ABSTRACT: Background. Cerebral hyperperfusion syndrome (HPS) results from autoregulatory failure of cerebral blood flow following carotid endarterectomy (CEA) or carotid artery stenting (CAS) and encompasses a range of neurological findings including headache, seizure, intracranial hemorrhage (ICH), altered mental status and focal neurological changes. This report is the largest single-operator series evaluating the incidence and predictors of HPS following CAS. Methods. A retrospective review was conducted on 482 consecutive patients who underwent CAS between August 1999 and December 2007 at Baptist Medical Center - Princeton, Birmingham, Alabama. All interventions were performed by a single operator (FM). The mean patient age was 70.4 ± 10.3 years and 36% were symptomatic. All patients were high-risk for CEA. After cerebral protection catheters were routinely available, they were used in all but 6 cases (98.1%) where the anatomy precluded delivery. Brain computed tomography (CT) was performed immediately for any neurological change or significant headache following CAS. After neurological consultation and imaging, HPS was diagnosed if: 1) a neurological change occurred (not simply a headache); 2) CT revealed ipsilateral sulcal effacement/cerebral edema; and 3) stroke or transient ischemic attack (TIA) was excluded. Results. Seven patients (1.45%) developed HPS following CAS. All patients achieved complete neurological recovery 6–24 hours following the procedure. Patients who developed HPS were significantly more likely to have had recent transient ischemic attack (TIA) symptoms than patients without HPS (p = 0.04). Unlike previous reports, there were no significant differences in procedural details, lesion characteristics and post-procedure blood pressure between the HPS and non-HPS patients, although the number of cases was small. Overall, the HPS cohort had a higher prevalence of comorbidites, though these differences did not reach statistical significance. Hypertension was present in all 7 HPS patients. Other complications in the series were death (0.83%), stroke (1.87%) and TIA (1.45%). Conclusions. The incidence of HPS is low (1.45%) following CAS, but it is an important complication to distinguish from stroke and TIA. Patients with a recent TIA may be predisposed to HPS. This report may underestimate the incidence of HPS, since patients with an isolated headache did not meet our diagnostic criteria and routine post-procedure brain CT imaging was not performed. The clinical predictors of HPS and its optimum management remain to be determined. J INVASIVE CARDIOL 2009;21:27–30 Cerebral hyperperfusion syndrome (HPS) is a recognized complication of carotid endarterectomy (CEA) and carotid artery stenting (CAS), with a reported incidence of 0.3–3% and 0.96–5%, respectively.1–11 HPS results from presumed autoregulatory failure of cerebral blood flow following CEA or CAS not related to ischemia and encompasses a range of neurological findings including headache, seizure, intracranial hemorrhage (ICH), altered mental status and focal neurological changes. Whereas HPS after CEA is a well-described complication, there have been few large studies conducted to evaluate HPS after CAS.6–11 This study is the largest single-operator series to date evaluating the incidence and determining predictors of hyperperfusion syndrome following CAS. Methods Patients. Between August 1999 and December 2007, 482 patients underwent CAS at Baptist Medical Center - Princeton, Birmingham, Alabama. Patients were eligible if they had neurological symptoms and > 50% diameter carotid artery stenosis or no symptoms and > 80% stenosis. The majority of patients were asymptomatic (64%) and were referred to us after duplex ultrasonography or angiography disclosed evidence of carotid occlusive disease. All patients had evidence of high-risk clinical features. All interventions were performed by a single operator (FM). Technique. The carotid stenting procedure was performed as previously described.12 All patients received aspirin 325 mg and clopidogrel 600 mg plus therapeutic anticoagulation. The initial 14 cases were performed without cerebral protection. After October 2002, cerebral protection devices were used on all but 6 cases where unfavorable anatomy precluded its delivery. Various cerebral protection devices (RX Accunet, n = 306, [Guidant Corp., St. Paul, Minnesota], FilterWire EZ, n = 112 [Boston Scientific Corp., Natick, Massachusetts], Emboshield, n = 4 [Abbott Laboratories, Abbott Park, Illinois], Angioguard, n = 40 [Cordis Corp., Miami Lakes, Florida]) and stents (Rx Acculink, n = 303 [Guidant Corp.], Dynalink, n = 147 [Guidant Corp.], Conformex, n = 17 [CR Bard; Murray Hill, New Jersey], Vivexx, n = 15 [CR Bard]) were used. The average time from placement of the carotid sheath to removal for all patients was 40 minutes (± 10). After the procedure, all patients were closely observed in a post-interventional unit and blood pressure was monitored noninvasively. When necessary, vasopressor or antihypertensive agents were used for hemodynamic instability at the discretion of the operator. Independent neurology consultation and computed tomographic (CT) brain scans were obtained immediately for any neurological change or significant headache. Data collection. A retrospective chart review was conducted on 482 consecutive patients who underwent CAS at our institution from August 1999 to December 2007. Demographic characteristics, angiographic data, symptomatic status, procedural details, hemodynamic data, anticoagulation use and periprocedural events, including the presence or absence of HPS, were recorded. HPS was diagnosed if the following criteria were met: 1) new focal neurological deficit, altered mental status, seizure or headache; 2) brain CT revealed ipsilateral sulcal effacement consistent with cerebral edema; 3) stroke or transient ischemic attack (TIA) was excluded by neurologic consultation and brain imaging. An isolated headache did not meet diagnostic criteria. However, if patients had any other neurological symptom than headache, it was recorded as part of the symptom complex. Statistical analysis. Fisher’s exact test was used to compare groups for discrete variables. The Mann-Whitney U-test was used for continuous variables. Data are given as mean ± standard deviation (SD) and counts (percent). Results Seven of 482 patients (1.45%) developed clinical and radiographic evidence of hyperperfusion syndrome following CAS (Table 1). No patient had focal neurologic deficits without other symptoms. All patients developed isolated HPS without ICH and achieved complete neurological recovery 12–24 hours following the procedure. Brain CT scans revealed cerebral edema and sulcal effacement in the ipsilateral cerebral hemisphere (Figure 1). One patient in the overall cohort with severe carotid artery stenosis (99.9%) developed a fatal ipsilateral intracerebral hemorrhage immediately after the intervention and was determined to have a hemorrhagic conversion of a prior stroke — the hemorrhage occurred immediately after the procedure. Other complications in this series were death (0.83%), stroke (1.87%) and TIA (1.45%). Patient demographics. Patient characteristics are summarized in Table 2. Patients who developed HPS were significantly more likely to have had recent TIA symptoms than those without HPS (p = 0.04). There were no other statistically significant differences found between patients who developed HPS and those who did not. However, the HPS cohort had a higher prevalence of comorbidites, though these differences did not reach statistical significance. Angiographic and procedural results. Angiographic and procedural results are summarized in Table 3. The overall procedural success rate was 99%. There were no significant differences in procedural details, lesion characteristics or post-procedure blood pressure between the HPS and non-HPS patients, although the number of cases was small. However, the HPS cohort did have a trend towards a higher post-operative blood pressure (p = 0.12), though this difference did not reach statistical significance. Discussion HPS was initially described in 1978 by Spetzler as “normal perfusion pressure breakthrough” following arteriovenous malformation resections.13 Sundt et al14 in 1981 recorded an ispsilateral increase in cerebral blood flow after CEA and was the first to associate “hyperperfusion syndrome” with carotid artery surgery. HPS has since been characterized by severe, throbbing ipsilateral headache, focal seizure activity and focal neurological defects that are secondary to intracerebral edema.5–7 The incidence of HPS in our series was comparable to that of TIA (1.45%) and cerebrovascular accidents (CVA) (1.87%). Certain features distinguish HPS from TIA and CVA. HPS is typically apparent several hours post procedure, not intraprocedurally, like most periprocedural strokes. While some HPS changes can mimic a CVA or TIA, seizures and altered mental status are less typical. Finally, the CT findings in HPS typically reveal ipsilateral sulcal effacement (Figure 1) and cerebral edema immediately following the onset of symptoms. The CT scan is usually normal with a TIA and can be normal within hours following a CVA. Others have reported that risk factors for HPS are similar in CAS and CEA patients. A number of factors all related to impaired cerebral hemodynamic reserve may play a role. Previous reports have documented hypertension, high-grade internal carotid artery stenosis, and contralateral disease as statistically significant risk factors, but none of these characteristics were significant in our study. Specifically, post-procedure hypertension has been identified as a critical finding in HPS patients following CEA and CAS.7 A recent large CAS series implemented an aggressive blood pressure protocol, which led to a statistically-significant reduction in the incidence of HPS.7 All 7 patients who developed HPS in our study had documented hypertension. The post-procedure blood pressure in the HPS cohort trended higher than the other patients, but this difference did not meet statistical significance (p = 0.12). Our data suggest that recent transient cerebral ischemia may predispose patients to HPS. Recent cerebral ischemia has been documented as a risk factor for HPS, but it is difficult to explain why transient ischemia in our study would be a significant risk factor and CVA would not be a predisposing variable. Increased expression of brain tissue vasoactive metabolites has previously been suggested by Mcfarlane et al as a possible mechanism of HPS.15 They proposed that the release of vasoactive neuropeptides from perivascular sensory nerves is likely causative. A possibility could be that infarcted brain tissue has less vasoactive metabolites than tissue transiently exposed to ischemia, though there is no scientific evidence to confirm this theory. Similar to Morrish et al,8 headache was not a major presenting factor in our patients. The exact incidence of headache associated with HPS is unknown, but other series have reported a high incidence of headache with HPS.6,7,9 Four (57%) of the HPS patients presented with seizure activity. A severe ipsilateral headache has been typically described preceding the seizure, but this was not present in our series. Study limitations. Limitations of our study include that it is a retrospective review and there was a small number of events, which provided very little power to find statistical differences between the HPS and non-HPS cohorts. Routine pre- and post-procedure independent neurology consultation as well as routine pre- and post-procedure CT imaging was not performed in all patients. Furthermore, this report may underestimate the incidence of HPS, since patients with an isolated headache did not meet our criteria. Study strengths. Strengths of our study include that it is a large, single-operator series with a high procedural success rate and low overall stroke and death rate. Also, the diagnosis required clinical features of HPS plus imaging documentation of HPS and exclusion of stroke. The stringent imaging requirements for diagnosis may have minimized the chance of mislabeling a patient as having HPS. The HPS incidence in this series is comparable with other large CAS and CEA series. Conclusion In conclusion, the incidence of HPS is low following CAS, but it is an important complication to distinguish from stroke and TIA, since its pathophysiology is different and its outcomes are typically very favorable.
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