Moyamoya disease is a group of cerebrovascular diseases characterized by progressive stenosis or occlusion of the ends of the internal carotid arteries bilaterally and the formation of an abnormal vascular network at the base of the skull. Japanese scholars Takeuchi and Shimizu first reported this disease as internal carotid artery hypoplasia in 1957, and in 1967, Jiro Suzuki proposed to name it as smog disease.
1.Epidemiological study
The disease is rare in Europe and the United States, but more frequent in Asia, especially in Japan, followed by China, and also reported in Korea and Southeast Asia. The incidence of this disease in Japan is 0.35/100,000, and 100 new patients will appear every year. The incidence of female is 1.7 times that of male, and about 8.82% of the cases can have family history, such as mother and son, brothers and sisters, and even twins have been reported, suggesting a certain genetic tendency. With the application of MRI and MRA, there is a tendency for the family incidence to increase. There are two peaks in the age of onset: in children under 10 years of age and in adults around 40 years of age.
2. Etiological studies
The etiology of smoker’s disease is still unknown and has been controversial. The presence of congenital and thrombophilia increases the occurrence of smog, and it is believed that the occurrence of smog is related to viral infection.
2.1 Genetics: The high incidence in Asian countries such as Japan and Korea, the characteristic of Japanese and Caucasian races with a family history (6-10% of smog cases have a family history) and reports of simultaneous onset in some twin brothers or sisters suggest that smog formation may be genetically related.
Ikeda et al. performed a genealogical analysis, genome-wide screening and linkage analysis of 16 families with smog disease, and found that chromosome 3p24 and 2-p26 regions were linked to familial smog disease.
2.2 Cell growth factors: Immunoreactivity of cell growth factors associated with smooth muscle cells and vascular neogenesis was measured in the cerebrospinal fluid of smog patients, and bFGF, PDGF, and MCP-1 were found to be significantly stronger than controls. Subsequent quantification of basic fibroblast growth factor (bFGF) in cerebrospinal fluid revealed that bFGF was 101 pg/ml in the cerebrospinal fluid of patients with smog and only 8 pg/ml in patients with atherosclerosis, whereas no bFGF was detected in the cerebrospinal fluid of patients with cervical spondylosis. immunohistochemical studies of the superficial temporal artery (STA) in smog revealed that the immunoreactivity of bFGF and its receptors The immunohistochemical study of the superficial temporal artery (STA) in smoker’s disease revealed a significant increase in the immune activity of bFGF and its receptors. Combined with the biological activity of bFGF itself, it is hypothesized that increased secretion of bFGF by vascular endothelial cells, smooth muscle cells or adjacent astrocytes in cerebral Willis causes the proliferation of endothelial cells and smooth muscle cells in the arteries of the internal carotid artery system, resulting in luminal narrowing or occlusion, as well as release into the cerebrospinal fluid, which circulates with the cerebrospinal fluid to the brain surface, leading to the formation of an abnormal vascular network at the skull base and between the dura mater and the brain surface. . In further studies, it was confirmed that bFGF is specifically increased, but in the study of unilateral type of smog, it was found that the bFGF level was low and not significantly different from the control, and it is speculated that the onset of such patients may be different from the typical cases of bilateral lesions, and the exact explanation needs to be studied in depth.
2.3 Infection, inflammation and immune response: Some studies have suggested that smog may be associated with viral or bacterial infections. Inoue et al. used DNA typing to find a close relationship between certain human leukocyte antigen (HLA) secondary sequences and smog, while Masaru et al. found that HLAB51, HLA-B67 and HLA-DR1 were significantly more frequent in smog patients than in normal controls. The analysis by logistic regression showed that HLAB-51 was significantly associated with smog.
Masuda et al. studied six autopsy specimens from patients with smog and confirmed by immunohistochemical staining that the intimal hyperplasia in the intracranial arterial trunk of patients with smog was mainly smooth muscle cells with macrophage and T lymphocyte infiltration, and that the majority of these cells were located in the superficial layer of the intima. The majority of these cells were located in the superficial layer of the intima.
3.Pathological study
The basic pathological changes of smoker’s disease are hyperplasia and thickening of the endothelial cells of the internal carotid artery and its branches, flexion and thickening of the intravascular elastic plate, which can be dissected as the disease progresses, and proliferation and degeneration of the smooth muscle cells of the intima, leading to narrowing and even occlusion of the lumen of the vessel. Previously, the disease was thought to be limited to the internal carotid artery system, but recent studies have found very similar pathological changes in the posterior cerebral artery, superficial temporal artery, middle meningeal artery, and even in the coronary artery, pulmonary artery, and renal artery. External carotid angiography shows that 20% of patients with smog have stenosis of the superficial temporal artery and middle meningeal artery, thus suggesting that smog is a systemic disease, but also related to local factors (e.g., hemodynamics) of the arterial ring at the base of the brain.
Immunohistochemical studies revealed positive staining for basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in the thickened and stenosed internal carotid arteries, while controls were negative. The presence of bFGF and its receptors on arterial smooth muscle cells and endothelial cells in the superficial temporal artery and meninges, and the important role of bFGF in regulating the proliferation, migration and invasion of vascular endothelial cells and smooth muscle cells, led to the hypothesis that bFGF is related to the pathogenesis of smog disease.
4.Clinical study
4.1 Clinical manifestations: pediatric patients have mainly ischemic symptoms, mostly transient ischemic attack (TIA), such as ischemia, motor, sensory and speech impairment in the middle cerebral artery region. Posterior cerebral artery ischemia visual impairment. Ischemia of the lower extremity motor and sensory impairment in the region of the anterior cerebral artery. Characteristically, these symptoms are mostly induced when crying, eating hot food, blowing up balloons, and other excessive breathing. The above symptoms are not only recurrent, but also frequently change from left to right side because of bilateral brain tissue involvement. When the disease progresses to cerebral infarction or cerebral atrophy, it shows mental retardation or corresponding neurological dysfunction. Thus, early diagnosis and early treatment before the appearance of severe cerebral infarction will significantly change the prognosis. Intracranial hemorrhage in pediatric patients is very rare. About half of the adult patients develop intracranial hemorrhage, but a careful history reveals signs of cerebral ischemia in the pediatric period. 70% to 80% of hemorrhages are due to rupture of the fragile smoldering blood vessels. Most of the bleeding occurs in the area of the penetrating branches of the basal ganglia, often breaking into the ventricles to form intraventricular hemorrhage, 40% in the basal ganglia, 15% in the thalamus, or 30% in the ventricles, followed by subarachnoid hemorrhage, usually due to rupture of the combined aneurysm. The prognosis of these patients is worse than that of ischemic patients, with rebleeding being the primary prognostic factor. There is a relationship between rebleeding and age, and the risk of rebleeding gradually increases in those aged 46 to 55 years.
4.2 Diagnosis
4.2.1 Diagnostic criteria for the imaging of smoldering disease: (1) stenosis or occlusion of the terminal internal carotid artery and the proximal anterior cerebral artery (ACA) and middle cerebral artery (MCA); (2) formation of an abnormal vascular network at the base of the skull; (3) extensive intracranial and external arterial anastomosis with bilateral involvement.
Routine cerebral angiography is necessary for the diagnosis of smog. In addition to the above-mentioned changes, soft meningeal vessels as collateral circulation or dural vessels of the external carotid artery system can be seen. In addition, for bloodstream reconstitution, not only double internal carotid arteriogram but also double external carotid arteriogram and vertebral arteriogram should be performed for angiography because external carotid arteriogram such as superficial temporal artery is used.
4.2.2 According to the location of smoldering neovascularization, the disease can be divided into the following four types: (1) basal type: the most common and typical type, due to the lesion of the intracranial segment of the ICA resulting in the formation of abnormal reticular vessels at the base of the brain, and the course of the disease develops according to Suzuki’s classification, as shown in Table 1; (2) sieve type: the anterior cranial fossa base and orbital roof reticular vessels with dilated collateral vessel formation and vaulted smoldering vessels, which are mainly supplied by branches of the ophthalmic artery. This type can gradually change to the basal type; (3) vault type: intracranial and extracranial vessels communicate through the dura and soft meninges on the side branches; (4) posterior circulation type: narrowing or occlusion of the PCA occurs causing compensatory side branch formation in the posterior cranial fossa.
With the development of MRI and MRA in recent years, the diagnosis of smoldering disease has been made easier with the help of MRA, which may be free of invasive stenosis or occlusion, but abnormal smoldering vessels are usually unsatisfactorily shown on MRA, whereas MRI is helpful in showing flow-space images of smoldering vessels in the basal ganglia and thalamic areas. Whether it is cerebral angiography, MRI or MRA, the imaging presentation must meet the above 3 criteria to reach a final diagnosis. Special attention should be paid to cases with unilateral ICA involvement, especially in pediatric patients, who show similar changes contralaterally after 1 to 2 years of follow-up. In adults, however, they are not obvious.
CT may show cerebral hemorrhage, cerebral infarction, and cerebral atrophy. About 40% of patients presenting with ischemic symptoms may show normal CT examinations. Hypodense areas may also be seen, often confined to the cortex or subcortex. The hypointense areas tend to be multiple and bilateral, especially in the area of the posterior cerebral artery supply, and are more common in children. Spiral CT allows for three-dimensional reconstruction of blood vessels to visualize lesions in the cerebral vasculature.
Smoldering disease has become a unique cerebrovascular disease of unknown etiology, but several other diseases are known to have vascular changes similar to smoldering disease, such as atherosclerosis, autoimmune system diseases, meningitis, Down’s syndrome, head trauma, and others. These diseases are sometimes called pseudosmogranuloma or smog syndrome, and we should pay attention to strictly distinguish the above diseases when making the diagnosis of smog.
4.3 Laboratory tests
4.3.1 Electroencephalography (EEG): The typical feature of EEG in pediatric patients with smog is the presence of a slow wave of Rebuild Up for 20-60 seconds after hyperventilation, called the “Rebuild Up phenomenon”, which is associated with reduced perfusion of ischemic brain tissue. When cerebral ischemia is improved and cerebral perfusion is increased through blood line reconstruction surgery, the rebound phenomenon can disappear, and this can be used as one of the indicators to evaluate the effect of surgery. However, hyperventilation and increased load may induce cerebral ischemic attack, so this experiment should be conducted with caution.
4.3.2 Cerebral blood flow examination: Cerebral blood flow can be examined by SPECT, PET, XeCT and so on. At present, 99mTc HM-PAO is mostly used for simple SPECT. PET can not only measure cerebral blood flow, but also oxygen metabolism, glucose metabolism, and cerebral blood volume. In pediatric smoker’s disease, the typical case Misery Perfussion, due to progressive stenotic lesions, shows reduced cerebral blood flow, unchanged oxygen metabolic rate, hyper-oxygen uptake rate, and increased cerebral blood volume. In addition, there is mostly a decrease in cerebral circulatory reserve energy, and the usual response of increased cerebral blood flow is not seen, even when acetazolamide load is given. On the other hand, it is not uncommon to see normal cerebral blood flow in the interval of TIA.
Doppler ultrasonography (CDE, CDFI, TCD) provides a more complete picture of the altered cerebral hemodynamics in smog. The internal carotid artery (ICA) in patients with smog disease exhibits a set of high-resistance spectra, whereas the external carotid artery (ECA) shows low-resistance changes. The pediatric type relies primarily on the compensatory posterior cerebral artery (PCA) for blood supply, whereas the adult type has significantly faster blood flow in the ophthalmic artery. Further study of the external carotid artery system revealed that the superficial temporal artery (TSA) had a more pronounced decrease in resistance and extremely fast flow velocity, and that the superficial temporal artery more accurately reflected the hemodynamic characteristics of the external carotid artery system than the beginning segment of the external carotid artery. Using energy Doppler ultrasound (CDE), smoldering vessels can be found to be punctate and their low-velocity, low-resistance flow can be measured.
4.4 Treatment: There are two types of treatment for smoldering disease: medical medication and surgical treatment. Internal treatment can be attempted with antiplatelet drugs, but they do not inhibit the progression of the lesion or increase cerebral blood flow; their purpose is to prevent thrombosis or embolism that accompanies stenotic lesions. After hematologic reconstructive surgery, aspirin may be given orally if symptoms such as TIA still do not improve.
Surgical treatment is further divided into two types of surgery: direct hemodialysis and indirect hemodialysis.
4.4.1 Pathophysiological basis of surgical treatment: In pediatric patients, cerebral ischemia is the main manifestation, while adults show different forms of intracranial hemorrhage symptoms due to the rupture of abnormal blood vessels proliferating at the skull base. Since the etiology is unknown, the treatment is mainly symptomatic. When cerebral blood flow examination reveals a significant decrease in cerebral blood flow in smog, then direct methods to increase cortical cerebral blood flow are available, and direct revascularization is based on this.
The abnormal vascular network formed at the skull base in smog is a compensatory change in cerebral ischemia due to narrowing or occlusion of the internal carotid artery. Its main sources are.
(1) The already narrowed or occluded ends of the internal carotid and posterior cerebral arteries.
(2) anastomosis of the ophthalmic and sieve arteries with extracranial vessels; (3) originating from the dural vessels. Under normal conditions, the formation of collateral circulation between the extracranial and cortical vessels is limited, and indirect blood flow reconstruction is performed to create conditions for such collateral circulation. In addition, the formation of collateral circulation vessels can reduce intracranial hemorrhage caused by microaneurysm formation and rupture due to abnormal smoke vasodilation at the skull base.
4.4.2 Surgical methods
4.4.2.1 Direct revascularization: i.e., direct anastomosis between extracranial vessels and cortical vessels. The blood supply artery is the superficial temporal artery (STA), and the middle meningeal artery (MMA) and occipital artery (OA) are also selected. The most commonly used surgical procedure is the STA-MCA anastomosis. The STA-MCA anastomosis was pioneered by Yasargil in 1972 for the treatment of atherosclerotic cerebrovascular disease and by Krayenbiihl in 1975 for the treatment of smoker’s disease, which has since become the traditional procedure for this disease. The advantage of this method is that it can immediately change the blood supply to the recipient area to make the symptoms relieved. The disadvantages are: (1) the cerebral vessels in this disease are thin and fragile, so the surgical technique is demanding, difficult to anastomose, and traumatic; (2) the original dural cerebral collateral circulation is destroyed; (3) the STA or the anastomosed MCA branches are narrowed or occluded, so the long-term effect is difficult to be sure; (4) the effect of anastomosis of one or two vessels is sometimes not very satisfactory; (5) the improvement of blood supply in the distribution areas of the anterior and posterior cerebral arteries is not (5) The improvement of blood supply in the distribution area of the anterior and posterior cerebral arteries is not obvious. Recently, anastomosis of the STA with the ACA has been reported, resulting in improved blood supply to the frontal lobe, but the procedure is more difficult.
4.4.2.2 Indirect revascularization: (1) brain-temporal muscle patching (EMS): Henscher pioneered this procedure in 1950, and it was later used by Karasawa et al. for the treatment of smoker’s disease, and the blood supply mainly comes from the deep anterior middle and posterior temporal arteries. Disadvantages of EMS: compression of brain tissue by the temporalis muscle; risk of postoperative seizures; destruction of established collateral circulation; slow improvement of blood supply after surgery; no direct improvement of ischemia in the anterior and posterior cerebral arteries. (2) Dural-arterial applanation (EDAS): Created by Matsushima in 1981, the frontal or parietal branch of the STA is selected according to the site of the ischemic cortex, and a tendon-arterial flap is formed near it (the distal end is not cut off) and sutured to the cut dural edge through a slender bone window. The procedure is simple, short, less traumatic, and does not destroy the formed collateral circulation, which makes it especially suitable for pediatric cases and is one of the most popular procedures at present. (3) Cerebral-dural-arterial-muscular apposition (EDAMS): This procedure was first reported by Kinugasa et al. Based on EDAS, the dura mater is cut in a serrated pattern along the middle meningeal artery, and the temporalis muscle is fixed to the free dural edge on the parietal side, in addition to suturing the parietal branch of the STA to the dural incision. The advantage of this method is that both the STA and MMA and the deep anterior middle and posterior temporal artery supplying the temporalis muscle are used as blood supply arteries, which facilitates the formation of a more extensive collateral circulation. (4) Brain-large omental patch (EOS): Brain-large omental patch (EOS) can be divided into free patch (large omental intracranial graft) and tipped large omental patch (large omental transfer). The greater omental graft was used successfully by Karasawa in 1980 for the treatment of smog, and later by Miyamato et al. for the treatment of smog with a predominantly posterior circulation ischemia. In this procedure, the greater omentum is first intercepted in the abdominal cavity, then the superficial temporal artery/vein or occipital artery/vein is freed in the temporal or occipital region, and it is anastomosed with the freed gastric and duodenal arteries/veins, and the greater omentum is successfully applied to the temporal or occipital cortex. The greater omentum is transferred from the abdominal cavity to the head through a subcutaneous tunnel with a vascular tip and is applied to the brain surface. These two methods are less commonly used nowadays because of the poor surgical results. However, some scholars recommend this procedure for patients who have failed STA-MCA or EDAS treatment, especially for those with ischemic symptoms in the area of the anterior or posterior cerebral artery distribution. The indirect revascularization approach described above is intended to improve blood flow in the middle cerebral artery but not in the distribution of the anterior cerebral artery, and can be corrected by: (i) drilling a hole in the top of the frontal area and opening the dura and arachnoid beneath it, i.e., multiple skull drilling. (2) Banded EDAS: Placement of tipped capitellum into bilateral longitudinal fissures. (5) Stellate ganglionectomy (supracarotid sympathectomy) and peri-carotid sympathectomy have not been shown to permanently increase cerebral blood flow.
Although statistical results of randomized grouping of large cases comparing the effects of surgical treatment with drug treatment have not been obtained, there have been reports of small samples in which surgical treatment is superior to drug treatment, and surgical treatment has now become mainstream. In Japan, in 1994, direct hemorrhage reconstruction accounted for 20%, indirect hemorrhage reconstruction for 36%, combined surgery for 20%, and drug therapy for 23%. Direct hemorrhage reconstruction can increase local cerebral blood flow and reduce ischemic attacks in ischemic patients, and the treatment results are better than drug treatment. In the treatment of hemorrhagic cases, the mortality rate of drug therapy is higher than that of surgical treatment, but surgical treatment does not prevent or reduce the occurrence of rebleeding, so there is no clear and effective treatment for hemorrhagic smoldering disease.
In the choice of surgical method, if conditions permit, try to adopt direct revascularization or combine with a kind of indirect revascularization. For younger children, indirect revascularization is appropriate because the lumen of superficial temporal artery is thin, the vascular anastomosis is difficult, and the possibility of restenosis exists. The improvement rate for pediatric patients is 82% and the mortality rate is 1%; for adult patients, the improvement rate is 31% and the mortality rate is 6%. All pediatric ischemic types are susceptible to revascularization, especially the proportion of young-onset cases migrating to severe cerebral infarction is high, and early diagnosis and timely surgery are essential.
In 2005, some scholars reported that brain-temporal muscle apposition surgery was performed in a rat model of chronic cerebral ischemia, and human vascular endothelial growth factor (ph-VEGF) was given at the same time, and it was found that the number and area of neovascularization between the brain and temporal muscle were 2.2 times and 2.5 times of the control, respectively, which suggested that human vascular endothelial growth factor might provide a new way for the treatment of smog disease, and also proposed Surgery combined with modern biological means to treat the disease is a new idea.
4.5 Prognosis: The mortality rate of adult-type smog (about 10%) is higher than that of juvenile-type smog (about 4.3%). Fifty-six percent of adolescents die from cerebral hemorrhage, compared to 63% of adults. 58% of patients treated have a good prognosis.
There is a growing body of research on gene therapy for CNS ischemic diseases, which is mostly limited to the animal stage. With the development of genetic engineering technology, it is expected that gene therapy can be used to prevent stenosis or occlusion of the internal carotid artery, promote angiogenesis in ischemic brain tissue, and find a good adjunct or even alternative to surgical treatment.