How to identify risk for cerebral hyperperfusion syndrome after carotid revascularization procedures hiperperfuzije nakon procedura karotidne revaskularizacije

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Introduction
Atherosclerotic lesions of the extracranial part of carotid arteries are one of the most common causes of stroke 1 . Carotid endarterectomy (CEA) and carotid stenting (CAS) are therapeutic options in the prevention of primary and secondary stroke in the patients with significant stenosis of internal carotid arteries (ICA) 2 . Although both of these procedures are considered to be relatively safe, there are certain neurological and non-neurological complications. The more serious one is the cerebral hyperperfusion syndrome (CHS). Albeit rare, CHS is a potentially devastating event that can even be fatal if intracranial hemorrhage (ICH) occurs [3][4][5][6][7] . In this review, we will summarize available data regarding this phenomenon and focus on its pathophysiology, prevention, diagnostics and management.

Definition of hyperperfusion and cerebral hyperperfusion syndrome
First and foremost, we must differentiate between the concept of hyperperfusion and CHS. In general, hyperperfusion occurs when cerebral blood flow (CBF) in the revascularized territory increases by 100%, or more, with respect to the baseline values 8,9 . However, not every patient with hyperperfusion develops CHS. The term CHS was used to describe the clinical entity consisting of symptoms triad: ipsilateral migraine-like headache, seizure, and transient focal neurologic deficits in the absence of cerebral ischemia in combination with the high post-procedural blood pressure (BP). This was first described by Sundt et al. 10 .

Pathophysiology
Although this phenomenon is well described in the relevant literature, not much is known about the pathophysiological mechanisms which lead to CHS. As mentioned before, not all patients with increased CBF develop CHS. In the series conducted by Ogasawara et al. 11 , 16.7%-28.6% of the patients with an increase in CBF 100% developed CHS. Also, in some cases with slightly elevated CBF, CHS can be developed 11,12 . That leads to the conclusion that other factors play a role in the occurrence of CHS.
All authors agree that two interlinked and synergized mechanisms lead to increased CBF; first, impaired cerebral autoregulation, and second, the increased postprocedural BP 13,14 .
The main autoregulatory mechanism is the cerebrovascular reactivity (CVR), the ability of the arterioles to constrict or dilate in response to the alterations of blood flow, or to other stimuli (i.e., hypocapnia) 13 . In order to compensate the reduced blood flow to the brain in the patients with severe ICA, stenosis arteriolae remain in the state of maximal dilation to maintain the sufficient cerebral blood supply.
The severity of CVR impairment is likely due to several different factors -a degree of ipsilateral and contralateral ICA stenosis, an incomplete circle of Willis and insufficient collateral flow 3,15,16 . However, the syndrome was described even in the patients without contralateral lesions, thereby gi- ving even more significance to the disturbed autoregulation mechanisms that can develop in the region of ipsilateral stenosis even without severe contralateral ICA lesion. After CEA, the increased nitric oxide levels during clamping of ICA and increased oxygen-derived free radicals produced during the restoration of the perfusion pressure are involved in the endothelium dysfunction and the deterioration of autoregulatory mechanisms 17 . Besides, several studies have demonstrated significant elevations in malondialdehyde, diene conjugates, or lipoperoxides, the products of free radicalinduced lipid peroxidation, in jugular vein plasma immediately after declamping of the ICA 18 .
Increased BP after CEA is largely attributed to the baroreceptor reflex failure after denervation during the procedure. This is especially expressed after bilateral CEA; the baroreflex breakdown induced hypertension leading to an increase of CBF. In contrast, the autoregulation mechanisms are diminished and thus lead to hyperperfusion in the previously hypoperfused tissue. Both cerebral hyperperfusion associated with cerebral edema and the elevated intracranial pressure may lead to an increase in central and peripheral norepinephrine levels and a subsequent further elevation of the systemic blood pressure.
Increased CBF, which cannot be controlled by the autoregulatory mechanisms, leads to the transudation of fluid into the pericapillary astrocytes and interstitium. This results in vasogenic white matter edema, especially in the vertebrobasilar circulation territory of the posterior parietal and occipital regions. New studies on rodent models are trying to shed more light on the mechanisms of occurrence of CHS 19 .

Clinical presentation, risk factors and diagnostics
CHS can develop at any time; immediately after the procedure to up to a month later, but the majority of patients develop symptoms within the first few days (mean 5 days) 7,20,21 . Although this most commonly appears after CAS and CEA, CHS was described and after the subclavian artery stenting 20 and after the endovascular reconstruction of carotid artery in a high-flow carotid-jugular fistula 21 . The reported incidence rate of CHS and ICH after CEA is 1.9% and 0.37% and 1.16% and 0.74% after CAS 3, 6, 7, 10-12, 22 . The most common symptoms include: headaches, fluctuation of consciousness, confusion and focal neurologic deficit (Table 1). Headaches are usually moderate to severe, ipsilateral to the revascularised artery, pounding and migrenous 23 . Focal neurologic deficit is a result of cerebral edema and usually is transient 6,15,24,25 . It includes the cortex derived symptomshemiplegia, hemiparesis, hemianopsia, dysphasia, seizures and less commonly ataxia and visual disorders. Seizures can sometimes present even as status epilepticus 26 .
By far the most devastating complication of CHS is ICH. It is a very rare complication, as previously stated, but it is often fatal (36%-63%), and up to 80% of survived patients are left with significant morbidity 15,27,28 . Since ICH is associated with CHS, the symptoms of increased intracranial pressure can be present (nausea, vomiting, or altered sensorium) 29 . There is a form of hyperacute ICH that occurs within hours after CAS, and it is almost always unpreventable since it occurs without prodromal signs. It could be a result of rupture of perforating arteries in basal ganglia which are exposed with suddenly normalized perfusion pressure after CAS 30 .
The occurrence of CHS is multifactorial, while the cerebral perfusion and autoregulation are individualized in each patient. CBF changes in each patient are variable, and there is no proof that a degree of stenosis is directly linked with the CBF variations 31 . This could be explained by the presence of collateral circulation and the degree of cerebral autoregulation impairment in each patient. Various studies indicated a potential role for risk factors, definitive prediction of subgroups of patients with an increased risk of developing CHS after CEA, or CAS, is not feasible. This point expresses not the ambiguity of the risk factors, but the complexity and the multifactorial contribution in the pathogenesis of the syndrome. The risk factors that were described to be significantly involved in developing CHS are shown in Table 2. Additionally, one study suggested that interval between two procedures should be no less than 3 months 3 . That study reported 6.6% of patients developing CHS after bilateral CEA within less than 3 months. The authors suggested that inconsistencies in baroreceptor function may be a causative factor for CHS.
The use of anticoagulants and antiplatelet agents is routine after CEA and CAS. In the absence of sufficient data, it remains uncertain whether the use of post-procedure anticoagulation therapy may be associated with an increased risk of developing CHS and ICH 27,28 .
There were several techniques suggested to identify the patients at risk for developing CHS. The most widely available method is transcranial color Doppler (TCD). It is used to determine CBF changes via monitoring cerebral blood flow velocities (CBFV) changes in intracranial vessels. TCD is used to assess cerebrovascular reactivity using vasodilator agents such as acetazolamide, CO 2 inhalation, or the breath holding test [34][35][36] . The blood flow is severely restricted when there is a critical ICA stenosis present and after being removed, the blood flow increases dramatically. In the patients with badly impaired cerebral autoregulation, this dramatically increases the mean flow velocity in the middle cerebral artery (MCA) [34][35][36] . The preoperative drop in CBFV is indicative of hypoperfusion and can lead to postoperative hyperperfusion and thus to the CHS.
However, TCD has several limitations. The first one is an insufficient cranial window and the second one is the experience of operater 24,37 . Despite these drawbacks, the TCD findings should always be evaluated carefully. Results in the TCD studies demonstrate that the blood flow redistribution through the anterior communicating pathway and the ophthalmic artery is achieved, in case of contralateral ICA stenosis, and in the patients with contralateral ICA occlusion through the posterior communicating pathway. Asher et al. 4 reported a significant increase in the mean internal carotid artery volume flow (MICAVF) in all patients with CHS during the symptomatic period. After the symptoms receded, the flow volume returned to normal.
Standard computed tomography (CT) has limited value preoperatively and can be completely normal postoperatively. It can still be useful as a quick tool to remove a suspicion of ICH. Also, the brain edema that can be seen early can be indicative of CHS (Figure 1). A recent study showed the pretreatment CT perfusion imaging (CTP) with acetazolamide challenge could identify the patients at risk for CHS after CAS. CTP maps were assessed for the absolute and relative cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT). Although the CTP parameter that the most accurately identified the patients at risk for HPS was the absolute value of post-acetazolamide MTT, resting MTT was sufficiently accurate [37][38][39][40][41][42][43][44][45][46][47] . Single photon emission CT (SPECT) can detect alterations in the preoperative cerebral perfusion (after administering acetazolamide) 47 . It is also very useful in differentiating between cerebral ischemia and hyperperfusion, and identifying the patients at risk of CEA. However, some studies did not find any correlation between preoperative asymmetry in brain perfusion in rest and CHS [39][40][41][42] . Ogasawara et al. 43 suggested that hyperperfusion lasting at least up to three postoperative days on SPECT predisposes to the CHS development. The magnetic resonance imaging (MRI) techniques also proved useful in diagnosis of CHS, and especially powerweighted (PW) MRI that can reveal intrahemispheric differences in CBF in the patients after CEA 11 . However, as it is not quantitative method, PWI MRI can only be used in absence of contralateral steno-occlusive ICA disease. The conventional MRI findings in the patients with CHS include white matter edema, focal infarction and a local, or a massive hemorrhage. These abnormalities, however, are not pathognomonic for CHS.
Alternative methods such as intraoperative electroencephalography (EEG) and ocular pneumoplethysmography were proposed for diagnosing CHS. However, these methods are yet to prove their worth 48,49 .

Managment of hyperperfusion syndrome
The most important stage in the prevention of CHS is the aggressive BP management postoperatively. This needs to be performed in order to prevent the most dangerous complication of CHS, the ICH. Further reduction of BP even in the normotensive patients should be considered if hyperperfusion is detected, as they can develop hypertension later. Drugs like labetalol and clonidine should be used. Vasodilating drugs with hydralazine, nitrate and Ca + channel blockers should be avoided since they can add to already existing brain swelling 23,[42][43][44] . Beyond this criteria, there is no evidence favoring any other specific drug. Also, beta blockers should be limited 43,44 .
The cerebral edema treatment includes adequate sedation, hyperventilation, manitol administration and hypertonic saline solution 10,41,45 . Corticosteroids were tried, but their effectiveness remains uncertain 10 Oxygen-derived free radicals produced during ischemia were implicated in the ischemia-reperfusion injury. In cerebral tissue, these radicals could lead to the endothelial dysfunction and a break in the blood brain barrier, leading to the postischemic hyperperfusion, edema and hemorrhage. In one small case series with historical controls, edaravone, a free-radical scavenger that inhibits lipid peroxidation and vascular endothelial injury decreased the incidence of hyperperfusion following CEA, mainly in the patients with decreased CVR 50 .

Conclusion
CHS is a rare, but potentially deadly complication of brain revascularization procedures. Two key, interlinked and synergistic mechanisms play part in its occurrence -impaired cerebral autoregulation and the elevated BP after procedure. It is important to understand the complexity and multiple factors that contribute to the symptom appearance. Although different studies developed risk factors, the determination of subgroups of patients in danger of developing CHS after CAS or CEA is still not feasible. If not treated promptly and properly, CHS can lead to fatal ICH. The treatment strategies were developed towards regulating the BP, reducing brain swelling, and most importantly, limiting the extreme blood flow rising in the patients at potential risk.