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Stroke. 1996;27:1750-1754

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(Stroke. 1996;27:1750-1754.)
© 1996 American Heart Association, Inc.

Articles

Early Development of Intimal Thickening in Superficial Temporal Arteries in Patients With Moyamoya Disease

Masaru Aoyagi, MD; Naomi Fukai, MD; Mari Yamamoto, PhD; Kazuhiko Nakagawa, MD; Yoshiharu Matsushima, MD Kiyotaka Yamamoto, PhD

the Department of Neurosurgery, Tokyo Medical and Dental University (M.A., K.N., Y.M.), and the Department of Cell Biology, Tokyo (Japan) Metropolitan Institute of Gerontology (M.A., N.F., M.Y., K.Y.).

Correspondence to Masaru Aoyagi, MD, Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
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Background and Purpose Moyamoya disease is a progressive cerebrovascular occlusive disease that occurs in children. The etiology is unknown. We examined the superficial temporal arteries from patients with moyamoya disease, particularly children, to determine whether the extracranial arteries as well as the intracranial arteries are involved in this disease.

Methods Small branches of the superficial temporal arteries were obtained from 22 patients with moyamoya disease during indirect arterial bypass surgery. Histological examinations were performed, and the findings were compared with those of arteries from 12 control patients.

Results Intimal thickening was observed in 9 of 17 patients with moyamoya disease younger than 20 years but in none of 7 control patients under the age of 20 years (P<.02, Fisher's exact test). Intimal thickening appeared from age 20 years in control patients. The arteries of moyamoya patients showed fibrocellular intimal thickening with a paucity of lipid. The arteries from moyamoya patients contained strongly stained multilayered elastic fibers in the thickened intima, while those from control patients showed only weakly stained elastic fibers in the intima.

Conclusions Our findings suggest that moyamoya disease is a systemic vascular disease. The results indicate systemic etiologic factors that may promote the early development of intimal thickening in moyamoya disease.


Key Words: arterial wall • etiology • histology • moyamoya disease


*    Introduction
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 up arrowAbstract
 *Introduction
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Moyamoya disease is a rare cerebrovascular occlusive disease characterized by progressive stenosis or occlusion at the distal ends of bilateral internal carotid arteries.1 2 An unusual vascular network at the base of the brain (moyamoya vessels) is considered to represent collateral channels formed as a result of progressive ischemic changes in the brain.3 The highest incidence of the disease is noted during the first decade of life, and the most common clinical manifestation in children is alternating hemiparesis due to cerebral ischemia.4 The etiology of the disease is not known. That the incidence of the disease is highest in, but not confined to, Japanese5 6 and that the condition is frequently familial7 8 suggest the involvement of a genetic factor in its pathogenesis.

Histopathologic investigations on autopsy subjects9 10 11 12 have demonstrated that the main vascular lesion in moyamoya disease is stenosis or occlusion by fibrocellular intimal thickening with multilayered elastic lamina and few lipid deposits. Previous reports have suggested the involvement of systemic arteries as well as intracranial arteries in moyamoya disease.9 13 14 15 16 However, these studies have examined arteries mainly from adult moyamoya patients. It may be difficult to make an accurate comparison between the arteries of adult moyamoya patients and control subjects because of the presence of atherosclerotic changes in the arteries.

In the present study we examined the branches of superficial temporal arteries obtained during indirect bypass surgery in moyamoya patients, particularly children. We histologically examined whether there is a significant difference between moyamoya patients and control subjects in the development of intimal thickening in one of the systemic arteries.


*    Subjects and Methods
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 up arrowIntroduction
 *Subjects and Methods
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Patient Population
From 1992 to 1995, 30 patients were newly diagnosed with moyamoya disease at our institution and underwent indirect arterial bypass surgery (encephaloduroarteriosynangiosis [EDAS]17 ). Moyamoya disease was confirmed by cerebral angiography, which showed bilateral stenosis or occlusion of the distal portions of the internal carotid arteries and moyamoya vessels near the circle of Willis.4 18 Cerebral angiograms of moyamoya patients were classified according to the angiographic staging system proposed by Suzuki and Kodama.3 4 Angiographic staging was defined from stages 1 to 6 according to the degree of basal moyamoya vessels and the degree of stenosis or occlusion of main cerebral arteries: stage 1, narrowing of carotid fork; stage 2, initiation of basal moyamoya vessels; stage 3, intensification of moyamoya vessels with defection of middle and anterior cerebral arteries; stage 4, minimization of moyamoya vessels with defection of posterior cerebral arteries; stage 5, reduction of moyamoya vessels with disappearance of all main cerebral arteries; and stage 6, disappearance of moyamoya vessels.

Small branches of superficial temporal arteries were obtained from 22 patients with moyamoya disease. Because main branches of the superficial temporal artery must remain intact during an EDAS procedure, we took small side branches for histological examination. These 22 patients form the basis of this report. Arterial specimens were also obtained from small branches of the superficial temporal arteries during other cranial operations on 12 patients who were confirmed not to have moyamoya disease by cerebral angiography or MR angiography. These specimens were used as controls. The size and location of arteries obtained from control patients were almost similar to those from moyamoya patients. Informed consent was obtained from the patients or their relatives, and the study was approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology.

Patients with moyamoya disease comprised 14 females and 8 males. The mean±SD age of the 22 moyamoya patients was 14.9±14.4 years, ranging from 2 to 55 years: 11 patients were under the age of 9 years, 6 patients were between the age of 10 and 19 years, and 5 patients were older than 20 years. The primary disease in the control patients was head injury in 2, brain tumor in 3, cerebral vascular disorders other than moyamoya disease in 5, and cranial bone disease in 2 patients. Control patients comprised 5 females and 7 males. The mean±SD age of the control patients was 17.9±13.5 years, ranging from 1 to 52 years: 2 patients were under the age of 9 years, 5 patients were between the age of 10 and 19 years, and 5 patients were older than 20 years.

Histological Examination
The arterial specimens were fixed in 4% paraformaldehyde in 0.1 mol/L phosphate buffer, pH 7.4, for 24 hours at 4°C, dehydrated in graded ethanol, and embedded in paraffin. Four-micrometer sections were prepared on silanized slides. After deparaffinization in xylene and rehydration in graded ethanol, serial sections were stained with hematoxylin and eosin. Sections were also stained with resorcin-fuchsin for the detection of elastin. Sections were immunostained with primary antibodies for muscle actins (HHF35,19 Dako), for macrophages (PG-M1, Dako), and for von Willebrand factor (Dako) to identify cells in the thickened intima. Sections were incubated for 60 minutes at room temperature with the primary antibodies, then reacted with biotinylated link antibody, and finally reacted with peroxidase-labeled streptavidin. The sections were finally developed with diaminobenzidine.

Some of the arterial specimens were fixed with 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer, pH 7.2, at 4°C for 16 hours, then washed with cacodylate buffer. The specimens were postfixed in 1% OsO4 at room temperature for 1 hour, dehydrated in a graded series of ethanol, displaced with propylenoxide, and embedded in Epon 812 (Nissin EM, Tokyo). Thin sections (1 µm) were stained with toluidine blue and examined with a Vanox microscope (Olympus).

Statistical Analysis
Fisher's exact and {chi}2 tests were used to compare the frequency of intimal thickening between moyamoya and control patients. Parametric clinical data were expressed as mean±SD. Differences in these data between groups were assessed with unpaired Student's t test. The angiographic staging in the different groups of moyamoya patients was compared by the Mann-Whitney U test. A value of P<.05 was considered statistically significant.


*    Results
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 *Results
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Clinical information on patients with moyamoya disease, including the type of stroke and the duration of symptoms, is shown in the TableDown. No associated disease was found in any of the 22 patients with moyamoya disease.


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  		Table 1. Clinical Characteristics, Angiographic Staging, and Intimal Thickening of Superficial Temporal Arteries in Patients With Moyamoya Disease

Intimal thickening of the arteries was found in 9 of 17 moyamoya patients (52.9%) but in none of 7 control patients younger than 20 years (P<.02, Fisher's exact test, Fig 1Down, Table). Intimal thickening was observed in 2 of 4 moyamoya patients younger than 5 years of age. In patients older than 20 years, intimal thickening was found in 4 of 5 patients with moyamoya disease and in 4 of 5 control patients. Three control patients who had intimal thickening in the superficial temporal arteries were in their twenties, suggesting that intimal thickening due to atherosclerosis had already developed during the third decade of life.



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  		Figure 1. Development of intimal thickening in the superficial temporal arteries of patients with moyamoya disease and control subjects. Data from 22 patients with moyamoya disease and 12 control patients were plotted according to age and the presence or absence of intimal thickening in the superficial temporal arteries. The frequency of intimal thickening observed in moyamoya patients (9 of 17) was significantly greater than that in control subjects (0 of 7) in subjects younger than 20 years of age (P<.02, Fisher's exact test).

The clinical and angiographic findings were examined for correlation with the presence or absence of intimal thickening of the superficial temporal arteries in moyamoya patients (TableUp). The means of the age at bypass surgery, age at onset, and duration of symptoms in moyamoya patients showing intimal thickening before 20 years of age were 8.4±4.4, 3.9±3.3, and 4.5±4.2 years, respectively, values not significantly different from those of moyamoya patients without intimal thickening (7.7±4.3, 4.8±2.4, and 3.0±3.1 years, respectively; unpaired t test). No significant correlation was found between the presence or degree of intimal thickening and angiographic staging in this series of moyamoya patients (Mann-Whitney U test). Stenotic lesions were seen on the angiograms in 6 of 22 moyamoya patients (27.3%; 1 in the superficial temporal arteries and 5 in the dural arteries) but in none in the control patients. No correlation was found between angiographic stenosis and the presence or absence of intimal thickening in the superficial temporal arteries.

The arteries of moyamoya patients showed fibrocellular intimal thickening with few lipid deposits, essentially the same as seen in the intracranial arteries of moyamoya patients (Fig 2Down). Among the young moyamoya patients examined here, intimal thickening was eccentric in 6 and diffuse in 3. Among the adults (above the age of 20 years), intimal thickening was diffuse in both moyamoya patients and control subjects. The degree of intimal thickening appeared essentially the same in adult moyamoya patients and adult control subjects. On immunohistochemical examination, the thickened intima of both moyamoya patients and control subjects was composed of smooth muscle cells except for endothelial cells in the luminal surface of the intima (Fig 3Down). No macrophages were found in the thickened intima of moyamoya patients or control subjects.



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  		Figure 2. Intimal thickening of the superficial temporal artery in a 13-year-old moyamoya patient (patient 8 in the TableUp). The cross section shows diffuse intimal thickening (toluidine blue stain; bar=30 µm).



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  		Figure 3. Immunostaining for muscle actins (A) and for von Willebrand factor (B) on cross sections from a 3-year-old female moyamoya patient (patient 2 in the TableUp). Endothelial cells in the superficial layer of the thickened intima (arrow) were positive for immunostaining for von Willebrand factor but were negative for muscle actins. I indicates intima; M, media. Arrowheads indicate external surface of the media. Bars=30 µm.

Resorcin-fuchsin staining showed that the intimal thickening in the arteries of moyamoya patients contained strongly stained multilayered elastic fibers, which are also characteristic of the intracranial arteries of moyamoya patients (Fig 4Down). In contrast, intimal thickening of the arteries of control patients showed only weakly stained elastic fibers in the intima. The formation of elastic fibers in the intima of arteries from moyamoya patients was seen even in focal or small intimal thickenings, suggesting the early formation of elastic fibers during the development of intimal thickening in moyamoya disease.



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  		Figure 4. Elastin staining of the superficial temporal artery with resorcin-fuchsin in a 3-year-old female moyamoya patient (patient 2 in the TableUp). The thickened intima contains strongly stained multilayered elastic fibers. Inset shows twofold higher magnification of the area indicated by the arrowhead. Bar=40 µm.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present study we demonstrated that the intimal thickening of superficial temporal arteries frequently appears in young patients with moyamoya disease (52.9%), while none of the young control patients studied showed intimal thickening in their arteries. Notably, intimal thickening was observed in 2 of 4 moyamoya patients aged younger than 5 years. The arteries of moyamoya patients showed fibrocellular intimal thickening with a paucity of lipid. Elastin staining showed strongly stained multilayered elastic fibers in the thickened intima of the moyamoya patients. These pathological findings are essentially the same as those of the thickened intima in the intracranial arteries of moyamoya disease. Our observations strongly suggest that moyamoya disease is a systemic vascular disease and has an etiologic factor that affects both intracranial and extracranial arteries.

Previous studies have shown that the extracranial arteries, particularly renal arteries, show similar stenosis with intimal thickening.9 13 14 15 16 Ikeda15 recently showed that the degree of intimal thickening in the systemic arteries of moyamoya patients was significantly greater than in the systemic arteries of age-matched control patients. Haltia et al9 and Li et al20 reported the presence of fibrocellular intimal thickening in the superficial temporal arteries obtained from moyamoya patients. However, these investigations were performed mainly with adult moyamoya patients or without sufficient control subjects. In the present study intimal thickening frequently appeared in control patients during the third decade of life. The atherosclerotic process is likely to become manifest and progress substantially in individuals aged between 15 and 34 years.21 22 Furthermore, intimal thickening may develop earlier in the superficial temporal arteries, which are frequently exposed to ultraviolet rays from the sun.23 The degree of intimal thickening was essentially the same between adult moyamoya and control patients. It is worthwhile in the present study to demonstrate the presence of intimal thickening in the superficial temporal arteries of moyamoya patients during early childhood.

In cerebral angiograms taken during the course of our study, stenotic lesions were seen in the superficial temporal arteries of 1 and in the dural arteries of 5 of the moyamoya patients. This is consistent with a previous report by Hoshimaru and Kikuchi,24 who found less frequent stenosis in the scalp arteries than in the dural arteries of moyamoya patients. No correlation was found between the angiographic findings and the presence of intimal thickening on histological examination. This may indicate the insidious occurrence of intimal thickening in the scalp arteries of moyamoya patients. Because our pathological examinations were limited to one or two small branches of the scalp arteries, the actual frequency of intimal thickening in the scalp arteries of moyamoya patients may be greater than observed in the present study.

The intimal lesions of the scalp arteries of moyamoya patients contained strongly stained multilayered elastic fibers that were distinct from those of the arteries of control patients. The formation of strongly stained elastic fibers was seen even in the early phases of intimal thickening observed in juvenile moyamoya patients. Previous reports have suggested that the recurrent microthrombi and subsequent organization may contribute to the layered structures separated by multiple elastic fibers in the thickened intima of moyamoya patients.10 15 25 However, the possibility still remains that microthrombus formation is secondary to the development of intimal thickening or to preceding chronic inflammation.15 26 Masuda et al26 recently showed that macrophages and T lymphocytes localize in the superficial layer of the intimal thickening of the intracranial arteries in moyamoya disease, suggesting a role of chronic inflammatory stimuli in smooth muscle cell proliferation in the thickened intima. We recently reported that moyamoya disease is associated with the HLA B51 phenotype and that moyamoya patients who have HLA B51 may be susceptible to a certain form of vasculitis through leukocyte activation.27 Cytokines inducible by inflammatory stimuli, particularly transforming growth factor-ß, may upregulate the expression of elastin gene and the elastin synthesis of smooth muscle cells during the development of intimal thickening in moyamoya disease.28 29 It is likely that unknown humoral factors or alterations in vascular cells30 31 may cause mild inflammatory stimuli leading to recurrent thrombus formation and subsequently to the development of intimal thickening in moyamoya disease.

It remains unclear why moyamoya disease affects specific anatomic sites in the intracranial arteries. The pathological process in the intracranial arteries of moyamoya patients is clearly more advanced than in the extracranial arteries. Our follow-up study of patients successfully revascularized with an EDAS procedure did not show progressive stenosis on arteriograms at the EDAS site after more than 10 years.32 This may indicate additional local factors promoting the pathological process in the basal vessels of the brain in moyamoya disease. One possibility is the presence of increased fluid shear stress around the terminal portion of the internal carotid arteries, which is the most frequently involved site in this disease. This increased fluid shear stress may cause increased permeability or activation of endothelial cells, leading to subsequent pathological processes in the development of intimal thickening of the arterial wall.33 34 Furthermore, Takahashi et al35 recently reported an increased concentration of basic fibroblast growth factor in the cerebrospinal fluid of moyamoya patients. This increased secretion of fibroblast growth factor in cerebrospinal fluid may also be a result of pathogenic factors affecting the basal vessels of the brain in moyamoya disease. Further studies are essential to elucidate the local as well as systemic etiologic factors involved in moyamoya disease.


*    Acknowledgments
 
This study was supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture, Japan.

Received February 19, 1996; revision received June 4, 1996; accepted June 18, 1996.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
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 *References
 

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