**2. Treatment modalities in moyamoya disease**

Without a known aetiology, the only treatment is symptomatic. The medical treatment does not affect this disease's relentless progression [103, 104], and patients under drug treatment alone have a 5-year 65% stroke risk [72, 105–107] which climbs up to a dismal 82% in case of bilateral involvement [105]. In children, it has been reported that under conservative treatment, 37% will present clinical symptoms of neurological damage, and 3% will eventually die [108]. It can be helpful, though, to alleviate some symptoms like headache or epileptic seizures [109]. Endovascular treatment has been attempted in some cases with unsatisfactory results [110–112]. The surgical treatment with BR offloads the haemodynamic stress [113] and reduces the risk of subsequent ischemic and haemorrhagic cerebrovascular events [104, 114–122], providing symptom improvement to 87% of patients [104].

BR techniques can be classified into two main groups: direct and indirect. The first involves artery-to-artery bypasses between an external carotid artery branch and a brain arterial vessel, usually between the superficial temporal (STA) and MCA [42, 115, 123]. Other donor vessels are the occipital [69, 124], deep temporal, and middle meningeal [125] arteries. The STA can be connected to a branch of the middle cerebral [126] or anterior cerebral [127] arteries. Meanwhile, the occipital artery is sutured to the PCA [128] but can also be used to revascularize the MCA territory [129]. The size of the donor artery should be >0.8 mm to allow the surgical manoeuvres [130]. In children under four years of age, both the STA and the possible recipient brain arteries usually have an insufficient diameter to enable a bypass [131]. Its most significant advantage is that it provides immediate brain haemodynamic improvement. This fast improvement in the brain blood flow reduces the risk of ischemic and haemorrhagic strokes faster than the indirect techniques, which require 3–4 months to achieve the same result [132]. Its main risk is a hyperperfusion-reperfusion syndrome, which can induce haemorrhages with neurological deterioration and worsening [115, 133, 134]. This risk can be minimised with strict

postoperative blood pressure control and mild hypotension in symptomatic cerebral hyperperfusion [135]. Direct BR is mainly used to increase the perfusion of the MCA territory [99]. Direct BR of the anterior or PCA branches is challenging as the donor's vessels are further away, a severe problem when those vascular territories are affected [99]. Under experienced hands, the patency rates are over 90% [136]. As the cortical arteries atrophy, it is increasingly difficult to find a suitable recipient vessel to perform a direct bypass [137]. The ideal is an M3 branch, but micro-anastomoses with these vessels are technically very difficult [138].

In the indirect BR, no arterial anastomoses are performed. Instead, a pedicle graft vascularized by the external carotid artery is placed over the brain's surface and rely on the new collateral vessel formation between the donor tissue and the ischemic underlying brain [139]. For a successful result, three elements are needed—first, a well-vascularized donor tissue. Second, intimate contact between donor tissue and recipient brain vascularization. And third, a good selection of the hypoperfused recipient brain areas [140]. Indirect BR requires forming a fibrous scar at the donor tissue-brain interface with new collateral vessel formation between the donor and recipient vascular beds [141]. The possibilities of indirect BR techniques are broad [104]. Depending on the donor tissue used, the options are encephalo-myo-synangiosis (EMS) [142] when a muscle is used, encephaloduro-synangiosis (EDS) [143] with dural graft, split-duro-encephalo-synangiosis (DES) [144, 145] with a split dura graft, encephalo-duro-myo-synangiosis (EDMS) [146] with dural and muscle graft, encephalo-duro-arterio-synangiosis (EDAS) [147–150] with dura and external carotid artery branch, encephalo-duro-arteriomyo-synagiosis (EDAMS) [151] with dura, an external carotid artery branch and muscle, encephalo-galeo-synangiosis (EGS) [152, 153] with galea, encephalopericranium-synangiosis (EPS) [140, 154, 155] with pericranium, omentum transplantation [156, 157] and multiple burr-hole (MBH) [158, 159]. This last surgical technique consists of performing numerous burr holes (10 to 24) through the frontal, parietal and occipital bones, opening the dura and arachnoid and introducing a pericranium flap inside each burr-hole [160]. It can be used isolated, as part of other BR techniques or as a rescue procedure when other surgical approaches have failed or proved insufficient [160–162]. Not only is it technically effortless and straightforward, but it can be performed under local anaesthesia, which is an advantage in patients in a seriously compromised status [161]. As the dura is also an essential source of collateral vessel formation, a small craniotomy (3–3.5 cm in diameter) placing the pericranium directly over the brain surface provides better results than MBH [140]. Contrarywise, extensive craniotomies are not recommended because they disrupt the already spontaneously formed collateral vascularization increasing the risk of postoperative brain ischemic events [140]. The EPS is particularly helpful to provide collateral circulation to the anterior and PCA territories, areas not easily covered by the STA [140]. Duropexy is crucial in all indirect BR techniques [140].

Direct BR is preferred whenever possible because the haemodynamically compromised hemisphere gets an immediate increase in blood flow, reducing sooner the ischemic and haemorrhagic stroke risk [113, 163]. In contrast, with the indirect techniques, the new collateral vascularization takes 3 to 4 months to develop [53, 164, 165], but long-term, the blood–brain supply is better than with the direct BR [141]. In this period in which the collateral vessel formation is taking place, may persist brain hypoperfusion symptoms, and at times the final result may require an additional surgical BR procedure [128, 166–168].

With the direct bypass, the brain perfusion improvement is limited to the area where it is undertaken and is not helpful to perfuse extensive ischemic areas [169]. Contrarywise indirect brain vascularization can cover vast vascular territories, mainly if different techniques are employed, like the EDAS combined with MBH [5, 159]. This combination can provide new blood supply to the whole brain, including the interhemispheric frontal areas and occipital lobe [68].

MMD related aneurysms were treated with embolization or surgical clipping [11], and many improved with BR alone [11, 12].
