eMedicine Specialties > Neurology > Neurological Infections

Neurological Sequelae of Infectious Endocarditis

Author: Aiesha Ahmed, MD, Fellow, Department of Neuromuscular Medicine, Pennsylvania State University, Milton S Hershey Medical Center
Coauthor(s): Kevin Hargrave, MD, Consulting Staff in Medicine/Neurology, Comprehensive Neurologics and Sleep; Justin R Fisher, MD, Fellow, Department of Neurophysiology, Penn State Milton S Hershey Medical Center; Milind J Kothari, DO, Professor and Vice-Chair, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Hershey Medical Center
Contributor Information and Disclosures

Updated: Feb 17, 2009

Introduction

Background

Endocarditis can have profound and devastating neurologic consequences. More than a century ago, Osler described the infective endocarditis triad of fever, heart murmur, and hemiplegia.¹ In 10-15% of patients with infective endocarditis, the nervous system yields the first clinical signs. The incidence of central nervous system (CNS) complications in infective endocarditis is approximately 30%.

The Massachusetts General Hospital experience from 1964-1973 yielded 218 patients with bacterial endocarditis, 84 of whom had neurologic complications (38%).² Another series of 133 patients demonstrated a similar proportion (41%) of patients with infective endocarditis with neurologic problems.³ The neurologic manifestations of infective endocarditis are often the first sign of illness (47% of the time in one series), and they are present before initiation of antimicrobial therapy in most cases (76%). The incidence of CNS complications varies by organism (Staphylococcus species, 54%; Enterococcus species or Streptococcus viridans, >19%) and by location (mitral valve with Staphylococcus aureus, 87%).

Pathophysiology

The incidence of neurologic complications of infective endocarditis is dependent on the organism and valvular location; the highest incidence is 87% with S aureus vegetations on the mitral valve. Mitral valve prolapse occurs in a significant proportion of patients with infective endocarditis. Mitral valve involvement is most common (28-45%), followed by aortic valve (5-36%) and a combination thereof (as much as 56%). Mitral valve endocarditis carries a higher risk of CNS embolization than aortic valve involvement (17% vs 9%). Interestingly, at least one case report exists of infective endocarditis arising from an endovascularly placed closure device for patent foramen ovale with atrial septal aneurysm.

Approximately 90% of native valve endocarditis (NVE) is caused by the following 3 organisms:

• S viridans (60%)
• S aureus (20%)
• Enterococcus species (10%)

Gram-negative bacteria and fungi make up the remainder, comprising a smaller percentage.

Staphylococcus species classically leads to embolization earlier than other organisms (ie, <2 wk) and often causes hemorrhage within the first 48 hours or even prior to other symptomatic presentation. S viridans subacute bacterial endocarditis (SBE) is more indolent, usually with a clinical course of 1-3 months.

Partially treated bacterial endocarditis usually has a slower time course as well. Pseudomonas species and other coliform bacteria, including Haemophilus influenzae and group B streptococci, produce large vegetations. Aspergillus and Candida species endocarditis also have a high incidence of embolic phenomena as a result of large valvular vegetations.

Stroke

A 0.5% risk of occurrence of stroke per day exists in patients with infective endocarditis. One series showed that of patients with CNS involvement, four fifths had ischemic strokes and one fifth had hemorrhages, which is a distribution similar to that of strokes in general. Approximately 15-50% of the CNS manifestations are due to embolic occlusion and/or stroke. In 1965, McDevitt reported that SBE accounted for 3% of all cerebral emboli. In addition, one recent study showed that 71% of all embolic events in patients with infective endocarditis involved the CNS.

The rate of major embolic events was 17% in one series (reported range, 6-31%). Of 38 events in 37 patients, 34 involved the middle cerebral artery (MCA) or its branches. If stroke recurs, it usually indicates that the infection is not controlled or has recurred. Embolization occurring greater than 2 months after presentation is uncommon. Strokes with infective endocarditis can be subtle or even subclinical.

One series showed 23 patients with multiple microscopic infarcts at autopsy that had been clinically silent. Microorganisms rarely were confirmed in the emboli. One study showed that embolic events decreased from 13 per 1000 patient-days in the first week of antibiotic therapy to 1.2 per 1000 patient-days after 2 weeks of antibiotic therapy. Approximately one half of patients with cerebral emboli also have systemic emboli. Systemic emboli (non-CNS) occur equally from involvement of mitral and aortic valves.

Infectious aneurysms

Osler coined the term mycotic aneurysm to describe a mushroom-shaped aneurysm associated with SBE. Originally referring to any infectious etiology, it still is used as a general term and is not specific for fungal etiology (responsible for 3-6% of all intracerebral aneurysms), and case reports exist of at least 26 extracranial and 19 intracavernous carotid artery aneurysms associated with endocarditis.

Mycotic aneurysms occur in as many as 15% of patients with infective endocarditis, and aneurysms of arteries supplying the brain comprise approximately 15% of the aneurysms occurring in infective endocarditis. Most infective endocarditis aneurysms occur at sites outside of the CNS. The proximal aorta, visceral arteries, and limb arteries account for 25%, 24%, and 22% of sites, respectively.

When aneurysms form, the most likely mechanism is bacterial induced weakening (originating from the adventitial side of the vessel wall and apparently after organisms traverse the vasa vasorum). According to animal studies, the pathology is not via direct endoluminal damage to the intima. Controversy exists as to whether the more virulent organisms are associated more commonly with aneurysms. Mycotic aneurysms are less common with acute bacterial endocarditis (ABE) than with SBE. However, when present, mycotic aneurysms become symptomatic earlier in the disease course of ABE than in SBE. Intracardiac tumors (eg, left atrial myxomas, metastatic choriocarcinoma) also can embolize fragments and cause aneurysms resembling mycotic aneurysms.

The incidence of clinically diagnosed intracranial mycotic aneurysm in patients with infective endocarditis is approximately 2% (compared with a 5-10% prevalence postmortem as determined at autopsy). The MCA territory is involved 4 times more commonly with mycotic aneurysms than either the anterior or posterior cerebral arteries. In contrast to berry aneurysms, which occur in or near the circle of Willis, mycotic aneurysms occur at secondary branches and bifurcations, usually in the lateral fissure near the trifurcation of the MCA.

Intracranial hemorrhage

The overall prevalence of hemorrhage in CNS involvement of infective endocarditis is 3-7%. One series showed that nearly 30% of these cases are due to staphylococci. The etiology of CNS hemorrhage in infective endocarditis is not completely clear. It once was believed to be due exclusively to aneurysmal rupture. This was not supported by angiographic and autopsy studies that did not reveal a consistent aneurysmal source of bleeding in all cases. In one series, 14 patients had CNS hemorrhage. Four definite mycotic aneurysms were identified, 6 were presumptive, and the other 4 were not felt to be aneurysm related.⁴ In another series, the source of subarachnoid hemorrhage in 6 out of 8 patients with infective endocarditis could not be identified by cerebral angiography.

Other etiologies include nonaneurysmal vascular wall necrosis and hemorrhagic transformation of ischemic strokes. Intraventricular hemorrhage from a mycotic aneurysm rupture is usually fatal. Subarachnoid hemorrhage in infective endocarditis is often focal and has been shown (in a recent series) to occur more frequently in the perisylvian and/or perirolandic regions.

In the Massachusetts General Hospital series of 218 patients, 33 had meningeal symptoms (15%).² Of patients with CNS involvement from infective endocarditis, one third had completely normal cerebrospinal fluid (CSF), one fourth had a slightly abnormal CSF but an aseptic culture, and one fourth had frankly purulent CSF. Noteworthy as well is that one sixth had hemorrhagic fluid. Purulent meningitis or abscess occurred in more than one half of patients with acute infective endocarditis, whereas this occurred in fewer than 5% of patients with SBE.

When abscess occurs, the CSF can be nearly normal with a mildly increased protein, modest number of cells, normal glucose, and negative Gram stain. Conversely, S aureus abscesses usually are associated with purulent CSF containing polymorphonuclear neutrophilic leucocytes. If the CSF is abnormal, it usually represents an inflammatory consequence (meningeal reaction) rather than a primary infection. This is especially true in patients with acute staphylococcal bacterial endocarditis.

A leak of a mycotic aneurysm or an underlying focal lesion can produce meningeal irritation and cause a secondary aseptic meningitis. Cases of true meningeal infection can occur with infective endocarditis, but pneumococci are the usual culprits in these cases. Of all patients with infective endocarditis and concurrent bacterial meningitis, 70% have pneumococci as the infecting organisms (although pneumococci account for only 1-2% of infective endocarditis cases). In patients without a history of trauma, neurosurgery, or CSF leak who have staphylococcal meningitis, a 33% chance exists that they have concurrent staphylococcal endocarditis.

Spinal epidural abscess is also an important complication to recognize in infective endocarditis, and it most commonly presents with motor deficits or back pain. One study found that infective endocarditis was the cause in 10 out of 48 patients admitted with spinal epidural abscess (only slightly behind intravenous drug use as a leading cause).⁵

Seizures

Seizures were part of the presenting complex in 5 of 218 patients in the Massachusetts General Hospital series and were present at some time in the course in 11% (24/218).² Focal seizures may indicate an embolic etiology, whereas generalized seizures can result from meningitis, pharmacologic adverse effects, or systemic conditions such as uremia or hypoxia.

Nonfocal symptoms and/or encephalopathy

Nonfocal symptoms or encephalopathy can be the result of microscopic emboli and subsequent ischemia. This scenario is present in as many as 25% of patients with infective endocarditis. Approximately one half of these cases are due to evident metabolic derangements. The other one half was believed to be related to the infective endocarditis since no other etiology could be identified. Most of the nonfocal symptoms, such as headache or encephalopathy, usually resolve shortly after instituting antibiotics.

Immune phenomena

Late proliferative endarteritis in cerebral blood vessels with thrombotic occlusion and subsequent stroke can be due to immune phenomena. In one case report of streptococcal endocarditis with immune complex vasculitis, episodes of neurologic deterioration improved after dexamethasone therapy after a lack of prior improvement with antibiotic therapy.

Nonbacterial thrombotic endocarditis

The previous term for nonbacterial thrombotic endocarditis (NBTE) was marantic endocarditis, from the Greek marantikos, meaning "wasting away." NBTE is found in 1.6% of all autopsies. An estimated 10% of cerebral emboli occur in the setting of NBTE. A Japanese series of 86 strokes of cardiac origin showed 11% were related to NBTE.

Risk factors for NBTE include disseminated intravascular coagulation (DIC), abnormal heart valves, and mucin-producing tumors (leading to fibrin deposition and subsequent embolic phenomena). Approximately 80% of NBTE cases are associated with known carcinomas (eg, pancreas, colon, lung). Classically described with metastatic mucin-producing adenocarcinomas, it also occurs in localized cancers as well as in noncancerous states such as pregnancy, drug overdose, cirrhosis, vasculitis, and rheumatic heart disease.

Patients with NBTE who do not have cancer often have rheumatic or arteriosclerotic heart disease. NBTE also occurs in patients with AIDS. Hypercoagulable indices suggest a diagnosis of NBTE. One study reports that 30% of patients with NBTE who have CNS manifestations have nonfocal findings. Another series showed 18% NBTE in autopsied patients with cancer and associated neurologic complications.

Frequency

United States

Incidence of infective endocarditis is 2-4 cases per 100,000 population.

International

Frequency is similar in published data from the United Kingdom and is unchanged when compared to the preantibiotic era.

In patients with prosthetic mitral valves, the risk of endocarditis is 0.5% per year.

Mortality/Morbidity

• In the preantibiotic era, the mortality of endocarditis was nearly 100%. Currently, it is 20-50% overall. Death is often the result of congestive heart failure or acute valvular insufficiency. Studies show that the mortality of patients with bacterial endocarditis with CNS involvement is much greater (58-74%) than that of patients who do not have CNS involvement (20-56%). In one study, during the acute phase of infective endocarditis, 24% of patients with neurologic complications died while only 10% of those without neurologic complications died. Among the patients with neurologic involvement, mortality was 25% in those treated medically, and 20% in those treated surgically.
• In one series, 38 major embolic events occurred in 37 patients. Thirty of these 37 patients died (81% mortality).

Sex

• The male-to-female ratio is 1.7:1 (average of several series).
• In the presence of infective endocarditis and aortic valve rheumatic disease alone, the male-to-female ratio is 4:1.
• If the mitral valve alone is involved as a sequela to rheumatic fever, the male-to-female ratio is 1:2.

Age

• Patients younger than 30 years account for 26%.
• Patients aged 31-60 years account for 54%.
• Patients older than 60 years account for 21%.

Clinical

History

Nonspecific symptoms such as fatigue, malaise, anorexia, and weight loss are common.

• Symptoms are sometimes nonfocal, and even amnesia can herald a diagnosis of infective endocarditis.
• Mental status changes (without focal findings) have been attributed to microemboli (11% in the Massachusetts General Hospital series² ).
• Cancer patients who appear to have reactive or behavioral (psychiatric) symptoms actually may have organic embolic disease. If fever, seizures, and/or DIC are present in a patient with cancer, culture-negative bacterial endocarditis may be misdiagnosed as psychiatric disease.
• Transient ischemic attack-like (TIA-like) presentations also can occur with fluctuating focal neurologic signs. Presumably, the transient nature (resolution) results from the disintegration and dislodgement of small emboli.
• Lumbar pain and fever are reported to herald the diagnosis of infective endocarditis in approximately 3% of patients.

Physical

• Fever and heart murmurs are often present. However, the valvular vegetations are usually not large enough to produce murmurs of their own accord. Thus, as many as 25% of patients with acute infective endocarditis do not have a cardiac murmur.
• Stigmata of systemic emboli and cardiac dysfunction are not always clinically apparent. When found, they occur in different body regions.
  • Immune phenomena occur in infective endocarditis with increases in polyclonal immunoglobulin (Ig)G and immune complexes. When deposited in the skin, they produce the characteristic Osler node (ie, painful finger nodules).
  • Janeway lesions are erythematous macules found on the palms and soles.
  • Roth spots are retinal hemorrhages.

Causes

• Those who abuse intravenous (IV) drugs have a slightly different profile, with 60% of all cases secondary to S aureus. This increases to 80% when the tricuspid valve is affected.
• High-risk groups include the following:
  • In the mid-1980s, rheumatic disease was felt to be a disease of the past since it accounted for less than 25% of cases, but since 1985, a resurgence has been reported in some parts of the United States.
  • Presently, the 3 main high-risk groups are (1) illicit drug users, (2) patients with prosthetic cardiac valves, and (3) patients with nosocomial-related endocarditis.
  • Infective endocarditis and other forms of endocarditis such as NBTE can affect patients with normal native heart valves. Differences in opinion remain as to whether patients with NVE or prosthetic valve endocarditis (PVE) are at greater risk of neurologic complications. One study suggested that infective endocarditis occurred more often in patients with mechanical valves than in those with bioprosthetic valves.⁶
• Dental procedure prophylaxis concerns are as follows:
  • Recently, a retrospective study was performed that questioned the use of antibiotic prophylaxis prior to dental work.
  • The only dental procedure with an increased risk of endocarditis was tooth extraction within 2 months after hospitalization.
• Patients with a history of valve abnormalities who were given antibiotics were not protected against endocarditis.
• Guidelines for antibiotic prophylaxis for endocarditis prevention are available from the American Heart Association.

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