1.4.3. Pathogenesis of cerebral ischemia and retinal ischemia in occlusion
internal carotid artery
1.4.3.1. Mechanisms of ischemia
Maybe you are interested!
-
Outcomes of Functional Recovery, Mortality, and Recurrence in Patients with Cerebral Infarction and Internal Carotid Artery Occlusion -
Survey of prognostic factors of cerebral infarction due to internal carotid artery occlusion - 2 -
Organizing physical education teaching activities at People's Security College I in the current reform period - 14 -
Details of the General P&I Premium Increase of the Associations -
Valid (V) and Invalid (I) Bits in a Page Table
Cerebral or retinal ischemia can occur by the following mechanisms [115]:
- Embolization: embolization is the most common mechanism in cerebral infarction due to occlusion of the internal carotid artery, accounting for up to 2/3 of cases [128]. The source of embolization is usually a fragment of thrombus separated from the distal end of the embolus that drifts to the branches of the internal carotid artery. Studies have shown that there is much pathological evidence consistent with the possibility of embolization from the distal end of this internal carotid artery occlusion [82]. The source of embolization can also be a fragment of thrombus separated from the proximal end of the embolus and even fragments of atherosclerotic plaque in the common carotid artery before the occlusion, in which case the embolized material drifts along the external carotid artery through collateral branches, occluding collateral vessels or occluding small branches in the brain.
- Reduced cerebral blood flow (CBF): this mechanism occurs due to inadequate collateral systems, combined with hemodynamic disturbances, causing decreased perfusion in the distal, marginal areas [128]. Recent studies using PET and SPECT have demonstrated that hemodynamic disturbances are independent risk factors predicting future cerebral infarction or transient ischemia [49], [138]. Internal carotid artery occlusion is also often associated with borderline infarction [71], suggesting a mechanism of hemodynamic failure.
- Combination of both vascular occlusion and hemodynamics : these two mechanisms can occur in the same patient, which can make the infarct larger than either mechanism alone [128].
1.4.3.2. Compensatory mechanisms in cerebral ischemia
Compensatory mechanisms may prevent cerebral ischemia in internal carotid artery occlusion [46],[128]. These mechanisms include development of collateral circulation, dilation of resistance vessels, and increased oxygen uptake fraction.
- The first mechanism is the development of collateral circulation. The most important collateral source is from the contralateral internal carotid artery through the circle of Willis. Important collateral sources
Another is from the orbital branches of the ipsilateral external carotid artery (via the maxillary, facial, frontal, and leptomeningeal branches), which anastomose with the ophthalmic artery of the internal carotid artery. Less commonly, collateral circulation comes from the vertebrobasilar system via the posterior communicating artery, or from the superficial cortical branches.
- If collateral circulation is inadequate, cerebral blood flow can be maintained despite a decrease in cerebral perfusion pressure due to dilation of resistance vessels (cerebral blood flow autoregulation). This autoregulatory vasodilation is clinically determined by a decrease or absence of cerebral blood flow response to vasodilator stimuli such as in the acetazolamide or hypercapnia cerebral vascular reactivity test. In internal carotid artery occlusion, vasodilator stimuli do not increase cerebral blood flow because autoregulation has already maximized vasodilation in response to a decrease in cerebral perfusion pressure.
- When autoregulatory vasodilation fails to maintain normal cerebral blood flow, the oxygen extraction fraction (OEF) of ischemic brain tissue increases to maintain normal cerebral metabolism [48], a state known as stage II hemodynamic impairment or misery perfusion [38]. Increased OEF has been shown to be a strong independent risk factor for subsequent ischemic stroke in patients with symptomatic internal carotid artery occlusion [138]. The annual risk of stroke in the subgroup of patients with all degrees of hemodynamic impairment was 12.5% for all strokes and 9.5% for ipsilateral strokes, indicating a clearly worse prognosis for patients with cerebral perfusion impairment compared with those without such impairment [82].
Collateral perfusion is an important factor determining the presence, location, and size of cerebral infarction lesions in patients with internal carotid artery occlusion, in which the most important collateral is through the circle of Willis. In addition to the severe form of damage when there is no collateral, damage to the perfusion boundary between arteries is a type of damage closely related to the hemodynamic mechanism, reduced perfusion due to inadequate collaterals. A study by Hendrikse et al. published in stroke 2001 [67] showed that in
In patients with unilateral internal carotid artery occlusion, the presence of collateral flow through the posterior communicating artery was associated with less borderline infarction, with the incidence of Willis polygon collaterals in patients with borderline cerebral infarction being 60%, lower than in patients without borderline infarction (92%). Similarly, a study by Bisschops et al. published in Neurology 2003 [39] of 68 patients with unilateral internal carotid artery occlusion showed that if collateral flow through the circle of Willis was present, the incidence and volume of borderline infarction were both lower than in the group of patients without this collateral.
1.4.4. Diagnosis of internal carotid artery occlusion
Patients with symptomatic subtotal stenosis of the internal carotid artery are considered to be at very high risk of recurrent infarction [40], and endarterectomy is a reasonable indication with proven benefit. In contrast, total occlusion of the internal carotid artery is not an indication for this surgery. Therefore, distinguishing between total occlusion and severe stenosis of the internal carotid artery is of great importance. Missing residual flow from a severe stenosis deprives the patient of the opportunity for surgery, and misdiagnosing a total occlusion as a non-occlusive stenosis may subject the patient to invasive investigation or even surgery when it is not actually indicated [128]. However, the importance of this distinction has recently been questioned, as a recent study by Fox et al. showed that surgery in a subtotal stenosis is of little benefit [55].
1.4.4.1. Ultrasound is often the initial imaging modality in the evaluation of symptomatic internal carotid artery disease. B-mode ultrasound is very accurate in assessing luminal stenosis and distinguishing normal arteries or arteries with small plaques from those with severe atherosclerosis (>70%). However, B-mode ultrasound is more difficult to distinguish between complete occlusion and near-occlusion. When pulsed Doppler or continuous wave Doppler techniques are combined with B-mode ultrasound to form a duplex system, this system provides additional qualitative and quantitative information about flow variations (velocity changes, eddies after stenosis). Occlusion of the internal carotid artery is characterized by total loss of
signals along the extracranial course of the internal carotid artery. Currently, B-mode ultrasound combined with spectral Doppler and color Doppler is the most accurate, sensitive, and convenient method for screening for carotid occlusion or stenosis. The accuracy of duplex ultrasound in diagnosing complete carotid occlusion is as high as 97%, with a positive predictive value of 96%, a negative predictive value of 98%, a sensitivity of 91%, and a specificity of 99% [26]. Newer techniques including color Doppler and power Doppler may further improve the ability to detect severe stenosis near occlusion [58]. The use of contrast in duplex ultrasound has also improved the reliability of differentiating between complete and proximal stenosis of the carotid artery, with 10 cases of suspected complete occlusion on Doppler ultrasound, after contrast injection, 7 cases of true occlusion, 3 cases of distal blood flow, according to a study by Ohm C. et al. published in 2005 [104]. However, the disadvantage of ultrasound is that this technique cannot visualize carotid occlusion well if it occurs high, outside the ultrasound window. In this case, carotid occlusion on ultrasound can only be inferred from indirect signs such as low velocity and high resistance flow in the proximal carotid artery, however this spectrum is sometimes seen with severe distal stenosis. Another disadvantage of ultrasound is that the accuracy of the results is highly operator-dependent, with knowledge, skills, and experience that can vary greatly.
1.4.4.2. Magnetic resonance angiography (MRA) with or without gadolinium injection provides good visualization of the cerebral arterial system. TOF MRA technique provides images of blood vessels that depend on blood movement; complete carotid occlusion is defined as loss of flow signal on all pulse sequences and at any point along the extracranial and intracranial internal carotid arteries with no flow signal distal to the artery. In cases of near-occlusion stenosis, a void of flow signal is seen, followed by return of the signal. If MRA with gadolinium injection is used, the sensitivity of this technique is at least as good as that of ultrasound in diagnosing complete occlusion of the carotid artery in the neck and may be better in near-occlusion stenosis [52]. El-Saden et al. in a retrospective study using a combination of MRA with and without contrast reported a sensitivity of 92% in detecting 37 cases of complete occlusion and a sensitivity of 100% in detecting 21 cases of stenosis.
near occlusion [52]. However, in cases where the occlusion is located above the bedplate, the diagnostic reliability of MRA is not as high.
1.4.4.3. CT angiography (CTA) is not flow-dependent like ultrasound and MRA, so it is better able to detect stenosis with very small remaining lumens. CT angiography since the time of using single-slice spiral machines has been able to differentiate arterial occlusion from severe stenosis with only a hair-sized lumen remaining with high accuracy [91]. CT technology has been increasingly improved, with the number of detector rows gradually increasing, 4, 16, 64 rows, and some places now use 128-row machines, reducing examination time, reducing the amount of contrast agent, increasing the length of the artery that can be examined in one injection, increasing the accuracy and increasing the spatial resolution of the image. Thanks to that, CTA today gives images that are increasingly approaching invasive contrast angiography (such as DSA). A study by Chen CJ et al. showed that CTA had a sensitivity and specificity of 100% in differentiating between complete and near-occlusive stenosis of the carotid artery, compared with catheter-based contrast angiography [43], and when combined with duplex ultrasound, contrast angiography could be almost avoided [69]. A meta-analysis and review of the literature by Koelemay et al. comparing CTA with conventional angiography and DSA concluded that CTA is an accurate method in detecting severe stenosis of the internal carotid artery, especially detecting complete stenosis of the carotid artery, with a sensitivity and specificity of 97% and 99%, respectively [85].
1.4.4.4. Digital subtraction angiography (DSA) is the gold standard for diagnosing carotid artery occlusion, especially with new generation machines that provide 3D rotational images. However, this is an invasive technique and should only be used when ultrasound or magnetic resonance cannot reliably distinguish between near-occlusion and complete occlusion. It is the best imaging modality for appropriate treatment decisions in patients with persistent or consecutive stenosis on MRA and those with low-velocity blood flow with increased resistance on Doppler ultrasound [128].
1.4.5. Outcome of internal carotid artery occlusion
1.4.5.1. Natural progression, risk of stroke recurrence, risk of death
In patients treated with antiplatelet agents and anticoagulants, the overall risk of subsequent stroke is 5–7% per year, and the risk of stroke ipsilateral to the occluded carotid artery is 2–6% per year [62],[66],[82]. Information on the prognosis of asymptomatic carotid artery occlusion is much less available, and published data are conflicting [41],[68],[135].
Asymptomatic carotid artery occlusion is considered to have a benign course [109]. In contrast, symptomatic internal carotid artery occlusion carries a significant risk of recurrence. Data from a study in Rochester, Minnesota, showed that among patients with transient ischemic attack in general, the risk of actual ischemic stroke at 1 month, 6 months, 1 year, and 5 years was estimated to be 7%, 10%, 13%, and 28%, respectively [128]. Meanwhile, a cohort study of 74 patients with ischemic stroke of large-vessel (stenosis and occlusion) origin, also in Rochester, showed that the risk of ischemic stroke was lower in patients with occlusion than in patients with carotid stenosis (5-year risk 14% vs. 40%), while the 5-year mortality rate was similar (29% vs. 32%) [128].
In a study published in 1975 by Grillo P. et al. [61], the author retrospectively examined 44 cases of cerebral infarction with internal carotid artery occlusion to study the disease progression and find indications for arterial revascularization surgery using the external carotid artery-internal carotid artery bypass grafting method. The results showed that during an average follow-up period of 3 years, 17/44 patients died, of which 8 died from stroke itself, the rest were mostly cardiac deaths.
In 1991, Hankey and Warlow reviewed prospective studies of a total of 1261 patients with symptomatic internal carotid artery occlusion confirmed by contrast angiography, and found that the average annual risk of cerebral infarction was at least 7% [66].
In 1997, Klijn et al. [82] pooled previous non-community-based studies of internal carotid artery occlusion and calculated the annual stroke rate to be
5.5% of 1923 patients, and the ipsilateral recurrence rate was 2.1%. Patients with hemodynamic impairment on functional imaging had a higher risk, up to 12.5% for all strokes, and 9.5% for ipsilateral strokes. Many of these studies excluded patients with severe strokes and were performed at a time when conventional angiography was the only means of diagnosing internal carotid artery occlusion [82].
According to a community study by Flaherty ML et al. published in 2004 [54], the risk of ischemic stroke after internal carotid artery occlusion during follow-up was 8% at 30 days, 10% at 1 year, and 14% at 5 years. Five of the 11 ischemic strokes occurred within the first week after diagnosis of occlusion. The mortality risks were 7%, 13%, and 29%, respectively. In this cohort, the long-term risk of ischemic stroke was lower than in most other studies of symptomatic internal carotid artery occlusion. In contrast, the short-term (1 week) risk of ischemic stroke after symptomatic internal carotid artery occlusion was significantly higher.
1.4.5.2. Risk factors for stroke recurrence in patients with symptomatic internal carotid artery occlusion
The risk of recurrent ischemic stroke after symptomatic internal carotid artery occlusion has been extensively studied. Recent attention has focused on hemodynamic impairment distal to the ICA occlusion. Hemodynamic impairment appears to be a factor in identifying subgroups of patients with symptomatic ICA occlusion who are at high risk for recurrent stroke. Several studies have been conducted to identify appropriate means of assessing this risk.
Increased oxygen extraction fraction (OEF), assessed by positron emission tomography (PET), is considered a marker of cerebral ischemia, due to inadequate collateral perfusion. The role of increased OEF in relation to the risk of recurrent stroke in patients with internal carotid artery occlusion has been documented in studies by Yamauchi et al. [139] (40 patients, 5-year follow-up); Grubb's study
et al. [62] (80 patients, 2-year follow-up, 29.2% relapsed in the group with increased OEF vs. 5.5% in the group without increased OEF).
Magnetic resonance imaging has also been used to predict the risk of recurrent cerebral infarction in patients with internal carotid artery occlusion. A study by Klijn CJM et al.
[81] in 115 patients showed that 1 H magnetic resonance spectroscopy can help identify high risk of recurrent cerebral infarction on the same side as the occluded artery.
Kajimoto et al. [76] performed a perfusion MRI study and showed that this technique provides important information for assessing hemodynamic disturbances, corresponding to increased OEF on PET.
With SPECT, the studies of Kuroda et al. [86] and Imaizumi et al.
[72] showed that this technique can also be applied to screen patients with poor perfusion areas, at high risk of recurrent cerebral infarction.
Transcranial Doppler has also been investigated for its ability to select patients at high risk of recurrent cerebral infarction, however, a study by Klijn CJM et al. [84] showed that the assessment of CO2 response on transcranial Doppler was not predictive of recurrence.
1.4.6. Treatment of symptomatic internal carotid artery occlusion
1.4.6.1. Acute internal carotid artery occlusion
Acute internal carotid artery occlusion is a therapeutic challenge because of poor neurological outcomes and few effective treatment options.
Regarding blood pressure, blood pressure should not be adjusted in the acute phase unless it reaches malignant hypertension. Hypotension should be avoided in these patients because it can cause severe hemodynamic disturbances. According to the study of Rothwell et al. [101], blood pressure does not affect much in simple unilateral internal carotid artery occlusion but has a strong effect in people with ≥70% bilateral carotid artery stenosis, so blood pressure should not be lowered too aggressively in these patients.