Keywords
infective endocarditis, stroke, cerebral embolism, stroke management, mycotic aneurysm
The relationship between infection of the heart valves and arterial embolization was first recognized by Rudolf Virchow in the mid-1800s and the classic clinical triad of fever, heart murmur, and hemiplegia was described 30 years later by Osler in his Gulstonian Lectures of 1885. The understanding of infective endocarditis (IE) has evolved since these early descriptions to a concept of the disease occurring with different predisposing conditions, different propensities for sites of valve infection, different infecting organisms, and different treatments; however, the proportion of patients with IE and neurologic manifestations has remained relatively constant. Neurologic complications are frequent and are often associated with increased morbidity and mortality in IE. Although the key to treating neurologic complications is appropriate antibiotic therapy, the presence of neurologic manifestations often alters the medical or surgical treatment of IE.
Epidemiology of Neurologic Complications
Neurologic events have long been recognized as frequent and severe complications of IE. A large prospective cohort study conducted in 25 countries from 2000 to 2005, the International Collaboration on Endocarditis, provides evidence regarding IE and its various complications. The overall frequency of neurologic complications of IE has remained relatively constant at approximately 15 to 30 percent ( Table 6-1 ). Nevertheless, because of the high overall incidence of stroke in the general population, IE is an unusual cause of stroke. Neurologic complications of IE can be divided into three major types: ischemic stroke, hemorrhagic stroke, and direct cerebral infection. Ischemic stroke is by far the most common, accounting for 50 to 75 percent of all neurologic complications. Primary hemorrhage, usually intraparenchymal or subarachnoid, is less common, reported in less than 10 percent of patients. Secondary hemorrhagic transformation of an ischemic stroke, however, is estimated to occur in 20 to 40 percent of ischemic strokes from IE. Cerebral infections may manifest, without previous clinical evidence of ischemic or hemorrhagic stroke, in less than 10 percent of cases; typical infectious complications include cerebritis, meningitis, and microabscesses or macroabscesses. Other neurologic symptoms, including seizures, headache, mental status changes, and neuropsychologic abnormalities, sometimes occur but are usually secondary to one of the three major complications. Rarely, endocarditis has been associated with spinal cord infarction or abscess, discitis, retinal ischemia, and ischemic cranial and peripheral neuropathies.
| Series | n | Ischemic Stroke | Hemorrhage | Primary Infection | All Neurologic Complications * |
|---|---|---|---|---|---|
| Heiro et al., 2000 | 218 | 13 (6%) | 4 (2%) | 10 (5%) | 55 (25%) |
| Hoen et al., 2002 | 390 | 60 (15%) | 21 (5%) | NR | NR |
| Durante et al., 2003 ‡ | 94 | 20 (21%) | NR | NR | NR |
| Thuny et al., 2005 ‡ | 384 | 76 (20%) | NR | NR | NR |
| Miro et al., 2005 § | 1348 | NR | NR | NR | 210 (16%) |
| Heiro et al., 2006 | 326 | 27 (8%) | 6 (2%) | 15 (5%) | 86 (26%) |
| Murdoch 2009 ** | 2781 | 462 (17%) | NR | NR | NR |
| Leone et al, 2012 ** | 1082 | 160 (15%) | NR | NR | NR |
* These complications include some not listed in this table.
‡ Includes both cerebral embolism prior to antibiotic treatment and after treatment.
§ Includes cerebral embolism, hemorrhage, and infection.
Pathophysiology of Neurologic Complications
Almost all the neurologic complications of IE have embolization as their primary cause ( Fig. 6-1 ). Although cerebral emboli are probably not more common than extracerebral emboli, they are more often symptomatic and thus typically reported more frequently; they are also associated with an increased morbidity and mortality compared to other systemic emboli. Cerebral emboli most often affect the middle cerebral artery (MCA) territory and may be septic or nonseptic. Cerebral emboli may present as stroke, but in many cases (36 to 48% in recent studies) are subclinical with only MRI evidence of infarction. Therefore, neuroimaging should be considered in all patients with IE, regardless of neurologic symptoms. Septic emboli may also lead to hemorrhagic stroke through the development of arteritis or mycotic aneurysm; to cerebral microabscess or macroabscess ( Fig. 6-2 ), usually through seeding ischemic tissue; and to cerebritis or meningitis by seeding the meninges.
Most primary intracerebral hemorrhages in IE result from septic embolism followed by septic necrosis and rupture of the vessel wall; less commonly, they result from rupture of mycotic aneurysms. In one study, it was found that 10 of 16 patients with IE and intracerebral bleeding had pyogenic arteritis, in 5 of whom rupture occurred without evidence of concomitant mycotic aneurysm; 13 of the 16 had either septic emboli or arteritis, or both. Intracerebral hemorrhage may also occur owing to a secondary hemorrhage into an ischemic infarct ( Fig. 6-3 ). In one histopathologic series of 17 patients, brain hemorrhage was due to secondary transformation of ischemic infarction in 24 percent of cases, necrotic arteritis in 24 percent, mycotic aneurysm in 12 percent, and other causes in 11 percent; in 29 percent it was of unknown etiology.
Mycotic aneurysm formation has been related to (1) septic embolization to the arterial lumen, producing intraluminal wall necrosis and outward extension of infection, and (2) septic embolization to the adventitial layer of the artery, resulting in destruction of the adventitia and muscularis layers and subsequent aneurysmal dilatation. Mycotic aneurysms are usually small, located at distal arterial bifurcations, rather than around the circle of Willis, and can be single or multiple. Branches of the MCA are the most common location for mycotic aneurysms ( Fig. 6-4 ).
Brain macroabscesses account for less than 1 percent of all neurologic complications of IE and may occur secondary to ischemic infarction from a septic embolus or to extension of infection from adjacent arteritis or mycotic aneurysm. Brain microabscesses are more common than macroabscesses, are often associated with Staphylococcus aureus infections, and usually occur in cases with multiple ischemic infarctions from distal migration of septic embolic fragments. Meningoencephalitis is usually a result of direct embolization to meningeal vessels, with subsequent parenchymal or cerebrospinal fluid (CSF) invasion of the infecting organism. Aseptic meningitis may also occur with subarachnoid hemorrhage due to a necrotic arteritis or ruptured mycotic aneurysm.
Risk Factors for Neurologic Complications
A variety of clinical and laboratory features have been associated with an increased risk of neurologic complications from IE ( Table 6-2 ).
| Risk Factor | Proposed Mechanism |
|---|---|
| Mitral valve infection | Increased valve mobility and left-sided position predispose to systemic embolization |
| “Virulent” organism | More rapid endothelial invasion leads to more friable, unstable valve surface |
| Acuteness of infection | More rapid endothelial invasion leads to more friable, unstable valve surface |
| Valvular vegetations | Increasing vegetation size and vegetation mobility may predispose to embolism |
| Hematologic factors | Increased endothelial cell activity, platelet aggregability, and antiphospholipid antibodies may be associated with increased risk of embolization |
Site of Infection
Neurologic complications are probably more common with left-sided IE than with right-sided valve involvement. A Finnish study spanning more than 20 years found that as the proportion of intravenous drug use–associated IE increased, the proportion with tricuspid valve involvement also increased. Cerebral embolization in right-sided endocarditis may occur through a patent foramen ovale or a pulmonary arteriovenous fistula ( Fig. 6-5 ). Most reports comparing native and prosthetic valve endocarditis indicate no significant difference in the proportion of patients with neurologic complications. Among those with prosthetic valve endocarditis, however, mechanical valves may be associated with complications more often than bioprosthetic valves.
Infecting Organism
Streptococci, staphylococci, and enterococci are the three most prevalent infecting organisms. Despite one United States population-based study reporting viridans group streptococci as the most common infecting organism, most recent studies show that staphylococcal infection is the most common responsbile pathogen. There is a growing prevalence of antibiotic resistance among these organisms, especially viridans group streptococci and methacillin- and vancomycin-resistant S. aureus. This changing resistance pattern is reflected in updated treatment guidelines.
It is unclear whether antibiotic susceptibility changes affect the risk of embolic complications, although infections that take longer to control might theoretically have an increased risk of embolization. Even after adjusting for other factors, S. aureus , and Streptococcus bovis are independently associated with embolism. In prosthetic valve endocarditis, Staphylococcus epidermidis may be associated with more neurologic complications than S. aureus. The virulence of the organism, the availability of effective antimicrobial therapy, and the potential development of large, friable vegetations all contribute to the propensity for embolization.
Acuteness of Infection
There is a higher risk of neurologic complications with acute endocarditis than with subacute endocarditis, probably relating to the specific typical etiologic agents noted in acute disease ( S. aureus and β-hemolytic streptococci) and the potential for large vegetations or valve damage acutely. The risk of cerebral embolization is highest in the first 1 to 2 weeks of infection, with most patients either presenting with a neurologic complication or experiencing an acute event in the first 48 hours after diagnosis. Similarly, the risk of embolization decreases as the duration of effective antibiotic treatment increases, with most events occurring in the first 2 weeks of therapy.
Valvular Vegetations
Valvular vegetations are detected by two-dimensional echocardiography in 50 to 80 percent of patients with IE and by transesophageal echocardiography (TEE) in more than 90 percent of cases. Because of its increased sensitivity and ability to evaluate the more posteriorly located aortic valve, TEE appears to be cost-effective as the initial study when clinical suspicion of IE is high. Although the findings in some clinical series have suggested no significant difference in the development of neurologic complications between patients with and without vegetations, others have linked the presence of vegetations, increased vegetation size, or vegetation mobility to an increased risk of embolization. A prospective study of 384 patients with IE, all of whom underwent TEE, found that vegetation length greater than 10 mm and vegetation mobility increased the risk of embolism; vegetation length greater than 15 mm independently increased 1-year mortality. The significance of changes in vegetations on serial echocardiography remains unclear; some investigators report that morphologic changes in size or consistency are not associated with complications, whereas others have found that an increase in vegetation size during antibiotic treatment is associated with more complications. A final echocardiographic variable that may be related to complications is the presence of spontaneous echo contrast imaging, possibly as a marker of increased spontaneous platelet aggregation. Current recommendations suggest that repeat echocardiography may be useful if clinical changes that suggest treatment failure occur during antibiotic therapy and that it should be performed urgently for unexplained progression of heart failure, new heart murmurs, or the development of atrioventricular block.
Hematologic Risk Factors
In addition to spontaneous echo contrast, some reports associate coagulation system activation and embolic events. In a series of 91 patients with IE, antiphospholipid antibodies were present in 62 percent of patients with embolic events compared to 23 percent of those without such events, and were also correlated significantly with other markers of endothelial cell activation, thrombin generation, and impaired fibrinolysis. Antiphospholipid antibodies have also been reported to decrease after successful treatment of IE. Soluble adhesion molecules have also been reported to independently increase the risk of embolism. At present, however, these hematologic studies do not clearly aid in risk prediction for patients with IE.
Ischemic and Hemorrhagic Stroke
Ischemic stroke secondary to embolization of friable valvular material is the most common neurologic complication of IE. Ischemic stroke is the presenting symptom of IE in up to 20 percent of cases and is most common in the acute stage of the infection, that is, before antibiotic treatment is begun or during the first several days of treatment (median time, 4 to 10 days). Because of this clustering of symptoms in the acute phase, transient focal neurologic symptoms in a febrile patient, especially in the presence of a regurgitant murmur, should always raise suspicion of IE.
Intracerebral hemorrhage in IE may be primary or secondary to ischemic stroke or other pharmacologic or hematologic conditions ( Table 6-3 ). Of the primary hemorrhages, intraparenchymal and sub-arachnoid hemorrhage are most common. Secondary transformation of an ischemic stroke is the most common form of intracerebral hemorrhage in IE, accounting for 24 to 56 percent of all hemorrhages. In one series, only 8 cases of subarachnoid hemorrhage occurred among 489 patients with IE; in 6 of these, no cause for the hemorrhage was identified by autopsy or angiography. The prevalence of asymptomatic mycotic aneurysms in patients with IE is not known, but seems to be low.
| Primary Intracerebral Hemorrhage |
| Arterial rupture secondary to arteritis |
| Rupture of a mycotic aneurysm |
| Secondary Intracerebral Hemorrhage |
| Hemorrhagic conversion of ischemic stroke |
| Anticoagulation |
| Hematologic disorder |
| Disseminated intravascular coagulopathy |
| Thrombocytopenia |
| Vitamin K deficiency |
| Preexisting central nervous system lesion (e.g., aneurysm, arteriovenous malformation) |
As discussed, in at least 40 percent of patients septic embolization is the first event leading to intra-cerebral hemorrhage. Depending on the location of the embolus, arteritis with secondary vessel rupture or development of a mycotic aneurysm may occur. Other conditions that sometimes accompany IE may also predispose to bleeding, including disseminated intravascular coagulation, thrombocytopenia, and vitamin K deficiency. Although mycotic aneurysms are most commonly found in the intra-cranial vessels, rarely these aneurysms may involve the extracranial carotid, thoracic, or abdominal vessels.
Clinical Presentation
In accordance with their embolic etiology, the majority of ischemic strokes involve the cortex rather than subcortical brain tissue. In one series, 62 percent of strokes affected the cerebral or cerebellar cortex (with or without additional subcortical involvement), and only 16 percent were exclusively subcortical. In addition to the more typical isolated cerebral hemispheric or brainstem syndromes, multiple microemboli are clinically manifest in at least 10 percent of cases, and in more than 50 percent of cases a shower of emboli are found on neuroimaging. Patients with multiple microemboli can present with nonlocalizing symptoms, including diminished level of consciousness, encephalopathy, or psychosis.
Clinical worsening of ischemic stroke may result from a variety of mechanisms, including development of cerebral edema, recurrent embolization, secondary hemorrhage into the ischemic area, and development of cerebral abscesses. Cerebral edema may occur regardless of ischemic stroke mechanism, is more likely to be symptomatic in larger strokes and in younger patients, and is typically maximal between 3 and 5 days after stroke. Recurrent embolization should be suspected when new focal deficits develop; this complication is most likely to occur early in the course of treatment or when infection is uncontrolled. Hemorrhagic transformation of an ischemic stroke occurs in 18 to 42 percent of all patients and has been reported to be more common in cardioembolic strokes. In an autopsy series of patients with neurologic complications of IE, hemorrhagic transformation of an ischemic infarct occurred in 9 of 16 patients. Hemorrhagic transformation of an ischemic stroke is often asymptomatic, although development of a large intra-infarct hematoma is more likely to be symptomatic than is the development of petechial hemorrhage. The term “septic infarction” has been used when, several days to weeks following an ischemic stroke, a cerebral abscess develops within the infarcted tissue.
As with ischemic stroke, intracerebral hemorrhage usually presents with focal neurologic disturbances, but nonlocalizing symptoms, such as headache and decreased level of consciousness, may also predominate. Seizures may occur at the onset of the hemorrhage or later in its course. When subarachnoid hemorrhage occurs, either from rupture of an arteritic vessel or from a mycotic aneurysm, meningismus may be a prominent feature. Headaches may be more diffuse and subacute than is typical with ruptured saccular aneurysms.
Seizures
Although seizures may occur in patients with IE from toxic or metabolic disturbances (e.g., hypoxia, antibiotic toxicity), most often seizures are secondary to ischemic or hemorrhagic stroke. Older series suggest that approximately 10 percent of patients with endocarditis have seizures at some point. Seizures that are secondary to stroke are usually focal in nature, with or without secondary generalization, whereas seizures due to metabolic or toxic factors are more often primarily generalized. The development of seizures during antibiotic treatment often signifies clinical worsening from recurrent stroke, hemorrhagic transformation, or abscess formation. Therefore, the new onset of seizures in a patient with IE should always prompt an urgent neuroimaging study. Rarely, seizures are secondary to antibiotic therapy, with imipenem being a commonly used antibiotic having the greatest seizure proclivity.
Evaluation of Patients
Brain Imaging
All patients with acute focal neurologic deficits should undergo either a noncontrast computed tomography (CT) scan of the head or brain magnetic resonance imaging (MRI). Noncontrast CT may be done more quickly than MRI in most settings. If IE is known or suspected, head CT with and without contrast may be useful; areas of increased contrast enhancement allow possible cerebral abscesses or mycotic aneurysms to be distinguished from areas of ischemia. However, brain MRI is the most sensitive modality for detecting the multiplicity of neurologic lesions seen in IE, especially small, multiple emboli ( Fig. 6-2 ). In one series, multiple lesions were found in 10 of 12 patients studied, with embolic branch infarction, multiple emboli and microabscesses, and hemorrhagic stroke being the most common findings. MRI findings have been categorized into four patterns: (1) embolic infarction, (2) multiple patchy infarctions (nonenhancing), (3) small nodular or ring-enhancing white matter lesions (probably microabscesses), and (4) hemorrhagic infarctions (intracerebral or subarachnoid). Multiple cerebral microbleeds, detected best on MRI, have also been described as a feature strongly associated with the presence of IE. Hemorrhagic transformation of ischemic infarcts is most often patchy and may follow the contour of the gyri, but may also appear as a homogeneous hematoma within an infarct. A clue to the presence of an underlying mycotic aneurysm may be a focal area of cortical enhancement adjacent to an area of hemorrhage.
Vascular Imaging
Based on evidence that subarachnoid hemorrhage can occur without preceding symptoms in more than 50 percent of patients with mycotic aneurysm, some have advocated that all patients with IE should undergo noninvasive vascular imaging with MR angiography (MRA) or CT angiography (CTA) for aneurysm screening. Guidelines suggest screening for mycotic aneurysms in patients with endocarditis and neurologic deficits, including severe headache, erythrocytes or xanthochromia in the CSF, confusion, seizure, or focal neurologic signs. In patients with intracranial hemorrhage or those in whom noninvasive imaging suggests aneurysm formation, conventional cerebral angiography should be performed. Since mycotic aneurysms tend to be small and—unlike saccular aneurysms—occur distally rather than at more proximal arterial branch points, conventional cerebral angiography is probably more sensitive for aneurysm detection than noninvasive modalities. Vascular imaging in IE has not been associated with a survival benefit, largely owing to the low prevalence of mycotic aneurysms and the low risk of their rupture in patients with adequate antibiotic therapy.
Patients with ischemic or hemorrhagic stroke who require long-term anticoagulation for mechanical valves or treatment of systemic thromboembolism may also benefit from repeat noninvasive angiography to exclude a mycotic aneurysm, even if initial studies performed at the time of presentation are negative. Patients with known mycotic aneurysms require serial monitoring of aneurysm size to ensure adequate response to therapy; CTA and MRA are likely adequate for this purpose.
Cerebrospinal Fluid Examination
CSF examination was once part of the standard evaluation of patients with IE and neurologic symptoms, but it does not often change management decisions for patients today. The interpretation of CSF findings in IE with acute stroke is complicated by the tendency for patients with stroke unrelated to endocarditis also to have mild to moderate increases in CSF white blood cells, red blood cells, or protein concentration. In one large series, CSF was abnormal in around 70 percent of patients with IE; of these, around one-third had a purulent profile, one-fourth were aseptic, and one-tenth were hemorrhagic in character. With the exception of purulent CSF in patients with meningismus, the CSF pattern did not correlate with neurologic symptoms. For these reasons, CSF examination does not usually aid in the diagnosis or management of patients with neurologic symptoms and IE.
Echocardiography and Stroke
The diagnosis of IE depends on the documentation of a responsible organism on serial blood cultures and, in part, on the presence of valvular abnormalities on echocardiography. Echocardiography is also important in assessing valvular function and excluding conditions such as valve thrombosis or abscess formation that would change clinical management. TEE is more sensitive to mitral and aortic valve pathology and has been reported to change patient management in as many as one-third of cases. TEE may be especially important in older patients with IE, who, in one large study, commonly had vegetations seen only on TEE. Whether serial echocardiography provides data that reliably predict risk of subsequent stroke or otherwise influence neurologic management is not known.
Treatment of Ischemic Stroke
Antibiotic Therapy
The cornerstone of treatment of IE is appropriate antibiotic therapy directed at the infecting organism. Numerous studies have shown that the risk of either initial or recurrent thromboembolism decreases sharply after the first few days of adequate antibiotic therapy. In 2007, the International Collaboration on Endocarditis published a large prospective cohort study that showed that the risk of stroke after 1 week of therapy declined to 1 to 3 percent, depending on the responsible organism. It is therefore critical to ensure that antibiotics are begun promptly and empirically, immediately after drawing initial blood for cultures (preferably three sets from separate sites) in febrile patients with stroke in whom IE is being considered. As effective long-term antimicrobial therapy will be required, the isolation and susceptibility testing of the pathogen are of critical importance. Involvement of a specialist in infectious diseases is recommended. Thorough discussion of a current approach to diagnosis and antimicrobial treatment in various clinical scenarios can be found in the American, European, and British guideline statements, including the appropriate conditions for which antibiotic prophylaxis for the prevention of IE should be considered. IE with or without accompanying valve infection is also an emerging complication of implantable cardiac devices; in this setting, device removal is also typically required.
Thrombolysis
Acute use of tissue plasminogen activator in patients with ischemic stroke and IE is generally felt to be inadvisable due to an increased bleeding risk. However, case reports differ in their reported outcome of thrombolysis and IE. Due to the probability of positive publication bias and the known risk of hemorrhagic conversion in patients with IE, the use of thrombolytics in patients with stroke resulting from IE should generally be undertaken only with caution. More recently, reports of successful endovascular interventions have emerged, suggesting an alternative approach to acute stroke management in IE.
Antiplatelet and Anticoagulant Therapy
In animal models of IE, aspirin or aspirin plus ticlopidine has been found to reduce vegetation weight, echocardiographic evidence of vegetation growth, bacterial titer of vegetations, or systemic emboli rates. Although a pilot study in humans confirmed this finding, a larger randomized controlled trial found no reduction of embolic events in patients treated with 325 mg aspirin compared to those given placebo, and there was a nonsignificant trend toward increased bleeding in the aspirin-treated group. Therefore, routine use of antiplatelet therapy for the purpose of decreasing embolic risk in patients with acute IE is not recommended. Several studies have also looked at the impact of prior antiplatelet therapy on outcomes after IE. One study showed that antiplatelet use in the 6 months prior to IE decreased the risk of symptomatic emboli. Other studies have shown mixed results, with one study showing a decreased need for valve replacement and another finding no overall mortality benefit.
Anticoagulation in patients with IE remains a controversial and complicated topic. Hemorrhagic complications are clearly more common in anticoagulated patients, but patients with mechanical prosthetic valves may require long-term anticoagulation, and the decision as to whether and for how long to withhold anticoagulants in these patients is complex, depending on the type of valve involved.
Anticoagulation in Native Valve Endocarditis
There is an increased risk of hemorrhagic complications in patients with native valve endocarditis and ischemic stroke who are treated with anticoagulation, and the risk of recurrent embolism is low in those patients receiving appropriate antibiotic therapy. Accordingly, there appears to be little benefit for stroke risk reduction to anticoagulate these patients routinely. An important consideration is whether, prior to the development of endocarditis, these patients were being anticoagulated for a specific indication such as clotting disorders, atrial fibrillation, or pulmonary embolism. In these cases, a review of MRI sequences, looking for occult hemorrhage, and of noninvasive angiography should be part of a risk-to-benefit analysis before anticoagulants are stopped. When anticoagulation is deemed to be necessary, switching from oral to intravenous medications is recommended for optimal control of anticoagulation. Whether lower-level anticoagulation (e.g., for prevention of deep venous thrombosis) is safe in patients with stroke and IE is unknown. Because other strategies, such as the use of sequential compression devices, may be equally efficacious, a conservative approach is to use these nonpharmacologic methods primarily.
Anticoagulation in Prosthetic Valve Endocarditis
Patients with bioprosthetic valves typically do not receive long-term anticoagulant therapy, and they have a lower risk of stroke in IE than patients with mechanical valves ; thus, the same approach as outlined for native valve endocarditis is recommended. Patients with mechanical prostheses who have endocarditis and stroke, however, present more difficult management dilemmas. Most studies indicate that the proportions of patients with native and prosthetic valves having endocarditis with cerebral embolism are similar. Therefore, initiating anticoagulation in a previously nonanticoagulated patient with IE and a prosthetic valve appears unwarranted.
If a patient with a mechanical valve is receiving long-term anticoagulant therapy and develops a cerebral embolus as a complication of IE, the decision as to whether to continue anticoagulation or temporarily withhold it depends on several factors. Because larger strokes, especially those secondary to emboli, may be more likely to develop secondary hemorrhagic complications, some authors favor temporarily withholding anticoagulation for several days, especially when S. aureus is the infecting organism. Other factors, including hemorrhage on CT scan, presence of mycotic aneurysm, uncontrolled infection or infection with S. aureus , history of bleeding diathesis, and possibly advanced patient age, also argue against the use of anticoagulants in patients with neurologic complications of mechanical valve endocarditis. Whether anticoagulation should be avoided on a long-term basis or discontinued just temporarily depends on the indication for anticoagulation and the patient’s specific clinical situation. When temporary discontinuation of anticoagulation is being considered, determination of the type of mechanical valve and consultation with a cardiologist or cardiothoracic surgeon concerning the risk of valve thrombosis will help guide the decision. If anticoagulation continues, converting to the most controllable and reversible (i.e., intravenous) form of therapy along with frequent monitoring of anticoagulation parameters (activated partial thromboplastin time or international normalized ratio [INR]) are recommended.
Surgical Treatment
Valve replacement is not recommended therapy for preventing initial or recurrent stroke. Typically, surgery is recommended for patients with acute or refractory congestive heart failure, perivalvular abscess, unstable valve prosthesis, continued embolism, infection with a pathogen resistant to effective antimicrobial agents, or inability to clear the infection. A study involving more than 4,000 patients with IE showed that adjusted in-hospital and 1-year mortality (including adjustment for the presence of stroke) was significantly lower in patients with congestive heart failure undergoing surgery than in those managed medically. In a subgroup of patients with the greatest indications, early surgery was associated with significant decreases in mortality. Surgery is required in almost half of patients with prosthetic valve endocarditis, but in-hospital mortality remains high and is increased by the presence of stroke and other neurologic complications.
If surgery is required, the timing of the procedure in the setting of stroke is controversial. Early surgery is associated with greatest benefit in reducing embolization since the risk is greatest in the first 2 weeks of the infection. The first 72 to 120 hours after stroke, however, is the period of maximal risk of cerebral edema and disruption of cerebral autoregulation. Thus, most authors recommend delaying cardiac surgery for at least 2 weeks after ischemic stroke and 4 weeks after hemorrhagic stroke if possible, as mortality rates for patients in the first postoperative week are as high as 31 percent. The Society of Thoracic Surgeons has a practice guideline for the surgical management of endocarditis, and practice may be shifting toward more rapid surgical interventions in those with specific risk factors including congestive heart failure, uncontrolled infection, valve abscess, or high embolic risk since, even in models adjusting for bias introduced by selection for treatment, early surgery appears to confer a survival benefit in these situations.
Treatment of Hemorrhagic Stroke
Intraparenchymal Hemorrhage
The mainstay of treatment for either primary or secondary intracerebral hemorrhage in patients with IE is the same as that for cerebral emboli: effective treatment of the underlying infectious organism. This is especially true for patients with pyogenic arteritis, but is also critical for the treatment of mycotic aneurysms. Some patients with intracerebral hemorrhage and progressive neurologic deterioration, either from expanding hematoma or from edema, may benefit from surgical evacuation of the clot, but no firm guidelines exist. Similarly, although recombinant factor VIIa was used successfully to reduce hematoma growth in one trial (and unsuccessfully in another), no data are available for its use in patients with IE and cerebral hemorrhage. Patients with mechanical valves often will have their anticoagulant discontinued temporarily or converted to an intravenous form. All patients with IE and hemorrhage should have close neurologic monitoring in an intensive care setting since deterioration from recurrent hemorrhage or edema is not uncommon.
Mycotic Aneurysms
The natural history of mycotic aneurysms is that approximately one-third resolve completely with 6 to 8 weeks of antibiotic treatment, one-third remain unchanged in size, and the remaining one-third are equally divided among those that increase and those that decrease in size. Because of their propensity to resolve with antibiotic therapy, the evaluation and treatment of mycotic aneurysms are controversial. Aspects of care that remain unclear are whether serial angiography is necessary to follow mycotic aneurysms and the indications for surgical repair.
Some authors recommend serial angiography of mycotic aneurysms every 2 weeks during antibiotic treatment. If an aneurysm enlarges, surgical treatment to prevent rupture may be advocated. The need for ongoing or subsequent long-term anticoagulation is another factor that may suggest the need for angiographic surveillance and surgical treatment. Since at least half of mycotic aneurysms persist after adequate antibiotic treatment and since new aneurysms can appear, it seems reasonable to at least repeat angiography, with either conventional or noninvasive techniques, at the conclusion of antibiotic therapy (usually 4 to 6 weeks). Late hemorrhage from a ruptured mycotic aneurysm in patients who have completed adequate antibiotic therapy is rare, occurring in none of 122 patients with a mean 40-month follow-up ; therefore continued surveillance of a stable aneurysm following antibiotic treatment is probably unnecessary.
Once an aneurysm is discovered, controversy also exists regarding treatment. Asymptomatic aneurysms are often treated medically, with surgical intervention reserved for those that enlarge. Although symptomatic aneurysms may also resolve with antibiotic treatment, some authors favor surgical treatment of any ruptured mycotic aneurysm in addition to antibiotic therapy. This recommendation is usually based on the fear of recurrent bleeding (which is low) and the associated increased morbidity and mortality with rerupture. Aneurysm accessibility and number are other features that influence the decision for surgical treatment; single aneurysms in a peripheral location are more likely to be treated surgically. More proximal aneurysms may be successfully treated endovascularly, although the management and outcomes in these cases are highly individualized.
Because mycotic aneurysms often lack a defined neck amenable to clipping, other surgical techniques, including wrapping, trapping, excision, or endovascular therapy, may be necessary. Because mycotic aneurysms are often small and difficult to locate at the time of surgery, techniques including stereoscopic brain-surface imaging with MRA and stereotactic angiographic localization are sometimes used intraoperatively.
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