SEMINARS IN NEUROLOGY-VO1,UME
12, N O . 3 SEPTEMBER 1992
Neurologic Complications of Infective Endocarditis
HISTORICAL NOTE Entlocardilis was first clescribecl in 1846 by Virchow, who recognized the relationship between valvular vegetations arid arterial emboli at distant sites. In the 1870s, several reports described the presence of bacteria in the cardiac vegetations. William Osler discussed the subject in 1881, i r ~his publicatior~entitled "Infec~iousEndocartiitis."' In 1883, William Osler was elected into the Royal College of Physicians and selected to present the Gulstonian Lectures of 1885. For 2 years, he meticulously reviewed the records of 209 cases that fitted the description of endocarditis. In the now-famous "Gulstonian Lectures o n Malignant Endocarditis," he states, "[Tlhe protean character of the malady, the latency of the cardiac symptoms, and the close sirnulation of other clisorders, combine to render the detection peculiarly diff'ic u l t . " N o w , over a century later, how true Dr. Osler's words still are.
PATHOPHYSIOLOGY PATHOGENESIS OF ENDOCARDZTZS 'I'he developmetlt of infective endocarditis (IE) is a sequential process of specific organism-host interactions. Despite the vast numbers of known human pathogens, Staphylococcus and Streptococcus continue to be the most common microorganisms causing endocarditis.".' iZn overview of selecled predisposir~gcharacteristics (inclilding host risk Factors, microorganism virulence factors, and iatrogenic risk factors) will preface h e discussion on the paihoge~lesisof IE and its central nervous system (C:NS) corrlplications (Table 1).
nancy, disseminated intravascular coagulation, o r lupus ar~ticoagulant),the valvc bccomcs excessively prothrombotic so that mininlal injury o r disruption of the entlothelial lining leads to massive platelet-fibrin deposition and thrombus formation on the valve."-x .l'his sterile fibrin clot is the nidus for subsequent infection. An additional host risk factor for IE is the presence of an underlying congenital or acquired cardiac abnorrnality, such as mitral valvc prolapse, bicuspid o r unicuspid aortic valve, valvular stenosis o r insufficiency, patent ductus arteriosus, coarctation of the aorta, ventricular septal defect, hypertrophic cardiomyopathy, calcification o f t h e lnitral anulus, o r atheromatousldegenel-ative valvular changes.!' " Such cardiac defects producc turbulent jet flow, which can denude and traumatize the endothelial lining of the heart and valves. Atrial septal defect of the secundum type does not disrupt the normal blood flow and ~ h u appears s to have low o r no increased risk for IE."'~" T h e presence of an irrlrr~uneabrlorrnality iricreases the risk of IE with an unusual o r opportunistic pathogen. For example, patients with neutropenia are at increased risk for infection d u e to Pseudomonas and fungi, specifically Aspergillus arld Candida. Patients with defects in humoral immunity are unable to mount an antibody response to bactciial infection and are therefore at irlcreasecl risk for infection caused by encapsulated bacteria. In a compromised host, even tuberculosis can cause valvular vegetations and endocarditis. I;inally, illicit intravenous d r u g abuse is a risk factor f i ~ rIE. Repcated contaminated intravenous drug injections directly inoculate the host bloodstream with various bacteria and fungi that can infect cardiac val~es.'~.'!'
Organism Virulence Factors Host Risk Factors T h e endothelial lining of the native cardiac valve ~x)ssessesboth prothrombotic and antithrombotic propel-ties. Undel- physiologic conditions, intact valvular e n d o t h c l i ~ ~isn ~antithrombotic.' In the presence of a hypercoagulable state (such as in the presence of malig-
Some microorganisms have specific characteristics that make them particularly virulent to cardiac endothelium. An inherent ability to adhere to injured endothelial cells appears to be a necessary characteristic among pathogens that cause 1E."'-'' Gram-positive organisms, which account for the majority of cases of IF. (staphylococci, streptococci, cntcrococci), have been shown to
I)cp;~rt~i~cnt of Neurology, Indiana University School of' Medicine, Indianapolis Indiana Reprints rcclucsts: Dr. Koos: Associate Professor-of Neurology, Indiana Univcrsity Medical (:elrter, 1050 \Valrlut Street, RHC 6, Indianapolis, I N 46202 Copyright 0 1992 Ily Thieme hfedical Publishers, Inc., 381 Park Avcnuc South, New York, N Y 100 16. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
Aki K . Selky? M.L)., arul Karen L. Rum, M.D.
SEMINARS I N NEUROLOGY
VOLIJME 12, NUMBER 3
SEPTEMBER 1992
Table 1. Predisposing Factors for Infective Endocarditis Organism
Hypercoagulablestate
Microbial adherence substances (fibronectin, dextran, and others)
lnvasive procedure
Cardiac valvular disease
Platelet activation and aggregation
lntravascular device
Immunodeficiencystate
Isolation and sanctuary within platelet fibrin matrix
Antimicrobial therapy
Intravenous drug abuse
Small and large colony sizes
Prosthetic valves
have greater adherence to cultured endothelial cells in vitro, when compared with gram-negative organisms, which more commonly cause bacteremia and sepsis (Pseudomorias, Serratia, Escherichia coli, Klebsiella, F:nteroba~ter).?",~~~~'~ Substances that enhance microbial adhesion include subendothelial proteins like fibronectin, lamiriin, and collagen, as well as circulating plasma fibronectin, bacteria-secreted dextran, and slime and platelet aggregate^.?^-"" After attaching to injured endothelium and sterile platelet-fibrin deposits, the infecting microorganism can activate further platelet aggregation and local thrornbus formation via release of endotoxins, stimulation of enclothelial procoagulants, and induction of inflammatory cytokines,~:i~.92 Within 18 to 24 hours, a fibrinous surface overlying thc infected nidus can be detected microscopically, providing a sanctuary to the proliferating organisms buried within it.s".94 Once established in the vegetation, certain bacterial strains isolate into small colony tbrms. Small colony variants are ~tsirallydeeply embedded, less virulent, and slower growing than their larger parent colorly variants on the surfice layer. T h e use of multiple colony sizes has synergistic survival advantage^."^
Iatrogenic R i s k Factors
226
iatroaenic
T h e rapid evolutiori of rnedical diagnostic and therapeutic techniques has impacted on the scope of IE. For instance, office procedures with invasive instrumentation of gastrointestinal, genitourinary, and female genital tracts are corrirno~lplacenow. Such procedures are known to cause transient bacteremia from flora of the invaded rrlircous rnerribranes."'~""~"' Skin organisms can access the bloodstream along intravascularly placed catheters and devices. Advances in immunology, hematology, oncology, and AIDS treatment have brought potent drugs and, with them, unusual or opportunistic pathogens. Prolonged hospitalizations and invasive procedures have increased the risk for endocarditis among the elderly."",:iH ever^ the improved antimicrobial and surgical treatnierits for native valve IE can result i r ~damaged valves and prosthetic valves, two major risk factors for recurrent endocarditis."" As previously mentioned, normal valvular endothelium actively maintains a thromboresistant surface. In response to direct (turbulent blood flow) or indirect (cold, stress, malignancy) trauma to endo~heliuni,platelets and fibrin may be deposited on the disrupted surface arid form sterile agglutinated thrombi to produce nonbacterial thrombotic endocarditis (NBTE). Microorganisms are attracted to, and adhere to, the lesions of NB'Z'E. A coincident bacteremia of even 15 minutes' du-
ration can colonize lesions. Subsequent deposits of platelet-fibrin-pathogen create laminar growth of the vegetation. Depending on the virulence of the pathogen and the immune status of the host, the vegetatiorls of 1K can range from flat granular lesions to friable pedunculated mas~es.:"~~"
PATHOGENESIS OF CENTRAL NERVOUS SYSTEM COMPLICATIONS Embolization to the CNS is the singular initiating event in the pathogenesis of a myriad of neurologic cornplications (Table 2). 'l'he tirriing of most embolic episodes correlates with the period of most active, uncontrolled infection and rapid evolution o f t h e vegetations. For- that reason, most embolic episodes occur in the first 2 weeks
Table 2. Proposed Mechanisms of Various Neurologic Complications of Infective Endocarditis TIAlStroke
1. Ischemic occlusion by sterile emboli 2. lschemic occlusion by septic emboli 3. Hemorrhage
lntraparenchymal hemorrhage
1. Septic-necrotic arteritis with rupture 2. Conversion from bland infarction 3. Ruptured mycotic aneurysm 4. Secondarv disseminated intravascular coagulation or hemorrhagic diathesis (for example, warfarin)
Subarachnoid hemorrhage
1. Ruptured mycotic aneurysm
Meningitislmeningoencephalitis
1. Septic emboli to meningeal vessels 2. Suppurative extension from septic embolic infarction 3. "Sterile" inflammatory reaction
Abscess
1. Septic infarction and parenchymal invasion
Mycotic aneurysm
1. Septic emboli to vasa vasorum with subsequent adventitial infection and muscularis destruction 2. Direct intimal destruction bv arterial septic embolus 3. Immune complex deposition in arterial wall?
Seizure
1. 2. 3. 4. 5.
Encephalopathy
1. Multiple microabscesses 2. Meningoencephalitis
Emboli Meningitislmeningoencephalitis Abscess Hemorrhage Toxic-metabolic
Downloaded by: National University of Singapore. Copyrighted material.
Host
INFECTIVE ENDOCARDITIC C O M P I , I C K ~ I O N S - S ~ ~ROOS ~~,
12, N O . 3 SEPTEMBER 1992
Neurologic Complications of Infective Endocarditis
HISTORICAL NOTE Entlocardilis was first clescribecl in 1846 by Virchow, who recognized the relationship between valvular vegetations arid arterial emboli at distant sites. In the 1870s, several reports described the presence of bacteria in the cardiac vegetations. William Osler discussed the subject in 1881, i r ~his publicatior~entitled "Infec~iousEndocartiitis."' In 1883, William Osler was elected into the Royal College of Physicians and selected to present the Gulstonian Lectures of 1885. For 2 years, he meticulously reviewed the records of 209 cases that fitted the description of endocarditis. In the now-famous "Gulstonian Lectures o n Malignant Endocarditis," he states, "[Tlhe protean character of the malady, the latency of the cardiac symptoms, and the close sirnulation of other clisorders, combine to render the detection peculiarly diff'ic u l t . " N o w , over a century later, how true Dr. Osler's words still are.
PATHOPHYSIOLOGY PATHOGENESIS OF ENDOCARDZTZS 'I'he developmetlt of infective endocarditis (IE) is a sequential process of specific organism-host interactions. Despite the vast numbers of known human pathogens, Staphylococcus and Streptococcus continue to be the most common microorganisms causing endocarditis.".' iZn overview of selecled predisposir~gcharacteristics (inclilding host risk Factors, microorganism virulence factors, and iatrogenic risk factors) will preface h e discussion on the paihoge~lesisof IE and its central nervous system (C:NS) corrlplications (Table 1).
nancy, disseminated intravascular coagulation, o r lupus ar~ticoagulant),the valvc bccomcs excessively prothrombotic so that mininlal injury o r disruption of the entlothelial lining leads to massive platelet-fibrin deposition and thrombus formation on the valve."-x .l'his sterile fibrin clot is the nidus for subsequent infection. An additional host risk factor for IE is the presence of an underlying congenital or acquired cardiac abnorrnality, such as mitral valvc prolapse, bicuspid o r unicuspid aortic valve, valvular stenosis o r insufficiency, patent ductus arteriosus, coarctation of the aorta, ventricular septal defect, hypertrophic cardiomyopathy, calcification o f t h e lnitral anulus, o r atheromatousldegenel-ative valvular changes.!' " Such cardiac defects producc turbulent jet flow, which can denude and traumatize the endothelial lining of the heart and valves. Atrial septal defect of the secundum type does not disrupt the normal blood flow and ~ h u appears s to have low o r no increased risk for IE."'~" T h e presence of an irrlrr~uneabrlorrnality iricreases the risk of IE with an unusual o r opportunistic pathogen. For example, patients with neutropenia are at increased risk for infection d u e to Pseudomonas and fungi, specifically Aspergillus arld Candida. Patients with defects in humoral immunity are unable to mount an antibody response to bactciial infection and are therefore at irlcreasecl risk for infection caused by encapsulated bacteria. In a compromised host, even tuberculosis can cause valvular vegetations and endocarditis. I;inally, illicit intravenous d r u g abuse is a risk factor f i ~ rIE. Repcated contaminated intravenous drug injections directly inoculate the host bloodstream with various bacteria and fungi that can infect cardiac val~es.'~.'!'
Organism Virulence Factors Host Risk Factors T h e endothelial lining of the native cardiac valve ~x)ssessesboth prothrombotic and antithrombotic propel-ties. Undel- physiologic conditions, intact valvular e n d o t h c l i ~ ~isn ~antithrombotic.' In the presence of a hypercoagulable state (such as in the presence of malig-
Some microorganisms have specific characteristics that make them particularly virulent to cardiac endothelium. An inherent ability to adhere to injured endothelial cells appears to be a necessary characteristic among pathogens that cause 1E."'-'' Gram-positive organisms, which account for the majority of cases of IF. (staphylococci, streptococci, cntcrococci), have been shown to
I)cp;~rt~i~cnt of Neurology, Indiana University School of' Medicine, Indianapolis Indiana Reprints rcclucsts: Dr. Koos: Associate Professor-of Neurology, Indiana Univcrsity Medical (:elrter, 1050 \Valrlut Street, RHC 6, Indianapolis, I N 46202 Copyright 0 1992 Ily Thieme hfedical Publishers, Inc., 381 Park Avcnuc South, New York, N Y 100 16. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
Aki K . Selky? M.L)., arul Karen L. Rum, M.D.
SEMINARS I N NEUROLOGY
VOLIJME 12, NUMBER 3
SEPTEMBER 1992
Table 1. Predisposing Factors for Infective Endocarditis Organism
Hypercoagulablestate
Microbial adherence substances (fibronectin, dextran, and others)
lnvasive procedure
Cardiac valvular disease
Platelet activation and aggregation
lntravascular device
Immunodeficiencystate
Isolation and sanctuary within platelet fibrin matrix
Antimicrobial therapy
Intravenous drug abuse
Small and large colony sizes
Prosthetic valves
have greater adherence to cultured endothelial cells in vitro, when compared with gram-negative organisms, which more commonly cause bacteremia and sepsis (Pseudomorias, Serratia, Escherichia coli, Klebsiella, F:nteroba~ter).?",~~~~'~ Substances that enhance microbial adhesion include subendothelial proteins like fibronectin, lamiriin, and collagen, as well as circulating plasma fibronectin, bacteria-secreted dextran, and slime and platelet aggregate^.?^-"" After attaching to injured endothelium and sterile platelet-fibrin deposits, the infecting microorganism can activate further platelet aggregation and local thrornbus formation via release of endotoxins, stimulation of enclothelial procoagulants, and induction of inflammatory cytokines,~:i~.92 Within 18 to 24 hours, a fibrinous surface overlying thc infected nidus can be detected microscopically, providing a sanctuary to the proliferating organisms buried within it.s".94 Once established in the vegetation, certain bacterial strains isolate into small colony tbrms. Small colony variants are ~tsirallydeeply embedded, less virulent, and slower growing than their larger parent colorly variants on the surfice layer. T h e use of multiple colony sizes has synergistic survival advantage^."^
Iatrogenic R i s k Factors
226
iatroaenic
T h e rapid evolutiori of rnedical diagnostic and therapeutic techniques has impacted on the scope of IE. For instance, office procedures with invasive instrumentation of gastrointestinal, genitourinary, and female genital tracts are corrirno~lplacenow. Such procedures are known to cause transient bacteremia from flora of the invaded rrlircous rnerribranes."'~""~"' Skin organisms can access the bloodstream along intravascularly placed catheters and devices. Advances in immunology, hematology, oncology, and AIDS treatment have brought potent drugs and, with them, unusual or opportunistic pathogens. Prolonged hospitalizations and invasive procedures have increased the risk for endocarditis among the elderly."",:iH ever^ the improved antimicrobial and surgical treatnierits for native valve IE can result i r ~damaged valves and prosthetic valves, two major risk factors for recurrent endocarditis."" As previously mentioned, normal valvular endothelium actively maintains a thromboresistant surface. In response to direct (turbulent blood flow) or indirect (cold, stress, malignancy) trauma to endo~heliuni,platelets and fibrin may be deposited on the disrupted surface arid form sterile agglutinated thrombi to produce nonbacterial thrombotic endocarditis (NBTE). Microorganisms are attracted to, and adhere to, the lesions of NB'Z'E. A coincident bacteremia of even 15 minutes' du-
ration can colonize lesions. Subsequent deposits of platelet-fibrin-pathogen create laminar growth of the vegetation. Depending on the virulence of the pathogen and the immune status of the host, the vegetatiorls of 1K can range from flat granular lesions to friable pedunculated mas~es.:"~~"
PATHOGENESIS OF CENTRAL NERVOUS SYSTEM COMPLICATIONS Embolization to the CNS is the singular initiating event in the pathogenesis of a myriad of neurologic cornplications (Table 2). 'l'he tirriing of most embolic episodes correlates with the period of most active, uncontrolled infection and rapid evolution o f t h e vegetations. For- that reason, most embolic episodes occur in the first 2 weeks
Table 2. Proposed Mechanisms of Various Neurologic Complications of Infective Endocarditis TIAlStroke
1. Ischemic occlusion by sterile emboli 2. lschemic occlusion by septic emboli 3. Hemorrhage
lntraparenchymal hemorrhage
1. Septic-necrotic arteritis with rupture 2. Conversion from bland infarction 3. Ruptured mycotic aneurysm 4. Secondarv disseminated intravascular coagulation or hemorrhagic diathesis (for example, warfarin)
Subarachnoid hemorrhage
1. Ruptured mycotic aneurysm
Meningitislmeningoencephalitis
1. Septic emboli to meningeal vessels 2. Suppurative extension from septic embolic infarction 3. "Sterile" inflammatory reaction
Abscess
1. Septic infarction and parenchymal invasion
Mycotic aneurysm
1. Septic emboli to vasa vasorum with subsequent adventitial infection and muscularis destruction 2. Direct intimal destruction bv arterial septic embolus 3. Immune complex deposition in arterial wall?
Seizure
1. 2. 3. 4. 5.
Encephalopathy
1. Multiple microabscesses 2. Meningoencephalitis
Emboli Meningitislmeningoencephalitis Abscess Hemorrhage Toxic-metabolic
Downloaded by: National University of Singapore. Copyrighted material.
Host
INFECTIVE ENDOCARDITIC C O M P I , I C K ~ I O N S - S ~ ~ROOS ~~,
