Clinical manifestations

Presentation and course

The clinical manifestation of neurologic complications after cardiac surgery depends on the level of involvement of the nervous system. Neurologic complications of cardiac procedures can involve any part of the central and peripheral nervous systems (see Table 1).

Table 1. Neurologic Complications Associated with Cardiac Procedures

Coronary artery bypass grafting. Coronary artery bypass grafting (CABG) is the most common surgical procedure performed in the United States. On average, over one million coronary artery bypass grafting procedures are performed in the world every year with over half of these performed in the United States. This number of surgeries performed on patients with advanced age (ie, the octogenarian population), who often have several comorbid diseases making them high risk for cerebrovascular disease, will continue to rise.

After coronary artery bypass grafting, patients may present with signs and symptoms of dysfunction in four general categories: (1) cerebrovascular events, (2) encephalopathy or coma, (3) early or delayed cognitive impairment, and (4) other neurologic events.

Cerebrovascular events. The incidence of clinically detectable stroke after CABG varies from 0.8% to 5.0% (199; 13; 47; 43; 227). The incidence varies depending on a number of factors including whether the study was retrospective or prospective, the type of operation, age of the patient population, and the sensitivity of the tests performed. Using highly sensitive diffusion-weighted MRI increases the incidence of cerebral infarctions to 18%. However, about two thirds of these infarcts are asymptomatic (73). Most patients (61%) present with clinical evidence of stroke within the first 2 days after coronary artery bypass grafting, with the majority being intraoperatively (124; 135). Less commonly, strokes can occur after a few days of delay, often related to cardiac arrhythmias such as atrial fibrillation.

The largest and most significant independent risk factors for stroke after CABG include advanced age, prior stroke, prior peripheral arterial disease including carotid artery stenosis, and prolonged cardiopulmonary bypass time (135). Having a history of stroke or transient ischemic attack appears to portend a higher risk of postoperative cerebral ischemia (47).

Atheromatous aorta and carotid artery disease are known predictors for stroke after CABG. In patients with carotid occlusion or stenosis of greater than 75%, prophylactic cerebrovascular interventions and the selective use of aorta no-touch, off-pump coronary artery bypass can significantly reduce the incidence of perioperative stroke (156). A meta-analysis of 11,398 cases from eight studies corroborated the finding that avoidance of aortic manipulation during off-pump CABG decreases neurologic complications (144). This advantage of off-pump over the use of cardiopulmonary bypass, on-pump, CABG is likely to be more evident in those at highest risk, such as the elderly (75). Whether the routine use of cardiopulmonary bypass has a significant impact on the incidence of ischemic events is unclear. However, multiple systemic reviews have not found a significant benefit of off-pump compared with on-pump CABG with regard to incidence of stroke (148; 187).

Another controversial question is the timing of operative interventions for patients with concurrent carotid and coronary artery disease. It has not been proven that the benefit of either STAGED or SYNC CEA-CABG procedures outweigh the risks in asymptomatic patients; however, carotid revascularization may be justified in symptomatic or high-risk patients such as those with contralateral carotid occlusion or bilateral high-grade stenosis. Gopaldas and colleagues compared outcome data from a nationwide database of 6153 patients who underwent carotid endarterectomy (CEA) before or after CABG during the same hospital admission but not on the same day (STAGED) and 16,639 patients who underwent both procedures on the same day (SYNC) (82). They found no significant difference in mortality or neurologic complications between STAGED and SYNC approaches. On-pump CABG was associated with higher stroke rates in SYNC patients.

The clinical picture of cerebrovascular events following CABG varies, and it depends on the location, number, and extent of lesions affecting the brain. In a study of strokes after CABG, embolic strokes accounted for 62.1%, followed by multiple other etiologies (10.1%), including: hypoperfusion (8.8%), lacunar (3.1%), thrombotic (1.0%), and hemorrhage (1.0%). Nearly 14% of strokes after CABG were of unknown etiology. Nearly 45% (105 of 235) of the embolic, and 56% (18 of 32) of hypoperfusion strokes occurred within the first postoperative day, and an additional 20% occurred by day 2 (126). Further information about embolic cerebral infarctions, watershed (border-zone infarctions), and lacunar infarctions associated with CABG is discussed below.

Embolic cerebral infarctions. Embolic infarctions are the most common type of infarction occurring in the perioperative period with CABG.

Clinical manifestations of embolic infarctions may include a decreased level of consciousness at onset of stroke, a sudden onset of symptoms and signs that are maximal at onset, and symptoms reflecting involvement of different vascular territories of the brain due to multiple emboli. However, such a clear history may be difficult to obtain in cases of perioperative strokes. Cortical deficits, such as aphasia, visual field deficits, and neglect, commonly reflect involvement of the territories of the middle and posterior cerebral arteries and their branches. Multiple bilateral infarctions in the cerebral white matter may lead to spastic diplegia. Other, rare presentations have been reported, such as fixed, dilated pupils after cardiac surgery due to bilateral anteromedial midbrain infarctions (38; 29). On the general examination, there may be evidence of cardiac dysrhythmias such as atrial fibrillation or, rarely, other signs of systemic embolism.

In cases of arterial air embolism, clinical features include headaches, dizziness, visual manifestations, focal motor/sensory neurologic deficits, changes in sensorium, coma, seizures, and status epilepticus.

Watershed (border-zone) cerebral infarctions. Watershed (border-zone) infarctions typically occur in the setting of prolonged hypotension, but they can also occur in patients without documented hemodynamic instability. The cause in such situations is possibly secondary to sustained showers of microemboli that lodge in the terminal portions of the circulation. This results in a clinical and radiological picture resembling territories with perfusion failure (98).

In situations of generalized hypoperfusion, the vulnerable watershed regions are most commonly encountered in areas between the arterial distributions of the anterior and middle cerebral arteries. In addition, there is a boundary zone between the three major cerebral arteries, located in the posterior parietal lobe, and a similar boundary zone between the territories of supply of the superior cerebellar and posterior inferior cerebellar arteries. In general, these types of infarcts result in bilateral and symmetric lesions.

Watershed infarctions can produce distinctive clinical manifestations. Infarctions that occur in the regions between the middle and posterior cerebral arteries may result in Balint syndrome. Balint syndrome is characterized by visual or spatial disorientation, apraxia of gaze, optic ataxia, and simultanagnosia. Simultanagnosia is a rare condition when an individual is not capable of perceiving more than one object at a time. The syndrome may also initially result in cortical blindness that improves but leaves a residual of dyslexia, dyscalculia, dysgraphia, and memory defect of verbal and nonverbal material. Watershed ischemia of anterior, middle, and posterior cerebral arteries may result in bilateral lower altitudinal visual field defects and difficulty in judging size, distance, and movements. Bilateral ischemia between the anterior and middle cerebral arteries can result in bilateral arm sensory and motor impairments, which is also known as man-in-the-barrel syndrome. Watershed cerebellar ischemia can present as dizziness, vertigo, and ataxia.

Lacunar infarctions. A small number of patients (about 16%) will have evidence of lacunar infarctions involving the small subcortical territories after cardiac surgery (124). The clinical manifestations are similar to the traditional lacunar syndromes. However, unlike the traditional lacunar syndromes, the mechanism may be different. It has been suggested in animal models and in clinical studies that the mechanism of lacunar infarction in this population is due to microembolization of the terminal vessels. Lacunar infarction in this population is often due to small emboli that occlude single perforating arteries (22; 131; 124).

Encephalopathy or coma. Patients may present with signs and symptoms of encephalopathy. Often in the literature, terms “encephalopathy” and “delirium” are used interchangeably for the same phenomenon. Patients may emerge from anesthesia with persistent agitation or confusion, or they may simply remain in a state of reduced consciousness for longer than anticipated, but generally do not have evidence of focal motor or sensory deficits. Encephalopathy is usually evident after extubation and is a strong independent predictor of mortality up to 10 years postoperatively, especially in younger individuals and in those without prior stroke (84). Although metabolic and drug-related causes need to be ruled out, there is evidence that encephalopathy after CABG may be due to showers of microemboli. There may be evidence of multifocal small areas of brain ischemia on diffusion-weighted MRI after surgery. It has been suggested that encephalopathy, stroke, and coma represent a continuum of conditions with the same underlying mechanism of showers of embolic material to the brain (81; 141). In a prospective series of over 8000 patients undergoing CABG, postoperative delirium was present in 5.8% of patients. This independently predicted perioperative stroke and was associated with long-term risk of death and stroke (136).

Coma can occur in patients with brainstem or significant bilateral hemispheric ischemia. Severe global hypoperfusion can lead to severe brain injury, coma, or death.

Early and delayed cognitive impairment. Neuropsychological dysfunction or cognitive decline is a well-described complication of CABG. Neurocognitive decline is common after cardiac surgery, varying from 7% to 49% at 3 months and up to 33% after 1 year (173; 157; 214). This discrepancy in the frequency of its occurrence is likely due to differences in patient selection, the definition of neuropsychological decline, the timing and type of neuropsychological testing, and multiple other factors (70).

One of the most frequently described causes of neuropsychological decline after CABG is that related to showers of microemboli to the brain, as observed in autopsy studies and as documented by transcranial Doppler monitoring during cardiopulmonary bypass. Although there is little dispute that microembolism occurs, assessing the impact of this phenomena on short- and long-term cognitive functioning is more difficult for the reasons alluded to above. A significant relationship between intraoperative cerebral oxygen desaturation and early postoperative cognitive decline has also been described (196).

Newman and colleagues evaluated 261 patients undergoing CABG using cardiopulmonary bypass with a battery of cognitive tests before surgery and at intervals up to 5 years after surgery (157). The incidence of cognitive decline at discharge, 6 weeks, 6 months, and 5 years was 53%, 36%, 24%, and 42%, respectively. Cognitive function at discharge was a strong predictor of long-term function. The reason for the increase in cognitive decline at 5 years that was observed in this study is not known.

A study evaluating late progressive decline in memory and neurocognitive function after CABG done with a well-matched control group has failed to demonstrate significant cognitive decline, suggesting that the decline in cognition observed was likely related to preexisting vascular disease, new neurologic events, or other coexistent neurodegenerative disease, but not related to the cardiac bypass procedure (185; 142). Supporting this finding are the results of a longitudinal study of 170 patients who underwent neuropsychological testing at baseline and at 1 year following surgery (60). Although postoperative cognitive decline was observed in 18.2% of patients at 6 weeks, only half of those demonstrated the impairment at 1 year. An additional 15.8% of those who did not have cognitive impairment at 6 weeks developed it by 1-year follow-up, suggesting that factors other than the surgery are responsible for the majority of delayed cognitive impairment.

Minimally invasive endoscopic CABG (Endo-CABG) is a newer surgical technique that avoids medial sternotomy and allows for faster recovery. Rates of stroke, delirium, and postoperative cognitive dysfunction after Endo-CABG are 1.72%, 8.6%, and 13%, respectively (200). Rates of stroke and postoperative cognitive dysfunction were similar to percutaneous cardiac intervention, though a head-to-head comparison of neurologic outcomes after Endo-CABG versus traditional CABG has not been done.

Other neurologic events. Infarction of the spinal cord has rarely been described after CABG (218). Symptoms typically reflect involvement at the mid-thoracic spinal cord level, between the circulatory areas of the descending spinal arteries and the areas of the artery of Adamkiewicz. Patients may present with an anterior spinal artery syndrome with acute urinary retention, flaccid paraparesis, and a dissociated sensory loss, typically with a sensory level to pinprick and temperature sensations with intact position and vibration sense. There has been a case report of a modified Brown-Sequard syndrome secondary to CABG (83). Etiology is poorly understood, though hypotheses include hypoperfusion and embolism of atherosclerotic plaque. Certain surgical techniques may increase the risk of spinal cord ischemia, including manipulation of the aorta and interruption of collateral blood supply, by harvesting the internal mammary arteries.

Pituitary apoplexy is a rare phenomenon following CABG and is characterized by headache, nausea and vomiting, diplopia and changes in vision or visual fields, and cranial nerve palsies (09). Postulated mechanisms relate primarily to changes in physiology resulting from cardiopulmonary bypass, leading Levy and colleagues to recommend operating on patients with pituitary adenoma who need a CABG off pump in order to prevent pituitary apoplexy (122).

Central retinal artery occlusion or branch retinal artery occlusion may occur with CABG, most commonly due to embolism. Patients are noted to have acute onset of complete visual loss in one eye (with central retinal artery occlusion) or acute onset of partial visual loss in one eye (with branch retinal artery occlusion).

Ischemic optic neuropathy is an extremely rare event after cardiac surgery, with an overall frequency of 0.06% (159). Anterior ischemic optic neuropathy is characterized by sudden painless visual loss involving mainly the lower part of the visual field in one eye with optic disc swelling. Posterior ischemic optic neuropathy is characterized by unilateral or bilateral loss of visual acuity, visual fields or blindness without disc swelling. Factors associated with visual loss after cardiopulmonary bypass include anemia, history of clinically severe vascular disease, and preoperative coronary angiogram within 48 hours of surgery (159).

An uncommon cause of transient ischemic attack is the coronary-subclavian steal syndrome caused by atherosclerotic disease or the proximal left subclavian artery in the post-coronary artery bypass graft patient. This can present with angina or with lightheadedness, left arm numbness or weakness, and a difference in systolic blood pressure between the right and the left arm (178).

Peripheral nerve dysfunction. The most common nerves to be injured in cardiac surgery are the lower trunk of the brachial plexus and the phrenic nerve. Other nerves that may be damaged include the ulnar nerve, the recurrent laryngeal nerve, the saphenous nerve, the common peroneal nerve, and the cervical sympathetic chain.

Brachial plexopathy may occur when the brachial plexus is stretched during a median sternotomy. At the time of median sternotomy, it may be disrupted by the use of sternal retractors or when there may be direct trauma to the brachial plexus from first rib fracture fragments or an associated fracture hematoma directly compressing the nerves (188; 35). Clinically, patients with a lower trunk brachial plexopathy may present with sensory loss on the dorsal and palmar surfaces of the fifth digit and medial half of the fourth digit and the ulnar part of the wrist to the hand. There may be paresis or paralysis of all intrinsic hand muscles and a “claw hand” deformity. Patients with injured nerves tend to be older and to have had longer operation times. Also, an ulnar neuropathy can occur due to compression at the elbow or at the wrist and hand.

Phrenic nerve injury, resulting in unilateral or bilateral diaphragmatic paralysis, may result from direct manipulation of the nerve, trauma to the nerve during internal mammary artery dissection, ischemia, or topical hypothermia (58; 106; 188).

The left recurrent laryngeal nerve may be injured during internal mammary artery dissection and may be affected by ice water that is introduced to the pleural cavity. Other mechanisms of damage may occur during endotracheal intubation, central venous catheter placement, or surgical dissection (188).

The saphenous nerve may be injured during harvesting of the long saphenous vein. Patients present with a saphenous neuralgia, which is characterized by anesthesia, hyperesthesia, and pain along the medial calf and foot to the great toe.

Very rarely (in 0.19% of patients), the common peroneal nerve may be affected during CABG with damage to the nerve at the fibular head due to nerve ischemia from compression or stretching (215).

Finally, the cervical sympathetic chain, which lies medial to the inferior trunk of the brachial plexus, may be injured during sternal retraction with a posterior first rib fracture (188). Clinical findings are Horner syndrome with ptosis, miosis, and anhidrosis.

Ventricular assist devices. Ventricular assist devices (VADs) are implanted continuous flow pumps that assist and support circulation. Due to the growing prevalence of end-stage heart failure, ventricular assist devices are being inserted into an increasing number of patients with advanced heart failure. These devices improve survival and quality of life (197). Most patients (> 90%) receive a left ventricular assist device (LVAD). Others receive biventricular support, otherwise known as a biventricular devices (BiVAD), which includes a right ventricular assist device (RVAD) in addition to the left, an isolated RVAD, or a total artificial heart (189; 147). Neurologic complications are the second most common cause of death of LVADs after multisystem organ failure and include ischemic stroke, intracerebral hemorrhage, and air embolism (147). Risk factors for the development of neurologic complications beyond the presence of the device itself and the need for systemic anticoagulation include previous stroke, persistent malnutrition and inflammation, severity of heart failure, post-LVAD infections, atrial fibrillation, and mechanical factors associated with the device itself, including deposition of fibrin/protein material throughout the assembly (105; 222).

Ischemic or hemorrhagic stroke is the most common neurologic complication in patients with LVADs (192). Causes include inadequate anticoagulation, septic emboli from infected thrombus in the device, heparin-induced thrombocytopenia, and comorbid atrial fibrillation (206). In a series of 173 consecutive patients undergoing VAD implantation, 2.3% experienced a hemorrhagic stroke and 5.2% an ischemic stroke (114). Neurologic complications are more common in total artificial heart (TAH) implantation. Copeland and colleagues reported on a series of 101 patients who underwent TAH implantation (46). Of these, 7.9% experienced embolic strokes, of which five occurred within 9 days after device implantation. During 24 years of patient follow-up, only three strokes occurred while on chronic support, suggesting that the highest risk is in the perioperative period. One patient in this series experienced severe cerebral air embolism.

These implanted mechanical devices require systemic anticoagulation to an INR of 2.5 to 3.5 in addition to antiplatelet therapy in order to prevent stasis or thrombosis of the device components. This, along with the effects of being on cardiopulmonary bypass, including platelet dysfunction, platelet consumption, and hemodilution of clotting factors, may increase the risk of bleeding complications. Intracerebral hemorrhage occurs in 13% to 14% of patients with VADs (56). The design of left ventricular assist devices continues to advance as technology improves, leading to a lower incidence of stroke with the newer devices (192).

Extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation (ECMO) is increasingly used as a last resort to maintain oxygenation when other treatment options for cardiopulmonary failure have failed. Neurologic complications have been reported to occur in up to half of patients, though the rate has declined over time, with recent reports of such complications in 13% of adults and 21.3% of children (128; 226). Reported neurologic complications include cognitive impairment, seizures, strokes, intracerebral hemorrhage, ischemic encephalopathy, brain death, foot drop, deafness, and paraplegia (225). Brachial plexus injury has also been reported and is postulated to result from axillary artery cannulation resulting in hematoma formation (145). In a series of 15 patients undergoing ECMO as a bridge to lung transplantation, 10 (66%) developed critical illness polyneuropathy (48).

Aortic surgery. According to The Society of Thoracic Surgeons Adult Cardiac Surgery Database, approximately over 14,000 surgeries for aortic aneurysms are performed each year, with the majority of these involving the ascending aorta (25). Complications related to surgery on the aorta are highlighted here.

Cerebral and brainstem ischemia. Rates of stroke following open surgery for thoracic aortic disease have been reported at 6% to 11% (151; 203). The report incidence of stroke after thoracic endovascular aortic repairs (TEVAR) ranges from 3.2% to 6.2% (212). Risk factors for cerebral ischemia included obesity, significant intraoperative blood loss, and evidence of peripheral vascular thrombosis. Severe atheromatous disease involving the aortic arch was strongly associated with perioperative stroke (88). Manipulation of the aorta has resulted in embolization of neo-endothelium to the vertebral artery and cerebellar infarction, as was reported in the case of a patient undergoing redilation of an aortic stent (23). In a retrospective review of patients who underwent TEVAR, all strokes were embolic, and patients with posterior circulation strokes were less likely to achieve a full neurologic recovery than those with anterior circulation strokes (211).

Seizures. A prospective database of 2578 consecutive patients undergoing cardiac surgeries, of which 290 were aortic, reported a 5% seizure incidence in aortic surgeries. The increased incidence of seizure in aortic surgeries is likely related to the requirement for deep hypothermic circulatory arrest. The OR for postoperative seizures among those undergoing deep hypothermic circulatory arrest among all cardiac surgeries was 7.4, representing the strongest predictor of seizures among this population, greater than extensive aortic calcification or atheroma (OR 3.1) (80).

Spinal cord ischemia. Spinal cord ischemia following endovascular procedures of the thoracic aorta can occur due to left subclavian artery coverage. Based on European Collaborators on Stent/Graft Techniques for Aortic Aneurysm Repair (EUROSTAR) registry data, rates of spinal cord ischemia range from 0% in patients who underwent prophylactic left subclavian artery revascularization to 8.4% when there was left subclavian artery coverage without revascularization (32). This is contrasted with reported rates for paraplegia following open surgery for thoracic aortic disease of 3% to 19% (151). Risk factors for SCI include older age, chronic obstructive pulmonary disease, chronic renal insufficiency, hypertension, aneurysm as an underlying pathology, the use of an iliac conduit, and coverage of the hypogastric artery (110; 181).

Peripheral nerve dysfunction. Peripheral nerve ischemia has been reported after internal iliac artery ligation, which may also be injured during endovascular repair. Likewise, ischemic injuries to the spinal cord, nerve roots, or lumbosacral plexus as well as chronic ischemic monomelic neuropathies may complicate emergent and reoperative abdominal aortic reconstruction or critical limb ischemia (168; 190; 220). The most common procedure-related complication for open traumatic thoracic aortic transactions is recurrent laryngeal nerve injury (204). The left recurrent laryngeal nerve wraps around the aortic arch with the vagus nerve; thus, surgery on the aortic arch may compress the nerve. These patients present with hoarseness and a low-pitched voice.

Other neurologic events. Several other neurologic syndromes have been described as occurring after surgery on the ascending aorta with or without aortic valve replacement. Mokri syndrome presents as a triad of supranuclear gaze palsy, dysarthria, and gait disturbance resembling progressive supranuclear palsy (146; 209). The disorder is biphasic, consisting of some symptoms acutely after anesthesia wears off, followed a latent progressive phase weeks to months later. Neuroimaging is largely normal in these patients.

A variety of isolated eye movement abnormalities following aortic surgery have been reported, with brain imaging in some patients revealing lesions in the dorsomedial pons, cerebellum, or cerebral hemispheres; mesial temporal sclerosis; or hippocampal atrophy (228; 65).

Cardiac valve surgery. Cardiac valve surgeries are performed in 99,000 patients each year in the United States (158). The most common valve surgery is isolated aortic valve replacement, and there are over 25,000 isolated aortic valve replacement surgeries each year (25). There are a number of variables in these surgeries, including whether the valve is repaired or replaced, whether open heart surgery, balloon valvuloplasty, or transcatheter placement is used, whether the prosthetic valve is mechanical or bioprosthetic, whether the valve is in the mitral or aortic position, whether concomitant procedures (eg, left atrial appendage closure, CABG, etc.) are performed, and whether adequate anticoagulation is used. In addition, outcomes are affected by the underlying pathology, the type of procedure, and the experience of the surgeon. These variables make it very difficult to make a comparison between studies and to compare stroke statistics.

Stroke. Stroke is the most common neurologic complication of these surgeries. Some generalizations can be made about the risk of stroke. First of all, stroke is more common with surgeries at the mitral position than the aortic position, with all valve types. The higher rates of stroke at the mitral position are attributed to an increased likelihood of atrial fibrillation, left atrial enlargement, and possible endocardial damage from rheumatic mitral valve disease (39). Second, the rate of stroke is considered to be equal between bioprosthetic and mechanical valves. One 11-year study showed a similar incidence of thromboembolism, endocarditis, and valve thrombosis comparing anticoagulated patients with mechanical valves and non-anticoagulated patients with bioprosthetic valves (90). Another study showed that there was no significant difference in the occurrence of embolism over a 12-year follow-up period when comparing mechanical and bioprosthetic valve surgery (21). If cardiac valve surgery is combined with CABG, repair of other cardiac abnormalities, or carotid endarterectomy, the risk of stroke is higher (224; 71).

Several studies will be reviewed to give a general estimate of the incidence of stroke with cardiac valve surgery. In a large cardiac database from Emory University of patients undergoing mitral valve surgery, there was a 4.2% incidence of postoperative strokes among 1250 patients (208). There was no difference between the mitral repair group and the mitral replacement group. In elderly patients undergoing mitral valve surgery, the risk of postoperative stroke was comparable at 5%, although the overall mortality was higher (79). Another prospective study found a lower risk of 1.3% for mitral bioprostheses and 2.3% for mitral mechanical valves (176). In long-term studies of the risk of thromboembolism with bioprosthetic valves, the risk was 0.2% to 2.3% per year for the aortic position and 0.7% to 2.6% per year for the mitral position (96). The incidence of thromboembolism after aortic valve replacement varies in the literature from 1.4% to 4.4% (06; 116). Another prospective study found that the risk was 1.3% per year for aortic bioprostheses, and 1.4% for aortic mechanical valves (176).

Transcatheter aortic valve replacement (TAVR) surgery is being increasingly used, especially in those who are higher risk for surgery (121). Previously the risk of stroke was higher in transcatheter aortic valve implantation (TAVI) than with surgical replacement (182). As the operator experience and the catheter systems have improved, the outcomes including incidence of stroke have decreased compared to the surgical procedure per the aforementioned trial. In comparing the primary end points of death and disabling stroke at 2 years, there was no significant difference between the two groups.

The autograft procedure for aortic valve replacement, also known as the Ross procedure, utilizes the patient’s own pulmonary valve to replace the diseased aortic valve, and then uses a pulmonary allograft to replace the pulmonary valve. Although the operation is complex and necessitates replacement of two valves, there is a lower risk of endocarditis, avoidance of anticoagulant therapy, and lower thrombogenicity. In a series of 347 patients who underwent this procedure, only two strokes occurred, both in patients with new-onset atrial fibrillation (193). In patients undergoing percutaneous mitral valvuloplasty for mitral stenosis, the rate of systemic embolization is 0.5% to 3.0%, with most of these representing symptomatic embolisms to the brain (62). Since the introduction of transesophageal echocardiography to detect atrial thrombi and with the use of the Inoue technique, which requires less left atrial manipulation, the incidence of systemic embolism has been lower with percutaneous mitral valvuloplasty (87).

Strokes can occur during either the intraoperative or postoperative period (see Table 2). During surgery, emboli and hypoperfusion are the most common causes of stroke. In the postoperative period, valve thrombosis, left-atrial thrombi secondary to atrial fibrillation, and endocarditis are most common. Patients with intraoperative strokes may be noted to have a failure to awaken from anesthesia as quickly as expected with the presence of encephalopathy or coma due to multifocal infarction. There may be evidence of a focal neurologic deficit such as speech deficit, visual field abnormality, or motor or sensory deficit. Patients who have a stroke after surgery will usually have a sudden onset of visual, speech, motor, or sensory deficits or multiple deficits in more than one vascular territory due to embolism.

Tranexamic acid is an antifibrinolytic used for bleeding during cardiac surgery. In dose-dependent fashion, it has been associated with an increased incidence of generalized seizures postoperatively (137; 07).

Table 2. Mechanism of Stroke During or After Valve Replacement Surgery

Important causes of stroke after valvular surgery include valve thrombosis, atrial fibrillation and left atrial thrombosis, and endocarditis. Also, issues related to anticoagulation will be discussed briefly.

Valve thrombosis. Both mechanical and bioprosthetic valves are associated with valve thrombosis. In patients with adequate anticoagulation, the rate of thrombotic events is equal with mechanical and bioprosthetic valves (90). Approximately 15% of patients with valvular thrombosis will have a stroke (175). The risk of stroke persists for a person’s lifetime after the valve surgery. Approximately 20% of patients with valve prostheses have an embolic stroke by 15 years after valve replacement (176).

Atrial fibrillation and left-atrial thrombus. Atrial fibrillation is the most significant risk factor for delayed stroke after surgery, specifically mitral valve replacement (18). It more commonly occurs in patients who are older and have a larger preoperative left atrial size (112). Approximately 90% of patients with late-onset stroke had atrial fibrillation in one study (18). There was a significant difference in the stroke-free survival 15 years after valve surgery between those in normal sinus rhythm (90.7%) and those in chronic atrial fibrillation (73.8%) (18). One autopsy study of early death (between 1 and 60 days) found a 61% rate of left-atrial thrombus formation (186). Percutaneous closure of the left atrial appendage is an effective alternative to chronic oral anticoagulation for stroke prevention in patients with atrial fibrillation, though it is indicated in people with nonvalvular atrial fibrillation (210). Procedural complications include stroke and device and air embolism (172).

Endocarditis. The development of endocarditis after prosthetic valve surgery is a major complication, with significant morbidity and a high mortality rate (55). Stroke is a major predictor of mortality in this condition.

Prosthetic valve endocarditis accounts for 7% to 25% of cases of infective endocarditis (153). The incidence of prosthetic valve endocarditis is reported to be 1% to 3% during the postoperative period. Up to 65% of embolic events in infective endocarditis involve the central nervous system. The incidence of neurologic complications is 20% to 40% in all cases of infective endocarditis (66; 93). Mechanical heart valves are probably at higher risk for infection than are bioprostheses during the first 3 months after surgery, but the rates of infection are similar at 5 years (100; 33; 15; 153). The cumulative risk of prosthetic valve endocarditis is approximately 1% at 12 months and 2% to 3% at 60 months (05; 216; 153).

Prosthetic valve endocarditis with onset before 60 days after surgery is called early prosthetic valve endocarditis. Early prosthetic valve endocarditis is usually hospital-acquired with the most common organisms being Staphylococcus aureus (35.9%), coagulase-negative staphylococci (17%) and culture-negative cases (17%) (219). Infections that occur more than 60 days after surgery are called late prosthetic valve endocarditis. The most common causes are coagulase-negative staphylococci (19.9%), S aureus (18.4%), Enterococcus (12.7%) and culture-negative cases (12.4%) (219).

Neurologic manifestations are usually consistent with ischemic stroke with events in the history that may indicate an embolic source (as previously described). Other clinical manifestations include fever in nearly all patients and a new or changing murmur as the disease progresses in over 50% of patients. The classic signs of native valve endocarditis (petechia, Roth spots, Janeway lesions, and Osler nodes) are often absent. Splenomegaly is present in 25% of patients in the early stages and 40% of patients in the later stages. Peripheral embolization may be evident in the extremities.

Rarely, patients with endocarditis may be found to have intracerebral hemorrhage, subarachnoid hemorrhage, cerebral abscess, or mycotic aneurysms. Overall, patients with prosthetic valve endocarditis have a 30-day mortality of 13%, compared with 5.6% in patients with native valve endocarditis (134). Both entities have similar long-term survivals.

Anticoagulation. The issue of anticoagulation in cardiac surgery patients is a debated topic. In general, patients with mechanical valves receive long-term anticoagulation whereas patients with bioprosthetic valves receive a 3-month course of warfarin (target INR 2.5), and then only antiplatelet therapy, such as aspirin. The recommended INR value ranges for various cardiac valve replacements (ie, bileaflet, aortic; tilting-disc, aortic; bileaflet, mitral; tilting-disc, mitral, caged-ball disc; etc.), are beyond the scope of this review. However, suffice it to say that anticoagulation control has a dramatic and significant influence on stroke risk and survival after valve replacement surgery (31).

Anticoagulation-related hemorrhages are a dreaded complication of oral anticoagulant therapy in patients with valve replacements. The incidence of intracranial and spinal bleeding was 0.57 per 100 patient-years on oral anticoagulation in patients with mechanical heart valves (36). Spontaneous intracranial hemorrhages have been reported in patients without supratherapeutic levels of anticoagulation following open heart surgery for valve replacement (155; 14; 160). The appropriate use and recommendations regarding anticoagulant therapy in patients with bioprosthetic and mechanical valve replacements are reviewed elsewhere (161).

Other neurologic complications. Peripheral nerve injuries can occur with cardiac valve surgery and are similar to those with CABG, as discussed previously.

Several studies have suggested, by different methods of evaluation, that there is cognitive decline after cardiac valve surgery. Altered cognition was demonstrated by delayed P-300 auditory evoked responses at 7 days after valve replacement surgery (230). Transcranial Doppler has demonstrated high intensity transient signals after valve replacement surgery and has been correlated with neurocognitive deficits in some studies (54), but others have questioned these findings (154). Subcortical brain abnormalities like those described with CABG, have been described in patients undergoing valve replacement surgery. These lesions were located subcortically and were associated with alterations in memory, attention, and speed of information processing. The neurocognitive symptoms resolved after 4 months (113).

Migrainous-like phenomena have been seen after insertion of prosthetic cardiac valves. This was first described by Caplan and colleagues in 1976 in two patients who satisfied criteria for “classic migraine” (37). The mechanism remains unclear. As these headaches can be associated with manifestations suggestive of transient central nervous system dysfunction, they can mimic recurrent cerebral emboli.

Cardiac transplantation. Cardiac transplantation is the treatment of choice for patients with advanced heart failure (49). Although major advances have been made since the early days of cardiac transplantation, there is still a 4% risk of death from all neurologic causes and a need to reduce neurologic morbidity associated with the procedure (24).

The incidence of neurologic complications with cardiac transplant is 19.5%, with noninfectious causes predominating (152). Neurologic complications can be divided into cerebrovascular complications (stroke, intracerebral hemorrhage), CNS infections, metabolic encephalopathy, seizures, drug toxicities, and neoplasms (78). Cerebrovascular events occurring in the immediate post-transplantation period are similar to those seen after valvular or coronary revascularization surgery. However, the overall incidence of complications is higher than with elective CABG or elective valve replacement surgery (99).

Cerebrovascular complications.

Ischemic stroke. Ischemic stroke occurs in 2% to14% of patients undergoing cardiac transplantation (97; Andrews al 1990; 02; 103; 139; 78). Strokes are the cause of early death (0 to 30 days) after transplantation in 6.7% of patients (205), and the 5-year stroke rate after the perioperative period is 4.1% (08). The etiology of stroke in the perioperative period includes cardioembolism of fibrin and platelet microthrombi, embolization of atherosclerotic debris during cross-clamping and cannulation of the aorta, air embolism during cardiectomy, and embolization of material from bacterial endocarditis from the donor patient (03; 02; 139; 78). Stroke occurring later may be related to diagnostic procedures such as cardiac catheterizations and right heart biopsy, acute rejection, and arrhythmias (78).

Intracerebral hemorrhage. Intracerebral hemorrhage has been reported in 5% of early transplant recipients (194). The etiologies of the hemorrhages may be secondary to systemic anticoagulation, disseminated intravascular coagulation, relative cerebral hyperperfusion in the presence of impaired cerebral autoregulation (“breakthrough cerebral hemorrhage”), and angioinvasive opportunistic infections, such as aspergillosis, and herpes encephalitis (194; 78).

CNS infections. CNS infections occur in approximately 3% of patients in adult cardiac transplant patients (139; 213). The types of CNS infections include meningitis, encephalitis, meningoencephalitis, and abscess. One study from the Mayo Clinic indicated that all of their patients with CNS infections presented within the first 4 years of cardiac transplant (213). Clinically, patients presented with acute or subacute confusion or headache 88% of the time, often without fever or meningismus. The number of possible infective agents causing CNS infection after cardiac transplant is staggering and has been described elsewhere, and may include phycomycosis, coccidioides, aspergillus, candida, cryptococcus, cytomegalovirus, herpes simplex virus, varicella-zoster virus, JC virus, nocardia, listeria, and toxoplasma (78). In the series from the Mayo Clinic, cryptococcal meningitis was the most common CNS infection (213).

In cases of meningoencephalitis or CNS mass lesions in cardiac transplant patients, the differential includes a broad spectrum of potential pathogens based on timing from the transplant date. In early cases (less than 1 month after transplant), the most common offending agents are aspergillus, candida, and cytomegalovirus. From 1 to 6 months after transplant, the most common infecting agents are aspergillus, cytomegalovirus, cryptococcus, Epstein-Barr virus, human herpes virus 6, toxoplasmosis, and varicella-zoster virus. In late cases (more than 6 months after transplant), aspergillus, cryptococcus, Epstein-Barr virus-associated lymphoma, molds, nocardia, and toxoplasmosis are the most common infecting agents (51). Progressive multifocal leukoencephalopathy, an opportunistic infection of the JC virus in the CNS, has also been described in transplant recipients (89; 72; 123; 213). Patients with progressive multifocal leukoencephalopathy presented with progressive neurologic deterioration at 15 and 36 months after cardiac transplant. Those who experience graft rejection are at higher risk for all types of infection due to the increased administration of immunosuppressant drugs.

Metabolic encephalopathy. Encephalopathy occurring after cardiac transplantation can be related to a global hypoxic-ischemic insult, metabolic abnormalities, hepatic or renal dysfunction, multiple organ failure, sepsis, or drug toxicity (194). Delirium or mental status changes often are the first signs of opportunistic CNS infections. Other common etiologic factors to consider as a cause for encephalopathy in the posttransplant patient are general anesthesia side effects, volume and electrolyte shifts, posterior reversible encephalopathy syndrome (PRES), drug toxicity (corticosteroids, cyclosporine, tacrolimus), fever, coagulopathy, infection, and psychoactive drug withdrawal (63; 195).

Seizures. Seizures, either generalized tonic-clonic or complex partial seizures, are reported in as many as 40% of patients in some series (149). The most common causes of seizures in this population are those related to drug toxicity and abnormal metabolic parameters. Medications that can cause seizures include cyclosporine, tacrolimus, and OKT3. Other etiologies include cerebral ischemia, anoxic brain injury, PRES, CNS infection, and tumor (78).

Drug toxicities. There are a number of drugs given to cardiac transplant patients that can cause neurologic symptoms. These include the maintenance immunosuppression of steroids, calcineurin inhibitors, mTOR inhibitors, steroids, and mycophenolate mofetil or azathioprine. Therapy may also often include induction therapy with polyclonal or monoclonal antibodies. These biological agents induce lysis of lymphocytes. The proinflammatory cytokine release may result in several symptoms including fever, headache, serum sickness, and anaphylaxis. Up to 10% of people may experience symptoms of aseptic meningitis (167). Steroids can cause proximal myopathy. Cyclosporine and tacrolimus can cause a number of neurologic syndromes (see Table 3). Immunosuppressive neurotoxicity is usually seen as an acute postoperative complication but can be seen months after transplantation. It may be a direct drug effect that is unrelated to dosing versus associated with elevated therapeutic drug levels. Reversible cerebral vasoconstriction (Call-Fleming syndrome) has rarely been described with the use of cyclosporine and tacrolimus (see clinical vignette, case 2). Patients may present with sudden onset of thunderclap headaches and focal neurologic deficits. Cyclosporine and tacrolimus are postulated to have a direct toxic effect on the vascular endothelial cells in the CNS, resulting in the release of endothelin, prostacyclin, and thromboxane, with resulting uncontrolled vasoconstriction and vasospasm in the cerebral vessels (111). Neuroimaging studies may reveal changes consistent with PRES. Angiography in the patient described in vignette case 2 revealed extensive multifocal narrowing and dilation of the intracranial vessels.

Table 3. Neurologic Complications Associated with Organ Transplantation and Immune Suppression with Cyclosporine and Tacrolimus

Posttransplant lymphoproliferative disorder occurs in 0.75% of cardiac transplant patients and is detected only in the CNS in 85% of patients (207). Patients present with mental status changes with or without a focal neurologic deficit associated with CT showing multicentric, symmetric, ring-enhancing lesions around the subependymal white matter and perivascular spaces (165).

Peripheral nerve injuries occur with cardiac transplant surgery and are similar to those described with CABG. Critical illness neuromyopathy occurs more frequently after cardiac transplantation than after other cardiac surgeries and procedures.

Cardiac catheterization. In the United States, about 1.5 million cardiac catheterization procedures are performed per year. The neurologic complications with cardiac catheterization include stroke, seizures, and peripheral nerve complications. Stroke among patients with acute coronary syndromes enrolled in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) I and II studies were associated with six-month mortality rates of 27% (50).

Clinically relevant embolic events during diagnostic cardiac catheterization occur in 0.1% to 0.4% of adult patients (184). In one 2-year study, the incidence of strokes after 3494 cardiac catheterization procedures was 0.4% (101). Interestingly, asymptomatic cerebral infarction is described in 15% of patients as detected by diffusion-weighted MRI in a study that included diagnostic and interventional cardiac catheterization (30).

Stroke with cardiac catheterization may occur during the procedure, immediately after the procedure while the femoral artery sheath is still intact or up to 36 hours after the procedure (184; 180).

Stroke in association with cardiac catheterization is approximately evenly split between the carotid circulation and the vertebrobasilar circulation. There is a suggestion that posterior circulation strokes are more common with the brachial artery approach and anterior circulation events are more common with the femoral artery approach (53; 115; 107; 120).

There are a number of factors that can predispose to cerebrovascular complications with cardiac catheterization (see Table 4) (45; 180). Cerebral microemboli are predominantly detected during catheter advancement, catheter flushing, contrast injection, and ventriculography (130). There is also a significant correlation between the number of microemboli and the volume of contrast used (130). There has been no definitive evidence to determine whether transradial catheterization is superior to femoral catheterization in terms of lesser incidence of stroke.

Table 4. Risk Factors for Cerebrovascular Complications with Cardiac Catheterization

Table 5 lists the etiologies of stroke with cardiac catheterization.

Table 5. Potential Etiologies of Cerebrovascular Complications during Cardiac Catheterization

Transient cortical blindness has been described extremely rarely with coronary angiography, and the condition may be related to direct neurotoxicity of the contrast media (201). In the cases described, the symptoms and signs resolved after 48 hours.

Seizures occur extremely rarely with cardiac catheterization in the adult population. However, in the pediatric population, seizures are a more common presenting symptom, usually representing a manifestation of stroke. In one 12-year prospective study, 0.24% of children had neurologic events during diagnostic cardiac catheterization and 1% of children undergoing percutaneous coronary intervention had neurologic complications (127). The majority of these events manifested as a seizure. However, stroke was determined to be the cause of neurologic symptoms in 57% of cases. Another 4-year study involving 1362 cardiac catheterization procedures in children less than 15 years of age revealed that 18 (1.3%) of children, without prior nervous system disease, developed neurologic sequelae within 24 hours of cardiac catheterization (221). Three presented with seizures only, 10 with neurologic deficits, and 5 with both focal seizures and stroke.

Peripheral nervous system complications can occur with cardiac catheterization. Peripheral nerve injuries can be divided into femoral nerve injuries, lumbosacral plexopathy, and median nerve injuries. The femoral nerve can be lacerated or compromised by a hematoma with groin puncture and can present with pain and paresthesias over the anterior thigh and medial calf, weakness of hip flexion and knee extension, and an absent patellar reflex. The severity of postcatheterization femoral neuropathy can range from mild transient sensory neuropathy to disabling paralysis. Average delay from catheterization to recognition of symptoms is 37 hours. Although initially disabling, the neuropathy usually resolves completely. Surgery is only recommended when there are coexisting complications (eg, development of a large hematoma) (108).

The lumbar plexus (primarily involving the femoral and obturator nerves) can be compressed by a retroperitoneal hematoma. Patients present with variable symptoms, depending on the rate of expansion of the hematoma and the structures that are compressed. Patients may have groin, flank, or abdominal pain that radiates to the anterior thigh associated with numbness of the anterior thigh and medial calf with a reduced or absent patellar reflex. The size of the retroperitoneal hematoma does not correlate well with the severity of the sensory or motor deficits. The lateral femoral cutaneous nerve can be injured from tight compression bandages, resulting in meralgia paresthetica.

Other rare conditions that can compress the femoral nerve include pseudo-aneurysm formation of the femoral profunda artery, presenting with a painful pulsatile groin mass and sometimes with a systolic bruit, and arteriovenous fistula with a continuous groin bruit or thrill. Superficial or common femoral artery occlusion may present as ischemic monomelic neuropathy of the lower extremity.

Median neuropathy is a rare complication of brachial artery catheterization. Nerve compromise due to direct injury in the antecubital region or secondary to hematoma formation has been described. Brachial plexopathy has been described after axillary angiography and may be secondary to hematoma, pseudoaneurysm formation, or direct compression (162).

Percutaneous coronary interventions. Coronary intervention procedures including balloon angioplasty and stent placement are performed very commonly, with over 1 million procedures performed annually in the United States.

The etiologies of cerebrovascular complications from percutaneous coronary intervention are numerous, and they overlap somewhat with those of cardiac catheterization (see Table 6).

Table 6. Etiologies of Cerebrovascular Complications during Percutaneous Coronary Intervention

In a retrospective study from a large database, unspecified neurologic complications occurred in 0.1% of patients undergoing percutaneous coronary interventions (132). Others have reported a higher incidence of complications. The incidence of stroke has been reported to be 0.08% to 0.4% for percutaneous coronary intervention (26; 74; 64; 132; 180).

Another study of approximately 6500 patients who underwent invasive cardiac procedures such as left heart catheterization, balloon angioplasty, and valvuloplasty described an overall 0.4% incidence of neurologic complications. The most common symptoms were visual disturbances (26%), hemiparesis (26%), and facial droop (26%). Deficits were localizable to the posterior circulation in 36% of patients and anterior circulation in 64%. Most of the embolic strokes during catheterization procedures are associated with an embolus located in either the common carotid bifurcation or the proximal middle cerebral artery (10). One study reported a posterior circulation predominance with up to 70% of patients presenting with confusion, visual field deficits, and brainstem signs. The remainder present with hemiparesis, hemisensory deficits, dysphasia, and retinal ischemia secondary to carotid distribution events (26; 44). In another study of strokes complicating 20,900 cardiac catheterization procedures, the posterior circulation was affected in 21 of the 39 infarcts (184).

The risk factors for stroke with percutaneous coronary interventions are similar to those with cardiac catheterization and are detailed in Table 7 (44; 94). In one study, stroke was significantly associated with the severity of coronary artery disease and the duration of the procedure (132). In patients undergoing percutaneous interventions, stiff, large-bore guiding catheters are used. These design characteristics can be more traumatic to the aorta than diagnostic catheters, which are more flexible and have smaller lumens and tapered tips (180).

Table 7. Major Risk Factors for Stroke with Percutaneous Coronary Intervention

Invasive electrophysiological procedures. The neurologic complications that can occur with invasive electrophysiological studies include TIA and stroke. Fortunately, the incidence of these events is extremely low. Table 8 lists the mechanisms of stroke with invasive electrophysiological procedures (104).

Table 8. Mechanisms of Stroke with Invasive Electrophysiological Procedures

Congenital heart disease. Children with congenital heart disease represent a diverse group. In this review, neurologic complications of pediatric cardiac surgery in general will be discussed rather than reviewing specific cardiac defects and procedures. The specific procedure of closure of a patent foramen ovale is discussed in detail separately.

The incidence of neurologic complications with pediatric cardiac surgery is reported to be from 0.54% to 25% (69; 68; 16; 12; 61). Disappointingly, stroke accounts for greater than 20% of the noncardiac causes of death in this population (166). Age, duration of bypass, and reoperation may be associated with stroke risk (61). A retrospective series of 900 children undergoing cardiac surgery reported a 4.2% incidence of neurologic complications (17). Central nervous system complications were associated with higher morbidity and longer hospitalization times.

The most common postoperative neurologic sequela of open heart surgery in children is seizures (17). Other neurologic findings that have been reported with cardiac surgeries include Horner syndrome due to interruption of preganglionic sympathetic fibers during aortic arch surgery (eg, Blalock-Taussig shunts), vocal cord paralysis during extensive aortic arch manipulation, spinal ischemia and injury with aortic arch surgery, subclavian steal syndrome with Blalock-Taussig shunt procedures for tetralogy of Fallot, superior vena cava syndrome with intracranial venous hypertension with the Mustard procedure to correct transpositions (125), and diaphragmatic paralysis after ventricular septal defect repair (3.9%), Glenn anastomosis (8.6%), Tetralogy of Fallot repair (4.3%), Senning operation (10%), arterial switch operation (3.2%), Fontan procedure (33%), coarctation of the aorta repair (7%), and pulmonary artery banding (6.4%) (67). Children with coarctation of the aorta have a 7% incidence of cerebral aneurysms, predisposing them to intracranial or subarachnoid hemorrhages. Other described neurologic complications include intracranial hemorrhages (intracerebral hemorrhages, subarachnoid hemorrhages, subdural hematomas, and epidural hematomas), arterial ischemic strokes, cerebral venous gas embolism (28), venous thrombosis, cerebral abscess, spinal cord ischemia, encephalopathy and coma, hypoxic-ischemic injury, cerebral atrophy, postpump choreoathetosis, and peripheral nervous system injuries (recurrent laryngeal nerve and phrenic nerves).

The causes of neurologic complication are multifactorial and include preoperative brain malformations, perioperative hypoxemia and low cardiac output states, sequelae of cardiopulmonary bypass, deep hypothermic circulatory arrest, and postoperative arrhythmias (12). It should also be noted that children with congenital heart disease undergoing surgery may have underlying genetic abnormalities (eg, genetic polymorphisms mediating inflammatory response to cardiopulmonary bypass) or acquired abnormalities (eg, hemoglobinopathies, coagulation disturbances) that predispose them to thrombosis (34). For example, patients with Smith-Magenis syndrome, who are known to have a high incidence of congenital heart disease, may have gene deletions that affect cholesterol homeostasis. A patient with this syndrome experienced a stroke after cardiac surgery presumably due to premature intracerebral atherosclerosis (41). There may be preoperative factors that have produced baseline neuropsychological deficits due to marginal cerebral blood flow and oxygen delivery from uncorrected heart defects prior to surgery. Long-term sequelae may include language and learning disorders, anxiety and depression, intellectual disability, epilepsy, and cerebral palsy (69; 95).

Invasive diagnostic tests such as cardiac catheterization and other procedures predispose these children to thrombosis and stroke (34; 91). Neurologic complications occur in 0.24% of diagnostic catheterizations in children (127). Stroke accounts for greater than half of the neurologic complications. However, two thirds of these children have no neurologic sequelae on long-term follow-up (127). The risk of complications increases with interventional procedures during the catheterization, with prolonged duration of the procedure and with the presence of a right-to-left shunt (127).

Surgery for tumors. Myxomas account for 40% to 50% of primary cardiac tumors, and they typically arise from left-sided cardiac structures, predominantly the left atrium. The most common neurologic manifestation of atrial myxoma is cerebral ischemia secondary to embolism of myxomatous material or thrombus. Intracerebral or subarachnoid hemorrhage can occur as can delayed complications from tumor recurrence with embolization, progressive vascular stenosis, aneurysm formation and rupture, or parenchymal metastasis (217). Neurologic sequelae after resection are rare and may occur without recurrence of the myxoma. Aneurysms may enlarge after tumor resection or they may appear for the first time (174). Fragments of tumor that have metastasized to vessel walls may enlarge, occluding the vessel and resulting in delayed cerebral ischemia (171). Scrofani and colleagues reported a series of 38 patients who underwent surgical resection of a cardiac myxoma and found that 7.9% of these developed postoperative neurologic complications including transient ischemic attacks and stroke (183). Recurrence of myxoma after resection is rare (2% to 3%) (140; 19), suggests incomplete resection at the initial operation, and has been reported to occur from 6 months to 11 years after the initial resection. Recurrence of tumor has been associated with recurrent cerebral infarctions and cerebral fusiform aneurysms (117). Intra-arterial (77) and intravenous (202) thrombolysis have been used safely in single case reports of cerebral embolic infarction due to atrial myxoma.

Closure of patent foramen ovale. The prevalence of patent foramen ovale in the general population is as high as 30%. It is estimated that about 70,000 strokes per year are associated with patent foramen ovale; however, this association is controversial. The prevalence of atrial septal aneurysms is estimated to be 1% based on necropsies. There is an association of atrial septal aneurysms and the presence of patent foramen ovale. The risk of stroke is higher if there is a patent foramen ovale associated with an atrial septal aneurysm (177). In clinical trials, closure of the patent foramen ovale is associated with a lower rate of recurrent ischemic strokes when compared to medical therapy alone (138). Of note, there was a higher risk of atrial fibrillation in those that had patent foramen ovale closure.

Table 9 outlines the reported complications of percutaneous patent foramen ovale closure. Periprocedural complications of patent foramen ovale closure that may increase stroke risk include the development of atrioventricular block and atrial fibrillation (129).

Table 9. Complications of Percutaneous PFO Closure

Prognosis and complications

The impact of stroke on early outcomes after cardiac surgery is significant with ICU stays that are twice as long, postoperative hospital lengths of stay that are 2.5 times longer, a doubling of the total hospital charges, and an increase in hospital mortality from between 4% to 5% for those without stroke to 19% to 33% for those with a stroke (179; 13). Patients with stroke after CABG have a 3-fold higher risk of dying in the 10-year period after the CABG when compared to those without a stroke (52). In a series of 100 patients having cardiac valve procedures, 24 had focal deficits. Of those 24, 13 (54%) had completely recovered in 2 months, and 22 (92%) had completely recovered in 5 months. The remaining two patients (8%) continued to have persistent disability throughout a 5-year follow-up period (198). Patients with neurologic complications after cardiac transplantation had longer ventilation times, longer stays in the ICU, and a higher incidence of pneumonia and sepsis when compared with patients without neurologic events (229). Also, there was a trend toward higher in-hospital mortality in the neurologic complication group (15%) when compared to those without neurologic complications (6%). Surprisingly, there was no difference in long-term survival (65% vs. 78%) (229). In most patients, neurologic complications were not the actual cause of death, but they significantly contributed to increased morbidity. The majority of patients who had a stroke following cardiac catheterization had an unfavorable outcome with a Rankin score of 3 to 6, ie, moderate disability to coma, with a high inpatient mortality rate (184).

Clinical vignette

Case 1. A 68-year-old man was admitted with prolonged substernal chest pain. He had a history of hypertension, diabetes mellitus, and hypercholesterolemia. EKG demonstrated an acute, non-ST elevation myocardial infarction. Coronary arteriography demonstrated severe 3-vessel coronary artery disease. The man underwent a CABG, and on awakening from anesthesia, he was noted to be less responsive than expected. He also could not move his right arm and leg as well as he could move the left. Neurologic examination was notable for right arm and leg paresis. A head CT scan showed subtle hypodensity in the left frontal and parietal regions consistent with ischemic stroke.

Case 2. A 41-year-old woman had a heart transplant because of a genetic dilated cardiomyopathy, not associated with muscular dystrophy or sensorineural hearing loss. Her father had died at the age of 35 years and her brother at the age of 38 years due to an apparent similar condition. She presented to the emergency department with new onset of excruciating headaches previously labeled as migraines. Her headaches were associated with confusion, disorientation, polyopia (she saw multiple images of her arms and legs), visual distortions described as “feeling something surreal,” and weakness of her limbs as if “my bones are leaving my body.” She had no history suggestive of palinopsia. Her immunosuppressant medications following heart transplant included mycophenolate 1500 mg twice daily and cyclosporine 125 mg twice daily.

Examination was noteworthy for cortical blindness, asymmetric quadriparesis, and a right Babinski sign. She underwent an unenhanced CT that showed no acute changes. MRI/MRA was not done due to remnant pacemaker leads. Cerebrospinal fluid examination was unremarkable. CT angiogram was performed.

The cyclosporine and mycophenolate were discontinued. Approximately 1 month later, she underwent repeat CTA with demonstrated improvement.

Another CTA 3 months after the initial scan revealed further improvement with nearly normal appearance of the cerebral vasculature.

The clinical impression was that she had clinical manifestations suggestive of possible PRES, as well as reversible segmental cerebral vasoconstriction (Call-Fleming syndrome) possibly due to treatment with cyclosporine. In this patient, the clinical and CTA findings were reversible. Another case is described in the literature of tacrolimus encephalopathy with MRI findings consistent with posterior leukoencephalopathy (111).

Case 3. A 69-year-old man underwent quadruple aortocoronary artery bypass graft, aortic valve replacement, and myomectomy for hypertrophic cardiomyopathy with idiopathic hypertrophic subaortic stenosis. When he awoke from surgery, he felt his vision was blurred. Examination showed optic disc pallor, decreased visual acuity, and afferent papillary defect in the left eye. He had suffered a nonarteritic anterior optic neuropathy, presumably due to intraoperative hypotension. MRI of the brain showed no abnormalities. At follow-up 3 years after his surgery, he reported that he only noticed his visual deficit when driving. Examination showed visual acuity of 20/40 in the left eye and 20/25 in the right, red desaturation, Marcus Gunn pupil, and temporal disc pallor in the left eye.

Case 4. A 55-year-old man presented with an acute myocardial infarction of several days’ duration and cardiogenic shock. An intra-aortic balloon pump was inserted in the cardiac cath lab. During the procedure he coded, requiring one round of epinephrine and chest compressions. He remained in cardiogenic shock despite the balloon pump. Because of the continued cardiogenic shock and the hypotension, he underwent emergency placement of a left ventricular assist device. Following surgery, he was started on dopamine, abciximab for 12 hours, aspirin, and clopidogrel and was continued on heparin drip. Within several days of the procedure, he awoke with complete loss of vision. Onset was abrupt, bilateral, painless, and nonprogressive. He had no light perception with either eye. Motility was full and painless. There was significant optic nerve pallor bilaterally. CT of the head was unremarkable, and MRI could not be performed because of his ventricular assist device. There were no symptoms to suggest temporal arteritis; however, given an elevated ESR of 69 mm/hr and CRP of 3.1 mg/dl, rheumatology was consulted, and he did undergo biopsy of the right temporal artery, which showed no evidence of arteritis. No visual-evoked responses were recorded in either eye following flash (strobe) monocular stimulation. He was evaluated by neurology and neuroopthalmology, and it was determined that the etiology of his vision loss was postoperative bilateral posterior ischemic optic neuropathy, most likely due to profound hypotension. Photographs of the fundi taken several weeks later showed pallor of the optic discs bilaterally.

Biological basis

Etiology and pathogenesis

The most common underlying pathophysiologic mechanisms producing stroke with cardiac surgery include preexisting cerebrovascular disease, emboli, hypoperfusion, and atrial fibrillation (141).

It is not surprising that patients undergoing cardiac surgery for atherosclerotic cardiac disease would have concomitant cerebrovascular disease. Factors that increase the risk of neurologic complications after cardiac surgery include a history of previous stroke, hypertension, diabetes, age, and the presence of a carotid bruit (141).

Emboli occurring during cardiac surgery can vary in size and come from a number of different potential sources (see Tables 10 and 11). These emboli may be divided into macroemboli (those occluding flow in arteries 200 microns or greater) or microemboli (those occluding smaller vessels) (20). The extracorporeal circulatory pump system can be a source of microembolism. In addition, microembolism can occur during aortic cannulation or aortic clamping/unclamping. MRI using diffusion-weighted imaging in the postoperative period after CABG can detect acute ischemic events related to microemboli and may demonstrate multiple lesions in a "watershed" pattern of distribution (223). Acute brain swelling on MRI in the immediate postoperative period may involve the cerebral cortex primarily, which correlates with the pathologic finding of small capillary and arteriolar dilatations in the cortex and deep gray matter (92).

Table 10. Embolic Material Produced During Cardiopulmonary Bypass and Open Heart Surgery

Table 11. Nongaseous Microemboli Reported During Cardiopulmonary Bypass

Hypoperfusion is another mechanism producing stroke during cardiac surgery. It is not clear what duration or degree of hypoperfusion can be tolerated intraoperatively, because other factors, such as comorbid diseases affecting cerebral autoregulation, play a role.

Atrial fibrillation occurs in approximately one third of patients in the early postoperative period after cardiac surgery and is the etiology of the stroke in 36% of patients with stroke (118).

Hematologic disturbances may result from cardiopulmonary bypass. There may be consumption of platelets and coagulation factors, decreased platelet adhesiveness, and abnormal activation of the coagulation cascade (04; 109).

Prevention

There are a number of risk factors associated with CABG (see Table 12) (70). Many of these risk factors are risk factors for ischemic stroke in general. If CABG is combined with other procedures, such as cardiac valve surgery, repair of other cardiac abnormalities, or carotid endarterectomy, the risk of stroke is higher (224; 71).

Table 12. Risk Factors for Stroke Associated with CABG

Risk factors associated with an increased risk of perioperative neurologic complications in cardiac transplant patients include a prior history of stroke, catecholamine dependence preoperatively, intraaortic balloon pump or ventricular assist device usage in the preoperative period, and known coronary artery disease (78).

Risk factors for postoperative delirium include a prior history of cerebrovascular disease, peripheral vascular disease, atrial fibrillation, diabetes, ejection fraction less than 30%, urgent operation, need for massive blood transfusion, and operation time more than 3 hours (27).

Risks associated with cardiac valve surgery are detailed in Table 13. In general, early onset postoperative stroke is usually due to embolization of atheromatous debris, while delayed (after 24 hours) stroke is usually due to cardiogenic embolism (39).

Table 13. Risk Factors for Stroke with Valve Replacement Surgery

Table 4 reviews the risk factors associated with cardiac catheterization and Table 7 reviews the major risk factors for stroke with percutaneous coronary interventions.

Attention should be focused on methods to prevent stroke. McKhann and colleagues have proposed methods to prevent stroke with cardiac surgery before, during, and after the procedure is performed (141). Table 14 outlines these potential strategies.

Other strategies have been explored but have not had positive results. One study sought to determine whether epiaortic ultrasound scanning reduces cerebral emboli before or during cardiopulmonary bypass. The study randomized patients to transcranial Doppler ultrasound of the middle cerebral arteries to continuously before, during, and after aortic manipulation compared to control. Although epiaortic scanning did lead to modifications in intraoperative surgical management in 29% of patients, including adjustments of the cannulation site and avoidance of aortic cross-clamping, these interventions did not lead to a reduced number of cerebral emboli (59).

To date, there are no approved pharmacologic therapies for the prevention or treatment of cardiac surgery-associated cerebral injury. Despite numerous studies with negative results, studies continue to be undertaken looking at new compounds as neuroprotective agents in the setting of cardiac surgery (86; 119).

Table 14. Neuroprotective Strategies for Cardiac Surgery

Differential diagnosis

Associated or underlying disorders

The differential diagnosis of neurologic changes during or after cardiac surgery includes metabolic derangements; residual effects of anesthetic agents such as opioids, benzodiazepines, and neuromuscular blocking agents; adverse reactions to cardiac medications; embolic stroke; intracranial hemorrhage; PRES; seizures; CNS infection; spinal cord injury; and peripheral nerve injury. CNS infections are uncommon in the immediate postoperative period but should be considered in patients with or without fever after cardiac transplantation.

Diagnostic workup

When evaluating patients with a suspected stroke during or after cardiac surgery, it is necessary to review important information from the preoperative history, including vascular risk factors and prior history of stroke. Next, information about the intraoperative course should be obtained, including, when applicable, the duration of cardiopulmonary bypass and intraoperative and postoperative arterial blood pressures and ECG to evaluate for periods of hypotension and cardiac rhythm disturbances. Patients with stroke after a diagnostic or interventional procedure should have a review of preprocedural risk factors and a review of intraprocedural vital signs and cardiac rhythm to evaluate for hypotension or cardiac arrhythmias. A thorough general examination should be performed, with attention given to vital signs, including temperature, whether there is a cardiac rhythm disturbance, and whether there is evidence of peripheral embolization. Neurologic examination should focus on determining if there are alterations in mental status, evaluating for focal motor or sensory deficits, and determining whether any deficit is due to central or peripheral nervous system involvement.

Laboratory data should be reviewed and appropriate tests ordered to rule out a metabolic cause of encephalopathy or coma. Initial tests to evaluate for stroke should include a head CT without contrast or an MRI of the brain with diffusion-weighted images. The most common pattern encountered is multiple embolic infarcts, located in the cortex of the hemispheres and in the cerebellar hemispheres. Lesions can occur in either hemisphere, as well in the anterior and posterior circulations. An EEG is appropriate in patients suspected of having seizures. Vigilant evaluation for infection is indicated in the cardiac transplant population, including, when appropriate, blood cultures, chest x-ray, CSF analysis, and head CT or MRI of the brain.

In the patient who has an ischemic stroke after cardiac transplant, general diagnostic tests as discussed above are applicable. For those suspected of having a posttransplant CNS infection, appropriate testing may include head CT without and with contrast, CSF analysis, blood cultures, blood serologies specific for suspected infectious agents, and in some cases, stereotactic brain biopsy. Those with seizures should be evaluated for a stroke and PRES. Thorough metabolic screening should be undertaken, including evaluating for hypomagnesemia, which in combination with cyclosporine toxicity may be an etiology for seizures. Levels of calcineurin inhibitors should be obtained. Patients should be evaluated for CNS infection as a cause of seizures. Seizures can be managed acutely with benzodiazepines. If long-term treatment is deemed necessary, antiseizure medications that do not induce hepatic enzymes that metabolize cyclosporine should be used (consider valproic acid, felbamate, lamotrigine, gabapentin, levetiracetam, or pregabalin).

In patients with ischemic stroke after cardiac valve surgery, diagnostic testing is similar to that described for stroke after CABG. Patients presenting with delayed stroke after mitral valve replacement should be evaluated for the presence of atrial fibrillation and left-atrial thrombus. In a patient with suspected prosthetic valve endocarditis, head CT or brain MRI, blood cultures, and transesophageal echocardiography should be obtained.

Management

A stroke involving occlusion of the proximal vessel in the anterior circulation can often lead to catastrophic outcomes including death and inability to have a functional quality of life even with standard therapy. In patients with stroke after cardiac surgery, use of intravenous tissue plasminogen activator (tPA) in select patients may be considered, but the potential increased risk of surgical-site hemorrhage should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits in each patient (170). Since multiple landmark trials were published in 2015 establishing the superiority of endovascular thrombectomy over medical management alone in patients with acute stroke due to large vessel occlusions, mechanical thrombectomy has become standard of care for the treatment of acute stroke and should be considered in eligible patients who present with stroke after a cardiac procedure (170; 102). A detailed discussion of patient eligibility for tPA and thrombectomy is beyond the scope of this review, and further information can be found in the Guidelines for the Early Management of Patients with Acute Ischemic Stroke from the American Heart Association/American Stroke Association (170).

Treatment of patients after ischemic stroke should include careful attention to maintaining normal body temperature, maintaining adequate oxygenation, avoiding hypotension/brain hypoperfusion, maintaining normal serum glucose, avoiding hypotonic intravenous fluids, preventing deep venous thrombosis, and avoiding aspiration pneumonia by evaluating swallowing capacities (70). If the etiology of the stroke is an air embolism, patients should be placed on 100% oxygen until they are transferred to a hyperbaric chamber facility (150).

Special considerations

Pregnancy

Heart disease is a leading cause of maternal death in developed countries. Most pregnant women with heart disease can be managed medically, though some do require invasive procedures or cardiac surgery to control their disease, the latter of which is associated with substantial risk to both the pregnant person and the fetus. The reported maternal mortality rate from cardiac surgery ranges from 3% to 11%, and fetal mortality has been reported to be as high as 30% (163; 169; 133; 40; 191). Timing of surgery is important. In the second trimester, organogenesis is complete, and the risk of premature labor is not as high, making this the safest time for surgical intervention.