Following CTO of the ICA, perfusion pressure at the vascular occlusion is decreased (27). In response to the deficient blood supply from main arteries, the cerebral blood flow (CBF) immediately establishes collateral circulation; this involves immediate diversion of blood flow in the event of large-vessel occlusion, as well as chronic compensation by secondary collaterals such as the ipsilateral ophthalmic artery, ipsilateral posterior communicating artery, anterior communicating artery and pia mater collaterals (28). Effective leptomeningeal collateral circulation and the presence of more than 2 collaterals have been associated with good clinical condition without severe disability (28).

Changes in microscopic brain blood flow. CVR, a key function of the cerebral vasculature, is defined as the increase in CBF in response to a vasodilatory stimulus (29). In CTO of the ICA, CVR is reduced; this impairment has been associated with increased risk of ischemic events and may be useful for stroke risk stratification (30). In normal cases, CVR is unimpaired (stage 0) (31). CVR impairment may be divided into three stages: In stage I hemodynamic failure, autoregulatory compensatory vasodilation is still able to maintain normal CBF, and the oxygen extraction fraction (OEF) remains normal. In stage II hemodynamic failure, also known as misery perfusion, autoregulatory compensation is exhausted and CBF is reduced; however, cerebral metabolic compensation occurs through an increased OEF from the delivered blood supply. In stage III hemodynamic failure, both CBF and OEF are reduced to the point of ischemia and ultimately infarction (32–34).

In certain cases of CTO of the ICA, effective compensatory collateral circulation provides sufficient arterial blood to meet the needs of the brain (39). These cases with a low degree of cerebral hemodynamic compromise, as well as some stage I cases with effective CVR function, may have a benign prognosis (40).

Certain cases of CTO of the ICA with poor compensatory collateral circulation may present ischemic symptoms (41). Cerebral ischemia reflects a deficiency of collateral flow that is blood pressure dependent, and may lead to a hemodynamic infarction pattern (42). Reversible low perfusion is often characterized by recurrent transient ischemic attack, while severe ischemia presents as minor/major stroke (43).

Some CTOs of the ICA are accompanied by full hemodynamic compensation, though nonetheless continuously produce cerebral infarcts (44). The emboli primarily originate from a narrow common or external carotid artery, from a proximal or distal ICA stump or from a diseased contralateral artery (16,44).

CTO of the ICA may be characterized solely by impairments in cognitive function, including declines in psychomotor speed, executive function and working memory (45,46). In these patients, chronic neuronal damage may be identified in the cerebral white matter, as indicated by reduced N-acetyl aspartate concentration (47). These pathological findings affect not only the ipsilateral but also the contralateral hemisphere (48). Successful treatment of CTO of the ICA may improve global cognitive function as well as attention and psychomotor processing speed (49–51).

CVR is a crucial diagnostic tool when evaluating CTO of the ICA. This variable has been identified as a predictor of ischemic stroke (62). CVR may be calculated according to the following formula: CVR = (CBFstimulated - CBFrest)/CBFrest × 100%. Transcranial Doppler studies are often used to assess vasoreactivity, and have suggested that in patients with CTO of the ICA, a breath-holding index of <0.69 is correlated with a high risk of subsequent stroke (63,64).

In addition, CVR may be measured by perfusion CT or MRI with inhalation of 8% CO₂ or injection of acetazolamide, with CVR impairment distinguished using a 10% cut-off point. If CVR is less than 10%, the risk of cerebral infarction is elevated (65,66). Certain novel MRI imaging modalities may also be used to examine CVR, including blood oxygenation level-dependent (BOLD) MRI or acetazolamide-augmented dynamic BOLD imaging (48,67).

OEF is important in the examination of CTO of the ICA and is considered to provide the strongest indication of the need for recanalization surgery (68). Positron emission tomography (PET) is the gold standard for measuring OEF (69–72). The OEF ratio is calculated based on measurements on the diseased and healthy sides. When the OEF ratio exceeds a certain level, cerebrovascular recanalization is required. The treatment standard is defined as an ipsilateral-to-contralateral OEF ratio greater than 1.13 (73). Furthermore, OEF may be measured by certain MRI sequences (74–77). In addition to MRI, the mean transit time of CT perfusion is an optimum correlate of PET-measured OEF, and thus also provides an effective measure of OEF (73,78).

The primary clinical symptoms include transient ischemic attack or ischemic stroke with mild to moderate permanent ischemic neurological deficit in the hemispheric carotid territory ipsilateral to the occluded carotid artery, occurring within 120 days (8). To receive optimal benefit from revascularization, patients should be in satisfactory clinical condition, though also symptomatic with clinical and radiographic confirmation of a recent non-embolic ischemic event (81).

OEF as measured by PET is a gold standard to evaluate cerebral blood flow. Testing conducted as part of the COSS established it as an important surgery standard applicable to recanalization treatment of CTO of the ICA; when the ipsilateral-to-contralateral OEF ratio is greater than 1.13, the indication for surgical treatment is considered to be clear (8). Patients with stage II hemodynamic failure comprise the majority of these cases as stage II hemodynamic failure causes collapse of the vascular reserve in combination with an increase in OEF (82). OEF as measured by PET is an effective predictor of subsequent stroke for symptomatic patients (15).

Retrograde filling is an important criterion for recanalization treatment of CTO of the ICA. The accumulated blood should at least fill the ophthalmic artery and, optimally, should reach the petrous level of the ICA (38). These angiographic features indicate the presence of a focal occlusion in the extracranial compartment of the ICA (83). However, guide wire manipulation is particularly difficult in this situation; therefore, visualization of the distal ICA by ipsilateral contrast injection may provide a clear reference for the wiring procedure (38).

Best medical treatment is indicated for CTO of the ICA with stable hemodynamics and full compensation (46,85). In addition, conservative treatments are adopted for patients who decline surgical retreatment. For patients receiving conservative treatments, oral antiplatelet aggregation drugs including as aspirin are required. Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization (86). However, best medical treatment is unable to comprehensively treat CTO of the ICA, and only minimizes the risk of stroke (84).

It is feasible to treat CTO of the ICA with CEA therapy, as an established method in the treatment of ICA occlusion (87). CEA may be performed in patients with retrograde filling to the skull base (88). However, CEA may also fail in severe cases exhibiting complex clot organization, and if the thrombotic process exhibits intracranial extension; thus restoring circulation following complete occlusion is a challenging procedure. Thompson et al reported that recanalization was achieved in only 41% of 118 patients undergoing CEA for chronic ICA occlusion after a 13-year follow-up (89).

In contrast to CEA, endovascular access is flexible and not limited to the extracranial space. A variety of tools are available to complete the intracranial revascularization process, though stenting is considered the most effective method for breaking down complex clots (40,90). In terms of surgical technique, initial penetration of the occluded stump from the anterior side may provide a maximal chance to access the ‘true lumen’. This may be related to the posterior-to-anterior progression of the plaque at the common carotid artery bifurcation (91).

Endovascular treatment may resolve CTO of the ICA. In 2008, Lin et al (49) reported the results of endovascular revascularization in a series of 54 patients; recanalization was achieved in 65% (35 patients). In 2016, Chen et al (38) reviewed attempted endovascular procedures in 138 consecutive patients with CTO of the ICA, and identified a technical success rate of 61.6%.

A prominent drawback of intravascular interventional therapy is that the thrombus may dislodge and enter the circulation during the balloon dilation or the release of the stent, and consequently block an intracranial artery (92). For this reason, some clinicians have attempted to use protection devices, in some cases to protect the common carotid artery, the external carotid artery and the ICA concurrently (93,94). For instance, the Parodi embolic protection system has been used (95,96). However, there may be limited application; for example, if the thrombus occupies an occluded vessel with retrograde flow, proximal occlusion would not necessarily provide additional protection (97). In addition to carotid artery stents, telescoped flow diverters may also be adopted to treat symptomatic CTO of the ICA (98).

In recent years, the increased feasibility of hybrid surgery has made it possible to combine CEA of the proximal ICA with endovascular angioplasty of the distal ICA in a hybrid operation procedure (99). Hybrid surgery is considered to be a feasible and favorable alternative surgical procedure; a higher success rate may be achieved using the hybrid technique as it can provide improved control of endovascular manipulation (100). In 2013, Shih et al (39) successfully used this method to treat 3 cases with recurrent ischemic attacks due to CTO of the ICA.

Hybrid surgery refers to a process in which CEA is first performed in the initial part of the ICA, following which a guiding catheter is placed into the surgical field via the common carotid artery; subsequently, a micro-guidewire and micro-guide catheter are placed in the distal end of the ICA in direct view and maneuvered to the cavernous sinus or the ophthalmic artery under radioscopy (101). Under microcatheter radiography, if the distal vessels are developed, the carotid artery is sutured and the CEA is completed, and the stent is laid down along the micro-guidewire until the artery is recanalized (102). Hybrid surgery is relatively safe as the CEA is open and debris may filtrate from the surgical field, aiding to prevent distal embolic accidents (100).

CTO of the ICA may be managed by EC-IC bypass, as tested in the COSS (8,103). However, EC-IC bypass surgeries typically connect the superficial temporal artery to the middle cerebral artery; this is a low-flow bypass, and the shunted blood flow may not be adequate (104). Additionally, compared with medical therapy alone, EC-IC bypass surgery plus medical therapy did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years (8).

The failure of EC-IC bypass in the COSS was probably caused by failure to select patients at high risk of stroke. Whether EC-IC bypass has applications in the treatment of advanced occlusive vascular disease patients requires verification (105).

Overall, future research should address the remaining challenges of developing and investigating novel surgical treatments for the disease process, and establish the clinical benefit of such treatments through randomized controlled trials (106).

The factor that most prominently affects the success rate of recanalization is the duration of occlusion. For acute and subacute occlusion of the ICA, both interventional surgery and hybrid surgery are relatively straightforward, mainly as the thrombosis in the ICA has not developed in structure and is relatively soft (91,107). Our experience corroborates this finding. For CTO of the ICA, the thrombosis at the distal end of the ICA may occasionally be directly pulled out following CEA, and the vessels may be recanalized (108). Under the restored blood flow and blood pressure, the atrophied and collapsed vessels distal to the thrombus are restored to normal diameter and morphology during follow-up (109). As the duration of ICA occlusion increases, the clot undergoes complete fibrotic organization at the ICA origin, hindering the passage of the micro-guidewire through the occluded arteries; the difficulty of recanalization is thereby increased, as is the risk of complications (110).

The longer the duration of a CTO of the ICA, the lower the predicted technical success of recanalization (111). A microwire must pass thorough the occluded arteries during recanalization, and this process is difficult due to the variable course of the vessel, which frequently results in false lumen creation (112). In 2016, Chen et al (38) categorized occlusion length using a cut-off of 5 cm, and identified that the technical success rates for occlusions shorter than 5 cm and longer than 5 cm were 73.7 and 59.7%, respectively, suggesting a higher success rate of recanalization for occlusions shorter than 5 cm. They also observed that the success rates of distal ICA reconstitution at the petrous segment or below; at the cavernous, clinoid and ophthalmic segments; and at the communicating segment or above were 93, 80, 73, 33 and 29%, respectively. This indicated that the lower the location of the ICA occlusion, the higher the success rate of recanalization (38).

If the CTO of the ICA is derived from atherosclerosis associated with calcification in the initial segment of the ICA, then severe atherosclerosis and calcification in the occluded segment may hinder the placement of the guidewire (113). Our experience is that for CTO of the ICA with recanalization, CTA or ultrasound inspection is often performed to judge whether severe atherosclerosis is present in the occlusion of the initial segment of the carotid artery. If there is arterial sclerosis or calcification, CEA is typically performed in a hybrid operating room first, followed by endovascular recanalization in the distal end of the carotid artery.

Recanalization of CTO of the ICA is not dependent on any one factor. Chen et al (38) reported in 2016 on 138 consecutive patients undergoing endovascular treatments for CTO of the ICA, and evaluated the following four factors: Neurological events, stump morphology, distal carotid artery reconstitution and level of distal carotid artery reconstitution. They identified that the absence of prior neurological events, a non-tapered stump, distal ICA reconstitution via contralateral injection and distal ICA reconstitution at the communicating or ophthalmic segment were independent negative predictors for technical success in endovascular recanalization for CTO of the ICA. These factors also affect the success rate of hybrid surgery (39). In addition, it is possible that the success of the procedure is associated with previous anticoagulant therapy, which maintains a soft consistency of the thrombus, facilitating advancement through the occlusion (114).

In certain cases, long-term carotid artery occlusion has impaired the CVR of the ipsilateral hemisphere, leaving the patient prone to excessive perfusion following recanalization; the characteristics of excessive perfusion include headache, bleeding disorders, epilepsy and in some cases, parenchymal and subarachnoid hemorrhage. Chen et al (38) used endovascular treatment on the 138 consecutive cases of CTO of the ICA, and hyperperfusion syndrome with delayed nonfatal intracranial hemorrhage developed in 2 patients. To mitigate this risk, the physician should retain the patient's systolic blood pressure low (<120 mmHg) in the periprocedural period (115).

These complications primarily arise from the carotid artery with recanalization, whereby detachment of the thrombus may result in symptomatic and asymptomatic embolic events (37). There is a high risk of distal migration of the thrombus upon catheterization through the thrombus and stenting; consequently, a protective device is sometimes required (116). In addition, the micro-guidewire may inflict injuries, including vessel perforation of the carotid artery, pseudoaneurysm, arterial dissection or carotid-cavernous fistula (93).