Neurologic Manifestations of Infective Endocarditis

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. Despite an increasing prevalence in recent decades of prosthetic valve and device-related infective endocarditis (IE), 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. Large prospective cohort studies, including the International Collaboration on Endocarditis, and the European Infective Endocarditis Registry provide 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 ), and clinically silent cerebral embolism on presentation may occur in nearly half of these cases. Nevertheless, due to 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. Mycotic aneurysms are reported in less than 2 percent of cases in most cohort studies, although studies that include angiography for all patients report a much higher proportion. 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 micro- 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 or spondylitis (4.7% in one series), retinal ischemia, and ischemic cranial and peripheral neuropathies.

Table 6-1

Common Neurologic Complications in Patients with Infective Endocarditis

Series	n	Ischemic Stroke (%)	Hemorrhage (%)	Primary Infection (%)	All Neurologic Complications (%) *
Garcia-Cabrera 2013	1,345	14	4	7	25
Rizzi 2014	1,456	15 *	2	NR	17
Munoz 2015	1,804	NR	NR	NR	20
Habib 2019 ^†	3,119	27	7	NR	NR

NR, not reported.

* Includes transient ischemic attack.

† Reporting does not distinguish cases with potentially more than one cerebral event so estimates may be inflated. Ischemic stroke includes cerebral embolism on admission, and cerebral embolism/TIA/stroke in follow-up. Hemorrhage includes hemorrhagic stroke on admission and follow-up and cerebral hemorrhage in follow-up.

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. In general, cerebral emboli most often affect the middle cerebral artery (MCA) territory and may be septic or nonseptic. In patients without neurologic symptoms, MRI shows cerebral lesions in at least 50 percent of cases, and the majority of these are ischemic. 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 (infectious) aneurysm; cerebral micro- or macroabscess ( Fig. 6-2 ), usually via seeding of ischemic tissue; and cerebritis or meningitis by seeding the meninges.

Figure 6-1, Embolization to various cerebral structures is responsible for most of the neurologic complications of IE. Emboli that lodge in the lumen of cerebral vessels may lead to ischemic stroke and can lead to arteritis or mycotic aneurysm formation with resultant vessel rupture and cerebral hemorrhage. Emboli to the meninges may produce meningitis, and emboli to the brain parenchyma, especially when associated with cerebral ischemia, may result in meningoencephalitis or abscess.

Figure 6-2, This patient presented with fever, new cardiac murmur, mental status changes, and right hemiparesis. A and B , Contrast-enhanced axial T1-weighted magnetic resonance imaging (MRI) shows multiple ring-enhancing lesions suggesting septic microembolization. C , Axial diffusion-weighted imaging (DWI) sequences show restricted diffusion associated with the lesions.

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. Intracerebral hemorrhage may also occur owing to a secondary hemorrhage into an ischemic infarct ( Fig. 6-3 ).

Figure 6-3, This patient presented with left hemiparesis and mitral valve endocarditis. A , Noncontrast head CT showed a focal low-density lesion in the right internal capsule and lentiform nucleus with a central area of hemorrhage (increased density) and cortical hemorrhage in the insula. B , With contrast, large confluent areas of enhancement representing leaky blood–brain barrier can be seen in the right caudate and lentiform nuclei, the insula, and the temporal cortex. C , Fluid-attenuated inversion recovery (FLAIR) MRI 2 days after the head CT showed diffuse increased signal in the regions of CT enhancement and the right thalamus. D , Following gadolinium administration, ring-like enhancement in the area of a previous infarct can be seen, representing possible secondary infection. This pattern is sometimes referred to as a “septic infarction.” This enhancement pattern resolved with antibiotic treatment and without development of a macroabscess.

Mycotic aneurysm formation has been related to (1) septic embolization to the arterial lumen or the vasa vasorum; (2) direct extension from an infection outside the vessel wall; (3) bacteremia causing direct infection of the intima; or (4) direct contamination during surgery or trauma. Mycotic aneurysms are usually small, located at distal arterial bifurcations rather than 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 ).

Figure 6-4, This patient presented with fever, new systolic murmur, sudden headache, and altered mental status without focal neurologic deficits. Noncontrast head CT showed a small subarachnoid hemorrhage (not shown). Sagittal CT angiogram, A demonstrated a mycotic aneurysm in the distal MCA, confirmed by conventional angiography, B . This aneurysm enlarged despite adequate antibiotic therapy, and the patient subsequently underwent successful clipping.

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 from 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 embolism or neurologic complications from IE ( Table 6-2 ).

Table 6-2

Suggested Risk Factors for Embolization in Infective Endocarditis

Risk Factor	Proposed Mechanism
Mitral valve infection	Increased valve mobility and left-sided position predispose to cerebral 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; acute infection is associated with hematologic factors that may promote thrombosis
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 more common with left-sided IE than with right-sided valve involvement, although embolization to any organ may be more common with right-sided endocarditis. Cerebral embolization in right-sided endocarditis may occur through a patent foramen ovale or a pulmonary arteriovenous fistula. 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. Both United States nationwide and multicenter European studies found S. aureus to be the most commonly identified organism, increasing in the United States from 38 percent in 1998 to 49 percent in 2009. In one United States study, 53 percent of the S. aureus cases were meticillin-resistant. This changing resistance pattern is reflected in updated treatment guidelines.

In most studies, S. aureus infection is independently associated with an increased risk of embolization; some authors have reported Streptococcus bovis and Candida species are also more likely to be associated with embolism. 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. 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.

Acuity 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 week of infection. Once effective antibiotic therapy is started there is a steep decline in the rate of embolization to 15 percent in the first week and only 4 percent in the second week after antibiotics.

Valvular Vegetations

Detection of valvular vegetations by either transthoracic (TTE) or transesophageal echocardiography (TEE) is a key step in diagnosing IE and also critical to patient management. 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, but management algorithms often recommend TTE as the initial study because it can be obtained more quickly and it also shows other cardiac abnormalities important in medical and surgical decision-making. Most studies have linked the presence of vegetations, especially increased vegetation size (often dichotomized at >10 mm), to an increased risk of embolization. A meta-analysis of 21 cohort studies suggested that in addition to size greater than 10 mm, the presence of any vegetations, multiple or mobile vegetations, and vegetations on prosthetic valves were independently related to risk of embolism. 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

Antiphospholipid antibodies have been associated with IE, and have also been reported to decrease after successful treatment of IE. A recent meta-analysis also found that elevated C-reactive protein was an independent risk for embolism among 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, especially prior to or during the first week of therapy. 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 subarachnoid hemorrhage are most common. In one series, only eight cases of subarachnoid hemorrhage occurred among 60 patients with IE and cerebral hemorrhage. Mycotic aneurysms are infrequently reported in large cohort studies, but are estimated to be present in nearly one-third of patients with left-sided IE (26 of 81 consecutive patients with CT angiography, although 15 of the 26 were clinically asymptomatic).

Table 6-3

Causes of Intracerebral Hemorrhage in Infective Endocarditis

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

Pre-existing central nervous system lesion (e.g., aneurysm, arteriovenous malformation)

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 intracranial 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, although finding multiple small emboli that are both cortical and subcortical in location is not uncommon ( Fig. 6-5 ). Patients with multiple microemboli can present with nonlocalizing symptoms, including headache, diminished level of consciousness, encephalopathy, or psychosis ( Fig. 6-5 ). 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 may occur, and may theoretically be more likely in strokes caused by infective endocarditis due to the resulting arteritis. Hemorrhagic transformation of an ischemic stroke is often asymptomatic, as are cerebral microhemorrhages, although development of a large intra-infarct hematoma may be symptomatic. The term “septic infarction” has been used when, several days to weeks following an ischemic stroke, a cerebral abscess develops within the infarcted tissue.

Figure 6-5, This 36-year-old man presented with fever and headache and was found to have aortic valve enterococcal endocarditis. These diffusion-weighted MRI sequences illustrate the prototypical small, often asymptomatic embolic ischemic strokes that can occur with left-sided endocarditis.

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. A United States nationwide administrative data-based study of endocarditis hospitalizations from 1998 to 2009 reported 3.8 percent of all cases experienced seizures during the hospitalization, likely an underestimate of clinical seizure frequency. 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 may signify 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 and fourth-generation cephalosporins most frequently associated with seizures.

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