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Cerebral hyperperfusion, or reperfusion syndrome, is a rare, but serious, complication following revascularization. Hyperperfusion is defined as a major increase in ipsilateral cerebral blood flow (CBF) that is well above the metabolic demands of the brain tissue. Quantitatively, hyperperfusion is a 100% or greater increase in CBF compared with baseline.
This definition also extends to rapid restoration of normal perfusion pressure, for example, with thrombolytic therapy for acute ischemic stroke. Reperfusion syndrome can occur as a complication of carotid endarterectomy (CEA), intracranial stenting, and even bland cerebral infarction.
The terms hyperperfusion and reperfusion are often used interchangeably. The former implies excessive flow, while the later suggests normalization of flow. Both can result in cerebral injury with similar clinical pictures, which is the reason for the substitution of terms. However, not all patients with hyperperfusion are symptomatic; conversely, patients with only moderate rises in CBF can have devastating outcomes. Therefore, some authors prefer to address this subject as reperfusion syndrome.
When patients are identified and treated early, the prognosis is better and the incidence of intracranial hemorrhage is decreased. Outcomes are dependent on timely recognition and prevention of precipitating factors. Most important is the treatment of hypertension before it can inflict damage in the form of edema or hemorrhage.
The prognosis following hemorrhagic transformation is poor. Mortality in such cases is 36-63%, and 80% of survivors have significant morbidity.
Studies indicate that reperfusion injury is involved directly in the potentiation of stroke damage. Components of the inflammatory response, including cytokine release and leukocyte adhesion, appear to play key roles in these deleterious effects.
Damage to the blood-brain barrier (BBB), an important factor in reperfusion injury, is seen in the image below.
Symptoms of Cerebral Reperfusion Syndrome
Cerebral reperfusion syndrome presents as a triad of ipsilateral headache, contralateral neurological deficits, and seizure.
The time frame in which symptoms arise can be from immediately after restoration of blood flow to up to 1 month after restoration. Patients are usually symptomatic within the first week.
Headache is the most common symptom (62%). Typically, patients display migrainous features with severe, ipsilateral, pounding headache.
Deficits are usually cortical (eg, hemiplegia, neglect, aphasia) or may involve worsening of a preexisting deficit. By the same token, seizures may present as focal or generalized, depending on the cortical area affected.
Causes of Cerebral Reperfusion Injury
Overview of risk factors
Several mechanisms have been proposed for the pathogenesis of cerebral reperfusion injury. As time passes following arterial occlusion or partial occlusion, the basic idea is that for a period of time collateral circulation will sustain normal neurological function, which is dependent on the individual and their risk factors. Eventually compensation for hypoperfusion will lead to increased vascular resistance and venous collapse. The extent of reperfusion injury will depend on the individuals time since collateral collapse and irreversibly damaged tissues. There are a number of events that can lead to this situation, such as postoperative hypertension, to molecular modalities, such as free oxygen radical release. Each theory is complex and none are widely accepted. For the time being, known risk factors include the following:
- • Postoperative hypertension
- • High-grade stenosis with poor collateral flow
- • Decreased cerebral vasoreactivity
- • Increased peak pressure, such as in contralateral carotid occlusion
- • Recent contralateral CEA (< 3 mo)
- • Intraoperative distal carotid pressure of less than 40 mm Hg
- • Intraoperative ischemia peak flow velocity
Hypertension
Elevated blood pressure is the most common factor found in symptomatic patients. During acute ischemic stroke, systemic blood pressure often rises as a physiologic compensation for cerebral ischemia. As a rule, elevated blood pressure is not treated, so as not to compromise flow to the tenuous penumbra. The key to reperfusion injury in this scenario is ischemic disruption of the blood-brain barrier (BBB). The offended BBB contains abnormally permeable ischemic capillaries.
Adding insult to injury, these small vessels do not have a substantial conduit to buffer systemic pressures. The injured endothelium is unable to maintain its structural integrity against systemic vascular resistance, thus resulting in reperfusion injury or hemorrhagic transformation. Hypertension-related hemorrhage is seen in the image below.
Dysautoregulation
Cerebral autoregulation protects the brain against changes in systemic blood pressure. A drop in blood pressure could lead to ischemia, while on the other hand, a sudden rise could lead to edema or hemorrhage. In patients with high-grade stenosis, CBF is maintained at the expense of maximal arteriolar vasodilatation.
Chronic cerebral hypoperfusion (eg, critical stenosis) leads to the production of carbon dioxide and nitric oxide. These are vasodilatory substances that cause endothelial dysfunction. In the absence of cerebral autoregulation, CBF is directly dependent on the systemic blood pressure. Correction of a critical stenosis causes rapid and large changes in the CBF, which can lead to edema or hemorrhage.
Ischemia-reperfusion
Ischemia-reperfusion injury is characterized by oxidant production, complement activation, and increased microvascular permeability. Various cytokines peak in the serum within the first 24 hours of an acute stroke and are thought to initiate the cascade of tissue damage. At the site of ischemia itself, activated leukocytes release free radicals and toxins, causing further destruction. The combination results in an impaired BBB, which can lead to cerebral edema and/or hemorrhage. These changes are especially important in the setting of hypertension, as indicated above.