Recent Infection and Stroke

A number of studies have provided evidence that acute infection in the week preceding stroke is an independent risk factor for stroke [1]. Especially respiratory and urinary tract infections can trigger ischemic stroke. Since a heterogeneous group of microbial pathogens is involved, the systemic inflammatory response to the pathogen may be more important than microbial invasion per se. However, a detailed molecular understanding of how infection causes a higher susceptibility to stroke is lacking. Numerous mechanisms have been discussed [2]. For example, inflammation has been implicated in atheroma instability and subsequent plaque rupture, alteration of the coagulation system, platelet aggregation, adhesion, and lysis. Furthermore, changes in the lipid metabolism, spasms in vascular smooth muscle, anti-phospholipid antibody formation, and impairment of endothelial function by endotoxin and bacterial toxins have been reported. Apart from these factors, dehydration, bed rest, and mechanical factors such as sneezing may play a role.

Aside from bacterial infection, common viral diseases such as seasonal flu may trigger stroke. Several observational studies suggest that influenza and pneumococcal vaccinations lower the risk of myocardial infarction and stroke in the elderly [3, 4]. However, conclusive evidence for a protective effect is still lacking.

Chronic Infections and Stroke

Atherosclerosis is a common disease and a major risk factor for stroke. Its etiology can largely be explained by the classic risk factors (age, gender, genetic predisposition, hypertension, diabetes, hypercholesterolemia, high-fat diet, smoking, low physical activity, etc.). Additionally, pathogens such as Helicobacter pylori, cytomegalovirus, herpes simplex virus, and Chlamydia pneumoniae have been proposed to be associated with atherosclerosis [5].

Most studies on the infectious etiology of atherosclerosis focused on C. pneumoniae, an obligate intracellular bacterium that usually causes mild upper respiratory tract infection, and occasionally pneumonia. Exposure to this agent is common and by the age of 20 years 50% of individuals are seropositive.

Animal models support a role of C. pneumoniae in the initiation, maintenance, and rupture of atherosclerotic lesions, but clinical and epidemiological studies have not come to conclusive results. This shortcoming might be explained by the difficulty in attributing causality to a common pathogen and a multifactorial disease.

As with atherosclerosis, the contribution of chronic bacterial infections to the etiology of stroke is unclear. Some studies found an increased risk of stroke in patients with elevated antibody titers suggesting previous C. pneumoniae infection, H. pylori gastritis, and periodontal disease (caused by a great variety of bacteria). Conflicting information has been published on these pathogens [6, 7] and randomized interventional trials, e.g. aiming at the eradication of C. pneumoniae by macrolide therapy, failed to reduce the incidence of vascular events [8, 9].

A newer concept is the “chronic infectious burden” hypothesis. According to this hypothesis, the combined exposure to above-mentioned pathogens, as measured by serological studies, leads to a higher risk of stroke [10]. However, results are conflicting [11] and which pathogens should be included in a stroke-risk panel remains an open question, as does, even more so, whether and when anti-microbial intervention may be appropriate.

Infectious Diseases that Cause Stroke

Multiple pathophysiological mechanisms can lead to stroke in bacterial, viral, and parasitic diseases. An overview of organisms implicated in infectious diseases that may lead to stroke and their associated pathophysiology is presented in Table 23.1. For example: (1) emboli from infected heart valves in bacterial or fungal endocarditis may obstruct cerebral arteries; (2) direct microbial invasion and inflammation of the vessel wall can lead to wall destruction and obliteration of the lumen, as in obliterative vasculitis or necrotizing panarteritis; (3) chronic inflammation of the meninges leads to stroke through several mechanisms; and (4) mycotic aneurysms can rupture and cause hemorrhagic stroke. In the following section we will review some of these diseases and associated pathogenic principles.

Infective Endocarditis

Infective endocarditis (IE) is an infection of the endocardium, a thin tissue layer that lines heart valves and mural myocardium (Figure 23.1). The incidence of IE is about 5–10 cases per 100 000 person-years and it is a serious disease with about 20% mortality. The main risk factors for endocarditis are an underlying structural heart disease (such as congenital heart defects or degenerative valvular lesions), injection drug use, hemodialysis, and invasive intravascular procedures [12]. Carriers of a prosthetic heart valve are especially at risk, with a 1–4% chance of developing IE within the first year following surgery.

Figure 23.1 Infective endocarditis: a 53-year-old male presented with a 1-week history of malaise, fever (up to 41°C), behavioral changes, and headache. On clinical examination mild meningeal signs, left-sided ataxia, and splinter hemorrhages (A) were noted. Computed tomography (CT) of the brain showed several ischemic lesions in both hemispheres and right cerebellum (B). Staphylococcus aureus was cultured from blood and cerebrospinal fluid. Transesophageal echocardiography revealed a large mitral valve vegetation (C) which was subsequently removed surgically (D, bar = 1 cm). A CT scan 3 weeks after initial symptoms showed abscess formation with contrast enhancement and marked edema (E).

(Courtesy of K Lackner, Department of Radiology, F Dodos, Department of Cardiology, and J Wippermann, Department of Cardiac Surgery, University Hospital of Cologne.)

IE is caused by bacteria or fungi that attach to and damage the endocardium or the prosthetic valve and grow into vegetations measuring up to several centimeters in size. If left untreated, destruction of the heart valve ultimately leads to heart failure and death. Complications, e.g. stroke, can arise when emboli break off from the vegetation and occlude blood vessels, leading to infarction of the dependant cerebral tissue.

Microbiology of IE

Many bacteria and fungi can cause IE, some of which are listed with their overall frequency of isolation in Table 23.2. Different clinical conditions favor certain microbes, e.g. right-sided endocarditis in injection drug users is commonly caused by Staphylococcus aureus (>80%). In patients with prosthetic heart valves, early-onset prosthetic valve endocarditis (PVE) (i.e. less than 12 months after surgery) is more often caused by coagulase-negative staphylococci (up to 50% of all cases) than by S. aureus and viridans group streptococci as is the case in late PVE [13]. Although fungal pathogens are rarely a cause of IE, Candida or Aspergillus spp. may occur in immunocompromised patients.

Depending on the causative organisms different clinical courses can be observed. S. aureus and less frequently Streptococcus pneumoniae, and Enterobacteriaceae such as Escherichia coli or Klebsiella pneumoniae, are associated with an acute course and high mortality (i.e. acute endocarditis). Patients with IE due to enterococci or viridans group streptococci usually report several weeks of symptoms before a clinical diagnosis is made (i.e. subacute endocarditis).

Clinical Presentation and Diagnostic Criteria in IE

Clinical signs and symptoms for IE are highly variable and often misleading. Fever, heart murmur, malaise, anorexia, weight loss, night sweats, and myalgia may or may not occur. The clinical course can be acute or subacute (see above). Therefore, IE is often recognized late, e.g. when complications have occurred.

To facilitate diagnosis of IE, diagnostic criteria have been developed. From the results of the clinical examination, blood cultures, and ultrasound imaging (preferably transesophageal echocardiography, TEE) a clinical score is derived that describes the likelihood of IE in a specific patient (e.g. modified Duke criteria, see Box 23.1).

Neurological complications of IE are common (about 20–40%) and are associated with a worse outcome [14, 15]. They include stroke, intracranial or subarachnoidal hemorrhage, meningitis, seizures, encephalopathy, brain abscess, and mycotic aneurysm (frequencies in Table 23.3). Many neurological complications may go unnoticed. In a study by Snygg-Martin et al. cerebrovascular events were detected by MRI in 65% of patients with left-sided IE, but clinical symptoms were observed in only 35% of patients [15].

Pathogenesis of IE

IE is the result of a complex interaction between microorganism, matrix molecules, and platelets at the site of endocardial cell damage. The pathophysiological process can be divided into several stages: formation of non-bacterial thrombotic endocarditis (NBTE), bacterial colonization of the lesion, and growth into vegetations [16].

Endocardial damage is the starting point of IE pathogenesis. It is caused by congenital or acquired heart diseases that are associated with a turbulent blood flow. Then, fibrin and platelets are deposited on traumatized endothelium, which results in NBTE. Microorganisms that have gained access to the bloodstream (bacteremia) and possess the necessary virulence factors may now colonize the lesion, multiply, and lead to IE.

A frequent cause of bacteremia is damage of the skin or a mucosal surface. The skin and mucosal surfaces, such as oral cavity, nasopharynx, gastrointestinal tract, urethra, or vagina, are populated by a dense endogenous flora with many diverse bacterial species. Even a minor trauma such as tooth brushing, a tooth extraction, or a colonic biopsy may lead to a temporary release of bacteria into the bloodstream (transient bacteremia).

After having gained access to the bloodstream, IE-causing pathogens adhere to the NBTE. Adhesion to fibrin and platelets or to the surface of medical devices, such as artificial heart valves, is facilitated by microbial surface components recognizing adhesive matrix molecules (MSCRAMM), many of which have been identified in staphylococci, streptococci, and enterococci.

Following adhesion, bacteria stimulate the deposition of further fibrin and platelets and a secluded compartment is formed, which hides bacteria from the host immunological defense. The microorganisms proliferate and produce a thick mucilaginous polysaccharide matrix which is called biofilm. In a biofilm less than 10% of bacteria divide actively and responsiveness to cell wall-active anti-microbials such as beta-lactams and glycopeptides is decreased. Since anti-microbials need to penetrate the biofilm to reach the bacterial targets, optimal anti-microbial treatment with high-dose bactericidal agents is crucial for a successful therapy of IE.

Pathogenic Mechanisms Leading to Stroke in IE

Sterile or septic emboli that originate from vegetations and occlude cerebral arteries are a common cause of stroke in IE. Impairment of the cerebral blood flow can lead to a transient ischemic attack (TIA) or stroke. Depending on the localization and duration of reduced blood flow, focal clinical signs occur. When multiple emboli occlude several independent vessels, multifocal clinical signs may become apparent.

The source of emboli to the central nervous system is usually the left heart, from vegetations on the mitral or aortic valve. Emboli from the right heart are filtered by intrapulmonary arteries and cause pulmonary embolism. Therefore, tricuspid valve endocarditis, which is common among intravenous drug users, rarely leads to stroke. However, in rare cases paradoxical embolism has been reported.

Other complications of IE, such as brain abscesses and meningitis, may also lead to stroke. A brain abscess occurs when bacteria have seeded via the bloodstream to the brain parenchyma. Brain abscesses are a rare complication of IE and occur in less than 1% of patients with IE [16]. A brain abscess typically develops over 2–3 weeks. Initial imaging studies show a poorly demarcated lesion with localized edema. Over the weeks a clearly defined lesion develops, often accompanied by an extensive edema. The early stage is called cerebritis and is histologically defined by acute inflammation without tissue necrosis. During abscess development tissue necrosis, liquefaction, and a fibrotic capsule become more prominent. A typical histological finding is a central necrotic area containing bacteria and debris and a hyperemic margin with bacteria and immune cells. In many cases anti-microbial therapy of a brain abscess alone is unsuccessful and has to be backed by surgical drainage.

Bacterial meningitis is caused by hematogenous seeding of microorganisms to the meninges. The inflammatory response can damage arterial vessel walls and cause mycotic aneurysms (see below). Ischemic stroke occurs through obstruction of inflamed vessels, hemorrhagic stroke through rupture of a mycotic aneurysm. The contribution of immune-mediated injury, e.g. by immune-complex deposition, is unknown.

Therapy of IE

Before the advent of anti-microbials, IE has inadvertently led to death. Despite major advances in anti-microbial and surgical therapy, in-hospital mortality is still 15–20% [17].

Anti-microbial therapy should be carefully selected according to the results of anti-microbial susceptibility testing of etiologic organisms. Many scientific societies have issued guidelines that recommend specific drug treatment schemes for different organisms [18, 19]. The standard duration of anti-microbial therapy is at least 4–6 weeks and in some cases a combination therapy of two anti-microbials with different modes of action is advised.

To perform susceptibility testing, the offending organism needs to be isolated from blood or valve tissue. With the use of current technology, an initial culture of 40–60 ml of blood (corresponding to two to three pairs of blood culture bottles) is considered sufficient. Chances of a successful isolation increase when blood cultures are drawn at the beginning of a fever slope, and before anti-microbial drugs are administered. Blood cultures need to be repeated when IE is suspected and initial cultures did not yield a plausible organism.

In addition to anti-microbial drug treatment, surgical therapy needs to be considered. Indications for surgery include severe heart failure, vegetation size >10 mm, uncontrolled infection (e.g. persistently positive blood cultures or a paravalvular abscess), and prevention of embolism [19].

Patients who have suffered a recent stroke are at risk of hemorrhagic transformation of a non-hemorrhagic infarct due to the anti-coagulation necessary for the cardiopulmonary bypass. Whether heart valve replacement can be safely performed within the first 2 weeks after stroke is a matter of debate. In a recent multicenter study delay of surgery did not lead to a survival benefit [20]. However, each individual patient needs to be carefully evaluated by a multidisciplinary team.

Embolic Stroke due to Chagas Disease

Chagas disease is an infection with the protozoan parasite Trypanosoma cruzi, which is most prevalent in South and Central America. The parasite is transmitted by the feces of an insect vector (Triatoma and other assassin bug species). Additionally, transmission occurs by vertical transmission from mother to child, contaminated foods, blood products, and organ transplant. Once inside the host, the parasite multiplies within various host cells and is distributed via the bloodstream. After an often asymptomatic acute infection, the parasite can persist in various tissues, including adipose tissue. Chronic infection can persist for years or decades and may be asymptomatic. In 10–30% of patients, parasitic invasion of the heart muscle leads to cardiomyopathy, probably through chronic inflammation [21].

Embolic stroke is common in patients with Chagas disease and may be the first sign of cardiac involvement. Conditions that predispose to cardiac emboli in Chagas disease are cardiac arrhythmias, congestive heart failure, apical aneurysms, and mural thrombus formation. By the time stroke occurs, the damage to the heart is irreversible. Thus, effort needs to be directed towards prevention of Trypanosoma infection by vector control and improvement of basic housing conditions, as well as early diagnosis and treatment.

Meningitis as a Cause of Stroke

Meningitis denotes the inflammation of the leptomeninges, which consist of the pia mater and arachnoid mater. These layers ensheath the spinal cord and brain and confine the subarachnoidal space, which contains cerebrospinal fluid (CSF). Infection of the meninges by bacteria or fungi leads to an inflammatory response which causes the typical clinical symptoms, headache and nuchal rigidity. Depending on the time course, meningitis can be classified as acute or chronic.

Acute bacterial meningitis is prevalent worldwide and accounts for substantial deaths and long-term disabling sequelae with an estimated 5.6 million disability-adjusted life years globally. The introduction of large-scale vaccination programs has substantially lowered the incidence. Nevertheless, large outbreaks with more than 10 000 cases still occur, especially in sub-Saharan Africa. Patients present with fever, nuchal rigidity, and lethargy or confusion. Other less frequent symptoms are photophobia, seizures, petechial bleeding, and arthritis. The disease occurs in all age groups, but the causative organisms vary depending on age (Table 23.4). If left untreated, the disease is fatal.

Diagnosis is based on clinical symptoms, CSF analysis, and microbiological testing. Empiric anti-microbial treatment needs to be initiated as early as possible with anti-microbials that reach adequate bactericidal concentrations in the CSF. The choice of anti-microbial agent needs to be reconsidered when the causative organism is identified and susceptibility testing results become available.

Common complications of acute bacterial meningitis include elevated intracranial pressure, seizures, and hyponatremia. Cerebral infarction occurs in about 15–25% of meningitis cases [22, 23]. The underlying molecular mechanisms of stroke in meningitis are not well explored. Most likely, the spreading inflammation involves intracranial vessels and leads to thrombosis and subsequent ischemia or hemorrhage [24].

Chronic meningitis has a subacute onset and lasts for more than 4 weeks. It is often accompanied by fever, headache, and vomiting. There are many infectious and non-infectious causes of chronic meningitis and despite advances in diagnostic techniques, such as polymerase chain reaction (PCR), about 30% of cases are idiopathic. In the following sections we will discuss several organisms that cause chronic meningitis with a high incidence of stroke.