Neurological Sequelae of Endocarditis

Etiology

Endocarditis is an infectious condition or inflammation of the cardiac valves or the endocardium.

• Valvular disease such as rheumatic heart disease and congenital heart abnormalities like a bicuspid aortic valve, ventricular septal defect, coarctation of the aorta are risk factors for infectious endocarditis. Pathogens that account for infectious endocarditis vary and depend on the risk factors including intravenous drug abuse, existing valvular dysfunction, poor oral hygiene, and dental procedure, immunocompromised status, the cardiac implantable electronic device (CIED), or previous history of infectious endocarditis. In infectious endocarditis, neurological complications correlate with the size of vegetation and bacterial load. Among all the causative pathogens, Staphylococci aureus is the most common microorganism of infective endocarditis in the United States and other developed countries. Staphylococci aureus IE is significantly more likely to result in embolic events than other pathogens. Neurological sequelae from IE are as following, 
  1. Embolic stroke is caused by vegetation debris that lodge in the cerebral blood vessels and ended up resulting in infarction; 
  2. Transient ischemic attack (TIA) is an episode of neurologic dysfunction attributed to ischemia of brain, spinal cord, or retina;
  3. Cerebral hemorrhage
  4. Meningitis
  5. Brain abscess
  6. Toxic encephalopathy
  7. Seizure
• Nonbacterial thrombotic endocarditis is associated with connective tissue disorders, autoimmune disorders, malignancy, and other hypercoagulable states. Vegetations in NBTE are usually small and can easily dislodge compared to IE. Hence, NBTE with vegetations has an increased risk of developing cerebral microemboli events and intracranial lesions.

Epidemiology

• Neurologic sequelae are the most common extra-cardiac complications in infectious endocarditis, which has been consistent over the past two decades. Neurologic complications present in twenty-five up to forty percent of infective endocarditis.[3] In one retrospective study, approximately half of the patients with infective endocarditis developed neurologic sequelae as the first sign. Significant cerebral embolisms (49%) are the leading neurologic complications followed by a transient ischemic attack (18%).[3] Vegetations as big as 10mm or more are a risk factor for embolization.[4] There is a high frequency of neurologic complications associated with endocarditis that contribute to high morbidity and mortality rates.[1]
• Approximately 80% of NBTE attributed to advanced underlying malignancy, whereas systemic lupus erythematosus is the second most common cause. Of note, up to half of the NBTE patients develop systemic emboli, which is the most common clinical manifestation rather than cardiac complications.[2]

Pathophysiology

• Current studies propose a combination of factors leading pathophysiological mechanisms. Injury-thrombus-infection theory and injury of endothelium with thrombotic vegetation following by bacterial adhesion are the generally accepted ideas for neurological complications in infectious endocarditis. Maiija H et al. reported that major cerebral embolisms account for 42% of neurologic episodes; 10% are cerebral hemorrhage, which is most likely due to anticoagulant therapy in patients with valvular diseases, septic arteritis, secondary hemorrhagic transformation of infarction or mycotic aneurysm rupture.[3]
• Several studies reported neurological events in cancer patients with NBTE; emboli travel to the central nervous system resulted in cerebral infarction or transient ischemic attack even though the most common sites of embolization are the spleen, kidney, and extremities.

History and Physical

Embolism is the most common neurological complications in both IE and NBTE. However, a wide range of clinical manifestations can occur. 

• Twenty to forty percent of patients with infectious endocarditis present with symptomatic neurological sequelae such as stroke, TIA, meningitis, or brain abscess. Patients may present neurological complications before or after the diagnosis of infectious endocarditis.[5] Hence, it is crucial to consider infectious endocarditis as one of the differentials in patients with unexplained fever accompanying neurologic signs. The diagnosis of infectious endocarditis is according to modified Duke criteria, which includes clinical manifestations, blood cultures, and echocardiography. A blood culture may be negative in infective endocarditis, also known as culture-negative endocarditis, previous antibiotic treatments, or living in developing countries are risks factors for culture-negative endocarditis. 
• Patients with NBTE are often asymptomatic. Previous autopsy study in cancer patients reported an approximately fifteen percent of cerebral vascular diseases, while only less than ten percent of patients experienced clinical neurological manifestations, e.g., stroke with focal neurological deficits, delirium, change of mental status. Fever is uncommon. However, the majority of NBTE patients have an advanced underlying malignancy or autoimmune diseases such as SLE; therefore, patients might present as febrile.

Evaluation

Diagnosis of infectious endocarditis has its basis on modified Duke criteria; therefore, studies of microorganism and echocardiography are necessary for a definitive diagnosis. Whereas definitive diagnosis for NBTE is only genuinely possible pathologically, yet valvular vegetations on echocardiography without systemic infection serve strong evidence for NBTE. The majority of endocarditis patients develop silent cerebral embolism. However, neurological sequelae are a poor prognostic factor. Recommendations are that physicians should perform rapid neurologic screening physical examinations bedside, including mental status, i.e., patients orientation, the function of cranial nerves, motor system, and sensation. For unstable patients, a CT scan without contrast is the test of choice. Diffusion-weighted MRI (DWI) is preferable to conventional MRI due to its advantages in detecting acute onset ischemic lesions, smaller lesions as well as differentiating acute/chronic lesions. For patients presenting headache, neck stiffness, and fever, cerebrospinal fluid (CSF) study is necessary for further investigation for central nervous system infection such as meningitis and brain abscess.

Treatment / Management

Patients should receive treatment according to their clinical manifestations and diagnoses. For patients with infectious endocarditis, proper antibiotic treatment for native (NVE) or prosthetic valve endocarditis (PVE) is the key to reducing mortality and morbidity. Management for neurological sequelae in endocarditis varies. Here, we discuss treatment respectively as below,

• Ischemic stroke:  Currently, large trials of management for ischemic stroke in endocarditis are lacking. Initiating early antibiotic treatment not only adequately control infection but also leads to less embolism and mortality rate. European Society of Cardiology recommended that warfarin replaced by heparin in PVE and cardiac surgery within 72 hours, if not contraindicated, reduce the rate of embolism[6] The roles of anticoagulants, antiplatelet, or thrombolysis after embolic events are not well-established. Few studies have suggested a fair outcome of intravenous recombinant tissue plasminogen activator; nevertheless, intravenous thrombolysis is currently not indicated for acute ischemic stroke in infectious endocarditis patients due to concerns for hemorrhage[7]. Acute ischemic stroke in endocarditis patients should be treated per guideline, acutely lowering blood pressure is associated with worse prognosis with an exception for hypertension crisis, urgency, emergency, or other comorbidities. Patients with NBTE with or without embolism, including CNS, spleen or other organs should be anticoagulated, due to the nature of smaller and more fragile vegetations in NBTE. Treating the underlying malignancy or associated autoimmune conditions is the key to embolism prevention in NBTE patients. 
• Intracranial hemorrhage: Intracranial hemorrhages (ICH) in endocarditis, including NBTE and infectious endocarditis, can be categorized into three mechanisms: (1) hemorrhage after ischaemic stroke (2) ruptured mycotic aneurysm, or (3) undetermined etiology. Once ICH occurs, all anticoagulant and antiplatelet agents should be discontinued for a minimum of two weeks; patients should also have treatment per guideline, i.e., blood pressure control, intracranial pressure management, the reversal of anticoagulation, deep venous thrombus prevention, prevention of aspiration pneumonia, seizure management, etc. Surgery in patients with ICH in endocarditis depends on the site of lesion and the clinical course.
• CNS infection (Meningitis, Brain abscess): Brain abscess occurs mostly in critically-ill patients. Pneumococci account for 70% of bacterial meningitis in patients with infective endocarditis even though pneumococci is the causative pathogen in less than two percent of infectious endocarditis. Early effective antibiotic therapy in infectious endocarditis reduces CNS infection. Adequate antibiotic coverage and adjunctive intravenous glucocorticoids in some instances may reduce the following neurological complications from CNS infection. 
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The role of cardiac surgery at an early stage to prevent embolism remains controversial and indications for early surgery to prevent embolism differ among studies. Overall, management for endocarditis patients with neurological sequelae requires a multidisciplinary team, including infectious disease, cardiology, neurology, neurology surgery, and cardiac surgery specialists to implement optimal treatment for patients. 

Differential Diagnosis

Symptomatic neurological sequelae may present a wide range of clinical manifestations. Careful investigation is necessary for nonspecific symptoms such as headache, vomiting, change of consciousness, etc. Cerebral embolism should be a consideration in cancer patients presented with psychiatric symptoms. Differential diagnosis as following, 

• Depression
• Psychiatric diseases, psychosis, fluctuating mental status due to other medical conditions
• Aseptic meningitis, viral encephalitis
• Cavernous sinus syndromes
• Dissection syndromes
• Metastatic brain disease in cancer patients 
• Cardioembolic stroke
• Cerebral aneurysms
• Subarachnoid hemorrhage

Prognosis

Neurological sequelae indicate poor prognosis in endocarditis patients. Symptomatic patients with severe neurological deficits and intracranial hemorrhages have the worst outcome. Mortality and morbidity rate are strongly associated with the lesions, types, and extension of brain injury. Maija H. et al. reported no significant difference between patients with NVE and PVE. Also, although Staphylococcus aureus is more likely to develop cerebral embolism than other microorganisms, there is no difference in the mortality rate either[3]. One study reported the Glasgow Coma Scale and valvular repair as prognostic factors in overall mortality; stroke alone was a strong predictor of mortality[8]. 

Complications

Neurological sequelae in endocarditis lead to further morbidities. Ischemic embolic infarction might lead to permanent neurological deficits and dysfunction. A mycotic aneurysm in infectious endocarditis may contribute to cerebral hemorrhagic stroke without adequate infection control. The seizure is secondary to brain abscess, embolic infarction, or intracranial hemorrhage, etc. Venous thromboembolism (VTE) due to immobilization after stroke and neurological deficits such as aphasia, dysphagia, urinary tract infection, urinary incontinence, and sexual dysfunction may also present.