Brain edema after carotid surgery

Analysis of patients.

Five patients developed the hyperperfusion syndrome during a 27-month period in which 184 CENs were performed at the New England Medical Center, a frequency of 2.7%. Four patients had CENs for severe ICA stenosis of >99%. One patient had a subclavian to ICA bypass for common carotid artery (CCA) occlusion. The contralateral ICA was occluded in one patient, and one patient had severe stenosis of the distal CCA. The contralateral ICA had moderate stenosis in three other patients. All patients developed headache, neurologic symptoms, and hypertension after discharge from the hospital. All five had white matter lucency indicative of edema on CT obtained when they developed focal neurologic signs. These lucencies resolved completely or partially on follow-up scans in three of the four surviving patients. Four of the five patients had focal seizures, and three had generalized seizures. One patient had headache, focal neurologic signs, and hemorrhage but no seizures. EEGs showed periodic lateralized epileptiform discharges (PLEDs) in two patients, ipsilateral hemispheral slowing in two patients, and was not done in one patient. The ICA was patent by ultrasound and/or angiography in all five patients. Two patients had headache before and two after hospital discharge.

Patient 1.

A 47-year-old smoker had elevated cholesterol levels and had been hypertensive for 10 years. He was referred for emergency right CEN because of frequent TIAs. For 3 months, he suffered many 5- to 10-minute episodes of right transient monocular blindness. During the past month, he had increasingly frequent 5- to 30-minute episodes of left body numbness, left hand clumsiness, and slurred speech. On admission, he had 2 hours of numbness of his left face and arm despite heparinization.

Examination showed a blood pressure of 160/90, pulse 72, a focal high-pitched right carotid bruit, and increased right facial pulses. Neurologic exam was normal except for decreased left face and arm sensation and increased left deep tendon reflexes. Bilateral carotid angiograms showed a severe (99%) right ICA stenosis and a moderate left ICA stenosis. An urgent right CEN with vein patch was done without recognized complications. Blood pressure intraoperatively ranged from 100/55 to 190/105.

Postoperatively, he was given neosynephrine because blood pressure ranged from 100/58 to 140/60 for the first 12 hours. Blood pressure then ranged from 145/80 to 160/100. The highest recorded blood pressure was 170/110 on one occasion. He did well for the first 24 hours and then had a throbbing headache on the right side. Neurologic exam was unchanged. Nifedipine was started for blood pressure control. Headache diminished by 48 to 72 hours after surgery, and he was discharged on postoperative day 3.

Headache returned on postoperative days 4 and 5. On postoperative day 5, he developed left visual and spatial neglect and a slight left hemiparesis. Blood pressure was 170/110. CT showed diffuse white matter edema (Figure 1 A, and Figure 1B) throughout the right frontal, parietal, and occipital lobes. Within hours, he became unresponsive and lost brainstem reflexes. Repeat CT (Figure 1C) showed areas of hemorrhage within the deep right frontal lobe white matter. Blood pressure remained elevated and labile ranging from 230/130 to 140/80. EEG showed continuous diffuse slow waves and right hemisphere (PLEDs). Carotid ultrasound showed patent carotid arteries. TCDs showed that the right ACA and MCA velocities were increased to twice normal. Despite aggressive treatment of both hypertension and increased intracranial pressure, he died. Necropsy was not performed.

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Figure 1. (A, B) Noncontrast head CT of Patient 1 performed on postoperative day 5 showing diffuse white matter edema throughout the right frontal and parietal lobes. (B) Small hyperdensity in the right frontal lobe representing a small hemorrhage. A midline shift is more evident. (C) Repeat noncontrast head CT of Patient 1 performed several hours after scan shown in A and B showing areas of hemorrhage within the deep white matter of the right frontal lobe and more extensive shift of the midline structures.

Patient 2.

An 82-year-old woman with elevated cholesterol, hypertension, and peripheral vascular disease had two spells of right hand and arm weakness lasting about 2 minutes, 2 and 4 months before admission. Preoperative exam showed a blood pressure of 130/70, bilateral carotid bruits, right-left confusion, and extinction to double simultaneous stimulation on the right. Carotid angiography showed a high-grade left ICA stenosis and a tight stenosis of the distal right common carotid artery. She had an uneventful left CEN. Blood pressure intraoperatively ranged from 110/70 to 180/90 (mostly around 160/70) with one reading of 200/90. She required Nipride for the first 4 postoperative hours for blood pressure control. Blood pressure remained in the 140/70 range for the first 24 hours, rose to a maximum of 170/80 on postoperative day 2, but remained in the 140/80 to 160/80 range until discharge on postoperative day 4. She was asymptomatic at discharge.

On postoperative day 8, she had a generalized seizure at home and another seizure at a local hospital. Examination showed a blood pressure of 164/74, aphasia, and right arm weakness. CT showed hypodensity in the left subcortical white matter (Figure 2 A, Figure 2B, and Figure 2C). Carotid ultrasound showed patent carotid arteries. Symptoms cleared quickly, and she was discharged home 12 days later with only aphasia and minimal weakness of her right face and arm. Follow-up CT 2 months later was improved.

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Figure 2. (A-C) Noncontrast head CT of Patient 2 performed on postoperative day 8 showing edema in the left subcortical white matter on three different sections.

Patient 5.

An 81-year-old woman with hypertension, coronary artery disease, and atrial fibrillation had a 3-month history of increasingly frequent attacks of weakness on her left side. Neurologic exam was normal and preoperative blood pressure ranged from 140/80 to 170/90. Angiography showed a severe right ICA stenosis. She had an uneventful right CEN. Intraoperative blood pressure ranged from 150/90 to 190/90.

Postoperatively blood pressure was slightly elevated in the 140/50 to 180/80 range, and her diltiazem controlled release dose was increased from 180 to 240 mg daily. Blood pressure on the day of discharge was 180/90 but then dropped to 105/50. She had occasional headache, but otherwise was well when discharged home on postoperative day 4.

The next day, she had severe headache on the right side, left focal seizures, increased blood pressure, confusion, left visual field loss, left hemiparesis, and left hemisensory loss. CT showed an old right posterior parietal infarct and white matter edema in the high right centrum semiovale. Carotid ultrasound showed patent carotid arteries. TCDs showed bilateral increased velocities in the MCAs >ACAs> PCAs. EEG showed right hemishpere PLEDs.

During the first 36 hours after admission, blood pressure was difficult to control despite multiple medications, including IV nitroprusside, and she continued to have left-sided epilepsia partialis continua, severe headache, left visual neglect, confusion, and left hemiplegia. As the blood pressure was controlled (125/65 to 145/70 range), focal seizure activity diminished and then stopped and her neurologic signs improved. By postoperative day 11, she had no further seizures. Blood pressure and neurologic examination improved, her TCD velocities decreased, and CT edema resolved.

During the next 10 days, she became confused, disoriented, agitated, paranoid, and had headache when the systolic blood pressure increased above 160 mm. Symptoms improved with reduction of systolic blood pressure to lower than 140 mm. Episodes gradually became less frequent. She was discharged to a rehabilitation hospital on postoperative day 27 and went home on postoperative day 46.

Hyperfusion syndrome.

Sundt et al ^[8] first used the term hyperperfusion syndrome to describe patients with headache, seizures, and brain hemorrhages after CEN because they all had unusually high ipsilateral CBF postoperatively. They found 20 patients with the hyperperfusion syndrome among 1145 consecutive CENs performed at the Mayo Clinic between 1972 and 1981, for a frequency of 1.8%. ^[8] Six patients had transient ischemic attacks with migrainous components occurring 5 to 7 days after surgery, one of whom had a persistent visual field defect. Eleven patients had focal seizures 5 to 7 days after CEN. There were no major ischemic infarctions. Five patients had postoperative ICH, four of whom died. Mean CBF after surgery doubled in patients with migrainous ischemia and seizures and nearly tripled in patients with ICH. ^[8]

Reigel et al ^[19] retrospectively reviewed the records of 2439 Mayo Clinic patients who had CEN between 1972 and 1985 and reported a few patients with unilateral headache and seizures several days after CEN. The combined frequency of seizures and ICH was 1%. Among 11 patients who developed postoperative seizures (0.45%), postoperative blood flow volume increased more than twofold and up to three- or fourfold in some patients. One of the seven patients described by Reigel et al ^[19] had patchy brain edema. CTs of the other six patients were normal. CTs have been normal in other patients with headache and seizures after CEN. ^{[12-15,18,21,27,31]}

The frequency of ICH after CEN ranges from 0.3% to 1.2%, ^{[8,11,15,17,20,23,24,26,29,30]} about equal to the frequency of recurrent thrombosis, ischemia during cross-clamping, and embolization as causes of perioperative stroke. ^[23,30] Peak postoperative blood pressures of most reported patients with ICH after CEN were higher than preoperative pressures. Among 2362 consecutive CENs performed at the Mayo Clinic between 1972 and 1986, 14 patients had ICH (0.6%). ^[24] Nine of these patients had at least a 100% increase in postoperative blood flow, and hyperperfusion was present in 12 of 14. Eight patients died, and only two patients made a good recovery. Nine patients had preoperative hypertension. Seven had peak postoperative blood pressures higher than preoperative pressures, and four had peak systolic pressures > 180 mm Hg. Schroeder et al ^[23] reported eight patients among 662 (1.2%) consecutive CENs who had postoperative ipsilateral ICH in brain regions with no preoperative infarction. ICH developed 3 hours after surgery and on postoperative days 1 to 5 in the other seven patients, all of whom developed moderate to severe hypertension. Four patients had seizures. Four of the eight patients died, two after ICH and two after brain edema and hemorrhage. Four patients made good recoveries. Seven patients had CTs; three showed hemorrhage and edema and four had hypodensity followed by hemorrhage or hemorrhage with severe edema more than expected for the hemorrhage size.

Schroeder et al ^[22] used intravenous xenon to measure CBF before surgery in 56 patients who had uncomplicated CEN. CBF studies were performed in 39 patients between postsurgical days 1 and 11 and in 11 patients 2 to 4 months after surgery. Within the first postoperative day, CBF increased on average 37% in the hemisphere ipsilateral to CEN and 33% in the contralateral hemisphere. More pronounced and persistent flow increases were found in 16 patients who had preoperative ICA:CCA pressure ratios < 0.7, all of whom had ICA stenoses > 50%. In patients with preoperative ICA:CCA ratios > 0.7, CBF returned to preoperative levels after the first postoperative day. In patients with an ICA:CCA ratio < 0.7, CBF increased most during the 4 days after surgery, but significant increases persisted during days 5 to 11. Flows normalized by 2 to 4 months after surgery. ^[22] TCD is now used to study regional blood flow velocities. ^[28,31]

Most reports do not note CT changes, but some describe hemorrhage into recently infarcted brain and "delayed postoperative infarction." Harrison et al ^[29] reported two post-CEN patients with headache and seizures, one of whom had a hemorrhage and died. Both patients had white matter hypodensity on CT consistent with edema, but this was not emphasized by the authors. Among the series by Reigel et al ^[19] among 10 patients with the hyperperfusion syndrome, 1 patient had bilateral diffuse patchy edema 5 days after surgery that later resolved.

All of our five patients with the hyperperfusion syndrome had similar brain edema abnormalities on CT. Edema was limited to white matter ipsilateral to the surgery; the cerebral cortical grey matter was always spared. The white matter of the high centrum semiovale was predominantly involved sometimes with finger-like projections into the subcortex. When edema was severe, the deeper white matter was involved, causing more mass effect.

Relation of brain edema to hypertension and autoregulation.

Hypertensive, encephalopathy is an acute condition in which severe hypertension is associated with headache, focal neurologic signs, seizures, and, later, depressed mental state and coma. ^[35-39] Sundt et al ^[8] first suggested the association of hypertensive encephalopathy and the hyperperfusion syndrome in 1981: "Cerebral hyperperfusion can result in a form of unilateral hypertensive encephalopathy with intracerebral hemorrhages, seizures, and migraine variants." The pathophysiology of hypertensive encephalopathy is probably high-pressure autoregulatory failure in which very high perfusion pressures overwhelm arteriolar vasoconstriction ability. ^[36,39-41] When the upper limit of autoregulation is exceeded, hyperperfusion of brain tissue ensues; capillaries leak; and cerebral edema, hemorrhage, and infarction occur. Studies in animal models show that the increase in intracapillary pressure occurs when the upper limit of autoregulation is exceeded, disrupting tight junctions of capillary endothelial cells and allowing extravasation of protein and fluid, causing brain edema. ^[42,43] CT often shows white matter lucencies that usually resolve with control of blood pressure, but permanent areas of damage are described. ^[44] Experimental data show that chronic white matter edema can cause gliosis, ^[45,46] providing a possible explanation for persistent changes.

The pathologic findings in the hyperperfusion syndrome after CEN ^[15,23,29] resemble those found in hypertensive encephalopathy ^[35-38] and in the reperfusion syndrome after resection of brain arteriovenous malformations. ^[47] All are characterized by fibrinoid necrosis and thrombosis of cerebral arterioles, microinfarctions, and petechial hemorrhages. ^{[15,23,29,35-38,47]} The degree and duration of blood pressure elevation correlates with the severity of edema on CT. ^[44] In two of our patients, episodic headache, seizures, confusion, and focal signs correlated very well chronologically with periodic uncontrolled hypertension.

Autoregulation describes the ability of brain arteries to vasodilate in response to a fall in perfusion pressure to maintain CBF and to vasoconstrict to limit brain perfusion in response to rises in systemic blood pressure. In patients with normal carotid arteries, MCA blood flow velocities increase during hypercapnia and decrease during hypocapnia. ^[48-50] CO₂ reactivity is reduced in some patients with severe ICA stenosis or occlusion in whom cerebral vessels are refractory to vasodilator stimuli such as CO₂ because they are already maximally dilated to maintain perfusion. ^[31,51] The loss of autoregulation associated with severe stenosis is probably critical for development of neurologic symptoms and white matter edema in the hyperperfusion syndrome. Without normal autoregulation, the increased perfusion pressure caused by elevated systemic blood pressure cannot be accommodated. The hyperperfusion syndrome also occurs in patients with normal blood pressure after resection of AVMs. ^[47]

All of our patients had a history of moderate to severe hypertension and severe (99%) carotid stenosis. All had hypertension after surgery, which, when combined with loss of autoregulation and maximal vasodilatation secondary to severe carotid stenosis, led them to develop unilateral brain edema. Most reports of the hyperperfusion syndrome note increased peak postoperative blood pressures. Blood pressures were higher at the time of presentation with the hyperperfusion syndrome than at discharge after CEN in all of our patients. Table 1 and Figure 3 show the blood pressures in our patients. The cause of postoperative rise in blood pressure is not known, but it is more common after bilateral carotid surgery and is likely caused by dysfunction of the carotid sinus reflex. ^[52,53]

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Figure 3. Graph of systolic blood pressures at various times during hospitalization.

Why has brain edema not been previously reported as a feature of the post-CEN hyperperfusion syndrome?

White matter edema has probably been overlooked in some patients because the changes were slight, and earlier generation CTs had lower resolution. In most patients, the edema was probably misinterpreted as infarction. In four of our five patients, CTs were first interpreted as showing infarction.

The frequency of the hyperperfusion syndrome was higher in our series than in earlier reports, ^[8,19] but our frequency of hemorrhage after CEN (0.5%) was the same as in other series (0.3% to 1.2%). The frequency of the hyperperfusion syndrome is difficult to estimate because cases have usually been reported as seizures or ICH. The hyperperfusion syndrome is underreported because symptoms often develop after discharge from the hospital, patients are readmitted to other hospitals and other medical service, and the findings are misinterpreted as reflecting TIAs or strokes. Postoperative seizures are often attributed to embolic stroke from the surgical site. Three of our patients were initially diagnosed as having postoperative strokes.

The hyperperfusion syndrome is more common than is now recognized.

Our cases show that the clinical definition should be expanded to include focal neurologic signs associated with white matter edema. Brain edema must be differentiated from thromboembolic stroke because the causes and treatment are different. Brain edema can be severe and even fatal as in patient 1. Good outcome in our other patients indicates that aggressive control of hypertension and edema is usually effective. The fact that this syndrome and hypertension developed in all of our five patients after hospital discharge indicates that it is critical to keep patients who have had CEN under careful surveillance, including measurement of blood pressure for >or=to2 weeks after surgery.