Moyamoya disease

To elucidate the initiation of Moyamoya disease, we analyzed the progression of angiographical stages in repeated angiographical studies. The clinical subjects consisted of 39 patients. Angiographical stages were classified by the criteria of Suzuki and Takaku. For examinations, conventional cerebral angiography or magnetic resonance angiography was performed. The follow-up period ranged from three months to 17 years. We found the following results. 7. Older patients presented with advanced angiographical stages. 2. Angiographical stages were usually progressive in pediatric patients, while stable in adult patients. In pediatric cases, the disease advanced to stage V within 10 years from the onset in the majority of patients. However, in certain cases the disease progressed after adolescence. 3. Among pediatric patients, certain cases, in whom the onset of the disease was later than five years of age, showed relatively slow progression of angiographical stages. Our data indicate that certain pediatric cases whose disease started after five years of age presented with stable temporal changes in the angiographical stages. These findings might indicate that in only a few adult cases does the disease initiate in adulthood and in the majority of adult patients the disease starts in childhood. [Neural Res 2003; 25: 405-410]

Keywords: Moyamoya disease; cerebral angiography; magnetic resonance imaging

INTRODUCTION

Moyamoya disease is a progressive occlusive cerebrovascular disease characterized by bilateral stenosis of the internal carotid arteries (ICAs) and the development of compensatory collateral vessels1,2. It most often affects pediatric patients, but also occurs in adults. The clinical presentations are different in pediatric and adult patients. While pediatric patients likely present with symptoms due to ischemia, adult patients often present with intracerebral hemorrhage. It has also been indicated that the disease is progressive and dynamic in childhood, whereas it becomes stable in adulthood2,3. These different clinical features might indicate the different pathogenesis of this disease in childhood and adulthood. However, several reports have indicated a linkage between these two types of the disease. It has been suggested that the initiation of the disease might occur in childhood, even in adult cases3,4. There have been few studies concerning the long-term follow-up of pediatric cases3,5 and it still remains unclear how this disease progresses after the initiation in childhood and whether Moyamoya disease might be initiated in adults.

Thus, in this study, we reviewed cases with Moyamoya disease, focusing on angiographical findings. Certain cases have had long-term follow-up with frequent angiographical studies. We analyzed the temporal profiles of the angiographical stages and investigated how Moyamoya disease progresses and when Moyamoya disease is initiated especially in adult cases. Although this study is retrospective and there are certain limitations in collecting and analyzing the data, there has been no longitudinal study on specific numbers of cases followed-up with frequent angiographical studies.

MATERIALS AND METHODS

Between 1983 and 2000, we experienced 39 patients with Moyamoya disease. Among them, 29 patients presented with ischemic symptoms as the initiation of the disease (transient ischemic attack (TIA) in 21 and complete stroke in eight). In the remaining 10 patients, eight patients presented with intracranial hemorrhage (including two patients who presented with subarachnoid hemorrhage due to rupture of associated basilar artery aneurysms). The two other patients were incidentally diagnosed. Both cases had a familial history of Moyamoya disease and magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) indicated the presence of the disease.

The onset of Moyamoya disease was defined by detailed interviews of illness history. The ischemic onset was defined as the time when patients initially had obvious neurological symptoms such as motor disturbance after hyperventilation. Other symptoms, such as usual headache or dizziness were not considered. In all 21 patients who presented with TIA, the initiation of TIA could be identified by interview from the patients and the family members. Among eight patients who presented with complete stroke, a previous episode of TIA was confirmed in two cases. Among adult patients with ischemic symptoms, a detailed interview of illness history strongly indicated childhood onset of the disease in three patients. These cases were considered as adult cases with pediatric onset.

The hemorrhagic onset was defined as the time when patients had headache or neurological symptoms with obvious radiological evidence of hemorrhage. All eight patients who presented with intracranial hemorrhage did not have any previous episodes suggesting a stroke had occurred. There was no interval between the age at initiation and at the diagnosis in cases with nonischemic symptoms. The ages at the initiation of the disease ranged from two to 49 years old. The distributions of age at the initiation of the disease and at the diagnosis are indicated in Tables 1 and 2.

In all cases, the diagnosis was confirmed by conventional cerebral angiographies. In two patients, the disease developed from unilateral involvement at the diagnosis to bilateral involvement. The other 37 patients presented with bilateral involvement at the initial diagnosis. Revascularization surgeries were performed in 29 patients shortly after the diagnosis. Indirect bypass surgeries were performed on 52 sides of 28 patients and direct bypass surgeries were performed on three sides of two patients.

Among the 39 patients, 34 received follow-up examinations. In the remaining five patients, three died shortly after the diagnosis (including two cases with subarachnoid hemorrhage) and the other two did not attend the follow-up examinations. The follow-up period ranged from three months to 17 years. Among 34 patients, 28 patients were followed-up for more than two years. For follow-up examinations, conventional cerebral angiography or MRA was performed. MRAs were performed by the three dimensional time of flight method using 1.5T Magnetome (Siemens, Germany). Because of the retrospective study, the interval and frequency of follow-up examinations were varied in each case. Usually, the operated patients received second conventional angiography to estimate the effects of surgical interventions within a year of the operation. Thereafter, the pediatric patients received the third conventional angiographies before they reached adolescence, usually at 14-16 years old. In three pediatric and four adult patients, additional conventional angiography was performed because there were possible episodes of recurrent stroke. In the other patients who did not have surgery, only one patient received repeated conventional angiographies because of possible episode of recurrent stroke. In addition to these, MRAs were performed for standard follow-up examinations. In 19 out of 34 patients, MRAs were performed annually as standard follow-up examinations and in the other 15 patients MRAs were performed occasionally. Thus, the 34 patients received 43 conventional angiographies and 71 MRAs during the follow-up examinations.

Angiographical stages were classified by the criteria of Suzuki and Takaku1,6 . These criteria depend on both the severity of stenosis of the major vessels that constitute the circles of Willis and the degree of formation of collateral vessels (Moyamoya vessels). Briefly, the criteria consisted of six stages:

1. Stenosis of the intracranial bifurcation of ICA.

2. Dilatation of the intracerebral arteries with Moyamoya vessels.

3. Stenosis of the middle and anterior cerebral arteries with increased Moyamoya vessels.

4. Disappearance of the middle and anterior cerebral arteries with fine Moyamoya vessels.

5. Disappearance of the intracerebral portion of ICA with shrinking of the Moyamoya vessels.

6. Disappearance of the Moyamoya vessels with collateral formation only from the external carotid artery.

For the classification of angiographical findings at the initial diagnosis, we used these criteria. In 15 patients, the angiographical stages were different in the right and left carotid angiographies. In one pediatric patient and one adult patient, only one side was involved at the diagnosis and the disease later progressed to the contralateral side. For these 15 cases, the stages were represented by those of advanced sides.

Since the principle pathophysiology of Moyamoya disease might be progressive stenosis of the major intracranial arteries, as the indicator of progression of the disease, we focused on the severity of stenosis of ICA. MRAs accurately represented these findings to determine the correct stages. Moreover, we compared findings of MRAs to those of conventional angiographies performed simultaneously, and there were accurate correlations in the severity of stenosis of ICA. Thus, for follow-up conventional angiographical and MRA findings, we aimed at the total occlusion of intracranial ICA, corresponding to stage 5 of the criteria of Suzuki and Takaku.

For statistics, the Student's t-test was used and data were considered as significant when p

RESULTS

Angiographical stages at the diagnosis (Table 3)

In 29 patients with ischemic onset, the angiographical stage was mainly 3 or 4. In one pediatric patient and two adult patients, the angiographical stage was already 5 at the diagnosis. Comparing the pediatric patients and the adult patients, the adult patients presented with significantly advanced angiographical stages (p

Among 10 cases with nonischemic onset, including two incidental cases, the stages were more advanced than 4 in seven patients. There was no obvious difference in the angiographical stages at the diagnosis between adult cases with ischemic onset and with nonischemic onset (p > 0.1).

The correlation between angiographical stages and the duration of the disease (Table 4)

In 29 patients with ischemic onset, the duration of the disease until the diagnosis ranged from 0 to 20 years. Only patients whose duration of the disease was less than three years presented with stage 3. Within two years from the onset, no patient presented with complete occlusion of the intracranial carotid arteries. In contrast, the long duration of the disease was not always associated with the progression of the disease and among five patients whose duration of the disease was more than 10 years, the angiographical stages remained at 4 in four patients. In three adult cases with pediatric onset, the initiation of the disease was at 7, 10 and 14 years of age. In two out of these three cases, the angiographical stages at the diagnosis remained at l4 after more than 12 years of the disease duration.

Long-term temporal profile of the angiographical stages (Tables 5 and 6)

The long-term temporal profile of the angiographical stages was analyzed in 28 patients who were followed-up for more than two years.

In one pediatric patient, the angiographical stage was 5 at the diagnosis. Among 21 pediatric patients and adult patients with pediatric onset, the angiographical stage was 5 at the diagnosis in one pediatric patient. Including this case, the angiographical stages developed to 5 or 6 in 12 patients (57.1%). Among nine patients in whom the stages did not develop to 5, three patients showed quite slow progression of the disease and the angiographical stages in these patients remained at 3 or 4 for more than 11 years after the initiation of the disease, with a maximum duration of 17 years (Table 5A). In all these three patients, the onset of the disease was later than five years old.

In 10 out of 14 patients whose angiographical stages were 5 at the diagnosis or at the follow-up examinations, the duration from the onset to the advancement to stage 5 was accurately estimated. In seven out of these cases, the disease advanced to stage 5 within 10 years from the onset. In three of the four remaining patients, although not exactly estimated due to sporadic examinations, the duration from the onset to the advancement to stage 5 was considered less than 10 years. Slow progression of the disease was observed only in patients with relatively older onset (Table 6).

In seven adult patients, only two patients showed progression of the angiographical stages and in these cases the angiographical stages reached 5 or 6 in the latest follow-up examinations. In the five other patients, the angiographical stages were stable and remained at 3 or 4 for a certain period (with a maximum duration of 16 years) (Table 5B).

In one adult patient who was not involved in the above seven cases, the disease developed rapidly from unilateral to bilateral involvement within a year from the onset, although the angiographical stage did not reach 5. In only this case, the initiation of the disease was definitely confirmed as adulthood.

Effects of revascularization surgeries on the advancement of the disease (Table 7)

In 41 sides of 22 patients who received revascularization surgeries, follow-up conventional angiographies were performed within a year. In 22% of the examined sides, there was obvious advancement of the disease, such as advancement of stages or progressive stenosis of the intracranial major vessels. In the pediatric patients, the immediate progression of the disease was significantly prominent compared to adult patients.

DISCUSSION

In this retrospective study, we found the following results.

1. Older patients presented with advanced angiographical stages.

2. Angiographical stages were usually progressive in the pediatric patients, while stable in the adult patients. In the pediatric cases, the disease advanced to stage 5 within 10 years from the onset in the majority of patients. However, in certain cases the disease progressed after adolescence.

3. Among the pediatric patients, certain cases showed relatively slow progression of angiographical stages. In these cases, including adult cases with pediatric onset, the onset of the disease was later than five years of age.

4. There was only one case whose onset of the disease was definitely confirmed as adult onset.

From previous studies concerning the progression of Moyamoya disease, it has been indicated that the disease is progressive and dynamic in childhood, whereas it becomes stable in adulthood1,3. However, there have been few studies based on longitudinal angiographical observations. From their experiences with nine cases, Ezura ef al.3 indicated that the disease progresses in angiographically-evident stages until adolescence and thereafter stabilizes after the patients reach adulthood. Houkin et al.4 also speculated that the disease progresses quickly during early childhood and becomes stable later in childhood and adolescence. However, these speculations were derived from a simple comparison of angiographical stages between pediatric and adult patients and they lacked temporal profiles of angiographical findings.

Our data might partly support these previous findings and speculations that the disease is progressive and dynamic in childhood, whereas it becomes stable in adulthood. However, our data indicate that Moyamoya disease is not always progressive even in childhood. Certain cases presented with slow temporal changes in the angiographical stages. Considering the presence of adult cases with pediatric onset, it might be that in certain pediatric cases with relatively older onset the disease could be slowly progressive and patients could reach adulthood with a minimum number of neurological episodes. Interestingly, in these cases, the disease started after five years of age.

There have been some controversies about the initiation of Moyamoya disease in adults. One theory is that in almost all cases the disease is initiated in childhood3,4. On the other hand, Ezura et al.3 indicated the presence of two different types of adult Moyamoya disease based on angiographical findings; one type with well-formed collateral circulation from the external carotid and vertebrobasilar arteries, and the other type with little collateral circulation from the external carotid and vertebrobasilar arteries. They speculated that in the latter type the initiation of the disease might be in adulthood and arteriolosclerotic changes might be attributable to causal genesis of these lesions. In our data, as described above, an adulthood start of the disease was highly possible in only one case. On the other hand, only one adult patient showed definite arteriosclerotic changes on the angiographies. The other adult patients were relatively young (less than 46 of age) and arteriosclerotic changes on the angiographies were minimum, if present at al. Thus, considering the relatively young ages of onset and the temporal profiles of the pediatric cases, it might indicate that the disease initiation occurs in childhood in the majority of adult patients.

Several reports have indicated adult patients with a rapid progression of Moyamoya disease, like our case7-9. These cases initially presented with unilateral involvement and later with bilateral involvement. These cases should definitely be differentiated from unilateral Moyamoya disease in adults without angiographical progression10. Thus, it is also suggested that in these cases the start of the disease might be in adulthood.

This study also indicated that Moyamoya disease does not always stabilize after adulthood and, in certain cases, again becomes progressive after long stable periods. However, in some cases, angiographical development of the diseases does not correlate with clinical presentations, and ischemic or hemorrhagic insults could occur without development of stages. Houkin et al.4 speculated that arteriosclerotic changes might be attributable to evoking ischemic or hemorrhagic insults in adult patients. However, the relatively young distribution of adult patients and minimum arteriosclerotic changes do not support this speculation. Although specific pathophysiology was indicated as the mechanism of hemorrhagic insults in adult cases2, the exact pathophysiology for clinical presentations in adult patients remains uncertain.

Since the majority of cases were surgically treated, analysis of the natural development of the disease was difficult. Moreover, we could not eliminate the effects of surgical interventions. Our data also indicated that revascularization surgery could affect the progression of the disease in some cases. For a better understanding of this unusual disease, collateral vessel formation should not be neglected. Thus, since we aimed at the progression of stenosis of ICA, it should be noted that we only observed modified development of Moyamoya disease. However, since the efficacy of revascularization surgery has been well recognized, especially in pediatric cases11-13, it should be hard to obtain long-term natural course of this disease. Furthermore another disadvantage was that our study was retrospective and there were some limitations in data sampling. To obtain accurate temporal profiles, longitudinal prospective studies with large numbers of cases are required.

REFERENCES

1 Suzuki J, Takaku A. Cerebrovascular 'Moyamoya' disease. Arch Neurol 1969; 20: 288-299

2 Suzuki J, Kodama N. Moyamoya disease - a review. Stroke 1983; 14: 104-109

3 Ezura M, Yoshimoto T, Fujiwara S, et al. Clinical and angiographic follow-up of childhood-onset Moyamoya disease. Childs Nerv Syst 1995; 11: 591-594

4 Houkin K, Yoshimoto T, Kuroda S, et al. Angiographic analysis of Moyamoya disease - How does Moyamoya disease progress? Neurol Med Chir (Tokyo) 1996; 36: 783-788

5 Takahashi A, Fujiwara S, Suzuki J. Long-term follow-up angiography of Moyamoya disease - Cases followed up from childhood to adolescence. No Shinkei Geka 1985; 13: 255-264 (Jpn)

6 Suzuki J, Takaku A, Asahi M. The disease showing the abnormal vascular net-work at the base of brain, particularly found in Japan. II. A follow-up study. No-to-Shinkei 1969; 18: 897-908 (Jpn)

7 Fujiwara F, Yamada Y, Hayashi S, et al. A case of adult Moyamoya disease showing fluminant clinical course associated with progression from unilateral to bilateral involvement. No Shinkei Geka 1997; 25: 79-84 (Jpn)

8 Tomida M, Muraki M, Yamasaki K. Angiographically verified progression of Moyamoya disease in an adult. J Neurosurg 2000; 93: 1055-1057

9 Wanifuchi H, Takeshita M, Aoki N, et al. Adult Moyamoya disease progression from unilateral to bilaterall involvement. Neurol Med Chir 1996; 36: 87-90

10 Houkin K, Abe H, Yoshimoto T, et al. Is 'unilateral' Moyamoya disease different from Moyamoya disease? J Neurosurg 1996; 85: 772-776

11 Choi JU, Kim DS, Kim EY, et al. Natural history of Moyamoya disease: Comparison of activity of daily living in surgery and non surgery groups. Clin Neurol Neurosurg 1997; 99 (Suppl 2): 11-18

12 Imaizumi T, Hayashi K, Osawa M, et al. Long-term outcomes of pediatric Moyamoya disease monitored to adulthood. Pediatr Neurol 1998; 18: 321-325

13 Olds MV, Griebel RW, Huffman HJ, et al. The surgical treatment of childhood Moyamoya disease. J Neurosurg 1987; 66: 675-680

Keisuke Ishii, Mitsuo Isono, Hidenori Kobayashi and Tohru Kamida

Department of Neurosurgery, Oita Medical University, Oita, Japan

Correspondence and reprint requests to: Mitsuo Isono, Department of Neurosurgery, Oita Medical University, 1-1, ldaigaoka, Hasamamachi, Oita, Japan 879-5593. [isonom@oita-med.ac.jp] Accepted for publication December 2002.

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