA was anastomosed to the M4 of the MCA (Fig. 1). These patients newly developed motor aphasia on the fifth or sixth postoperative day and were treated with a propofol coma. The neurological deficits in these patients resolved after termination of the coma. The incidence of postoperative cerebral hyperperfusion syndrome did not differ between younger and older cerebral hemispheres undergoing combined revascularization surgery (Table 4).

In the second study period, 10 cerebral hemispheres in 9 patients received indirect revascularization surgery alone (Table 3): 9 hemispheres in eight patients had an uneventful postoperative course, whereas one hemisphere in one patient had a transient ischemic attack with motor weakness in the side contralateral to surgery on the second postoperative day. Magnetic resonance imaging performed 7 days after this episode in the latter patient demonstrated no ischemic cerebral lesions. The patient who received combined revascularization surgery and developed postoperative cerebral hyperperfusion syndrome in the first study period underwent indirect revascularization surgery alone for the symptomatic contralateral hemisphere in the second study period (Fig. 1).

Based on the Matsushima Scale on cerebral angiography, two and three cerebral hemispheres receiving combined revascularization surgery in the first study period were determined as showing grades A (Fig. 1) and B, respectively (Table 3). Two, seven, and one cerebral hemisphere receiving indirect revascularization surgery alone in the second study period showed grades A (Fig. 2), B (Fig. 1), and C, respectively (Table 3). The incidence of grade A or B did not differ between cerebral hemispheres in the first study period that received combined revascularization surgery (100%) and in the second study period that received indirect revascularization surgery alone (90%) (p > 0.9999). In addition, no difference in incidence was found between younger and older cerebral hemispheres undergoing indirect revascularization surgery alone (Table 4).

Based on the neuropsychological assessments before and after surgery, two, one, and two cerebral hemispheres receiving combined revascularization surgery in the first study period were considered to have improved, unchanged, and declined cognition, respectively (Table 3). Six and four cerebral hemispheres receiving indirect revascularization surgery alone in the second study period were considered to have improved and unchanged cognition, respectively (Table 3). The incidence of declined cognition tended to be higher in cerebral hemispheres receiving combined revascularization surgery in the first study period (40%) than in cerebral hemispheres receiving indirect revascularization surgery alone in the second study period (0%), although the difference between the two study groups was not statistically significant (p = 0.0952). Two cerebral hemispheres with postoperative cerebral hyperperfusion syndrome exhibited declined cognition (Table 3). Declined cognition in one patient with postoperative cerebral hyperperfusion syndrome in the first study period recovered to unchanged cognition after indirect revascularization surgery alone for the contralateral hemisphere in the second study period (Fig. 1). Improved cognition was maintained after the second surgery in the other 2 patients undergoing bilateral revascularization surgery (Table 3). The incidence of declined cognition after combined revascularization surgery did not differ between younger and older cerebral hemispheres (Table 4). None of the younger or older cerebral hemispheres receiving indirect revascularization surgery alone had declined cognition, and the incidence of improved cognition after indirect revascularization surgery alone did not differ between younger and older cerebral hemispheres.

No patients developed recurrent ischemic episodes in the cerebral hemisphere ipsilateral to revascularization surgery during the 3-year follow-up. Two patients with postoperative cerebral hyperperfusion syndrome in the first study period did not return to their original educational institutions because of cognitive decline (Table 3). The other 10 patients were able to return to their original educational institution or job.

The present study found that patients in their 20s with ischemic MMD always exhibit misery perfusion in the affected hemisphere, unlike older patients, and occasionally develop cerebral hyperperfusion syndrome following combined revascularization surgery, leading to cognitive decline, similar to older patients. The present study also found that, similar to older patients, indirect revascularization surgery alone forms sufficient collateral circulation and restores cognitive function in patients in their 20s.

In the present study, patients in their 20s comprised 6% of all adult patients with ischemic MMD, which corresponded with the <10% seen in a database constructed by the Research Committee on Spontaneous Occlusion of the Circle of Willis in Japan [2]. In a study using the Korean National Health Insurance database, the familial risk of MMD according to age group showed marked age dependence: the highest familial risk was seen in the 0–10-year age group, and then declined with increasing age [25]. These findings support our findings of a higher incidence of familial MMD in patients in their 20 s.

A comparison of baseline characteristics at inclusion also showed a higher incidence of misery perfusion in the affected hemisphere in patients in their 20 s. These data corresponded with a previous finding of a greater oxygen extraction fraction in the cerebral cortex in pediatric compared with adult patients with MMD [26]. In particular, all of the patients in their 20s in the present study exhibited misery perfusion in the affected hemisphere. Several investigators have suggested that older patients with MMD who first present with ischemic cerebrovascular events between the ages of 30 and 60 years can be classified into two categories: disease still progressing even in adulthood, and addition of atherosclerotic burden to disease arrested in childhood [7‒10, 27]. Whereas the symptomatic hemisphere in the former exhibits misery perfusion with high probability that in the latter does not have such hemodynamics [7‒10, 27]. Pediatric patients, especially young patients (age <4 years), frequently show rapid disease progression leading to extensive cerebral infarction at the time of onset while waiting for surgical treatment, sometimes even in the early postoperative period [28]; the symptomatic hemisphere in these pediatric patients may also exhibit misery perfusion. Thus, in the patients in their 20s in the present study, steno-occlusive arterial lesions might have been in progress at inclusion, which could have resulted in the development of misery perfusion in the symptomatic hemisphere, even if the speed of this progression was slower in patients in their 20s than in pediatric patients.

None of our patients in their 20 s developed recurrent ischemic episodes in the cerebral hemisphere ipsilateral to revascularization surgery during the 3-year follow-up. Several investigators have suggested that while medical treatment alone may be insufficient for improving misery perfusion and result in considerably poor outcomes in older adult patients with misery perfusion due to ischemic MMD [9], revascularization surgery may resolve misery perfusion [29] and prevent the recurrence of ischemic episodes during a 5-year follow-up in such patients [15]. Considering our data and previous suggestions, in principle, patients in their 20s with ischemic MMD should undergo revascularization surgery.

In the present study, the following treatment outcomes were approximately equal between younger and older patients: the incidences of cerebral hyperperfusion syndrome and a resultant decrease in cognition after combined revascularization surgery; the incidences of sufficient collateral circulation formed from the external carotid artery, decreased cognition, and improved cognition after indirect revascularization surgery alone. Furthermore, whereas the incidence of sufficient collateral circulation formed from the external carotid artery was high and approximately equal among cerebral hemispheres receiving combined revascularization surgery and indirect revascularization surgery alone in patients in their 20s, the incidence of decreased cognition tended to be higher in cerebral hemispheres receiving combined revascularization surgery than in those receiving indirect revascularization surgery alone in such patients. In addition, patients with cerebral hyperperfusion syndrome following combined revascularization surgery did not return to their original educational institution because of cognitive decline. These findings suggest that indirect revascularization surgery alone rather than combined revascularization surgery may be more desirable, even for patients in their 20s.

As the combined administration of the Japanese traditional medicines, Keishi-bukuryo-Gan and Ji-daboku-Ippo, has been shown to reduce postoperative soft tissue swelling in adult patients undergoing revascularization surgery for ischemic MMD [19], we postoperatively administered these medicines to patients in their 20s undergoing indirect revascularization surgery alone. As a result, although a transient ischemic attack occurred in only one cerebral hemisphere in 1 patient, it did not lead to cognitive decline. This postoperative ischemic complication rate (10%) was comparable with that reported in patients undergoing combined revascularizations surgery without administration of Japanese traditional medicines [30].

The present study has several limitations. First, the sample size of patients in their 20 s with ischemic MMD was quite small; however, the prevalence of patients with ischemic MMD is inherently low. Further, as described above, regarding the age of initial onset of ischemic MMD among patients aged <60 years, patients in their 20 s are at the bottom of the distribution [2]. Second, the 3-year follow-up period in the present study was insufficient to assess the clinical course of MMD. Finally, this study was performed prospectively, but not randomly. To compare cognitive outcomes between combined revascularization and indirect revascularization alone for adult patients with ischemic MMD, including patients in their 20 s, a prospective randomization trial would be of benefit.

Patients in their 20s with ischemic MMD always exhibit misery perfusion in the affected hemisphere, unlike older patients, and occasionally develop cerebral hyperperfusion syndrome following combined revascularization surgery, leading to cognitive decline, similar to older patients. In addition, in patients in their 20s, indirect revascularization surgery alone forms sufficient collateral circulation and restores cognitive function, similar to older patients.

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. H23-45). All patients provided written informed consent prior to participation. For a vulnerable patient, written informed consent was obtained from the patient’s legal guardian. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

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.

This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (21K09108 and 21K09157) and Grants-in-Aid from the National Hospital Organization Kamaishi Hospital KENKYUHI.

Yutaro Ono, Yosuke Akamatsu, and Kuniaki Ogasawara: 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. Shizuka Araya, Masakazu Kobayashi, and 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. Ryouga Yamazaki: conception and design; revising 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. Takahiro Koji, Kazunori Terasaki, and Kohei Chida: 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.

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.