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.

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.

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. 

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. 

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

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]. 

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.

Endocarditis is inflamed or infected cardiac valve or heart lining. Risk factors are damaged heart valves, ongoing infection, prosthetic heart valves, advanced malignancy, systemic lupus erythematosus, etc. Clinical manifestations in endocarditis vary from person to person. Most common neurologic sequelae in endocarditis is a stroke. If a patient has the risk factors mentioned above, symptoms like difficulty speaking, muscle weakness, a headache may indicate further investigation for stroke or other neurological complications. 

Clinically, patients may present unspecific neurologic symptoms; many patients remain asymptomatic throughout the clinical course. It is crucial to bear in mind that neurological sequelae do not necessarily occur after the diagnosis of endocarditis. Complete workup, neurological screening exams, and close follow-up are warranted. Antimicrobial treatment is the cornerstone of infectious endocarditis management, whereas targeting the underlying diseases is also essential to reduce morbidity and mortality in NBTE. Of note, in SLE patients, the disease activity does not correlate with NBTE and embolism. Management for endocarditis with ischemic stroke is debatable; however, thrombolysis is generally not recommended despite a few successful case series. Cardiac surgery is the indication in most of the endocarditis patients; nevertheless, the timing for patients with neurological sequelae as well as its role in embolism prevention remains controversial.

Neurological sequelae are the second most common complications in infective endocarditis. Early antibiotic initiation reduces the rate of embolism as well as other complications.[9] [Level I] Limited studies on anticoagulant therapy, antiplatelet therapy or thrombolytic therapy on embolism in patients with infectious endocarditis, according to 2015 American Heart Association (AHA), none of these therapies were indicated.[7] [Level I] In patients with acute ischemic stroke who are already on anticoagulation, anticoagulant discontinuation should be for two weeks. [Level I] For patients with NBTE, embolism is the most common complication of all. Patients with NBTE with or without embolism, including CNS, spleen or other organs should be anticoagulated, with exception to contraindications such as intracranial hemorrhages and ongoing bleeding. [Level I] In SLE or cancer patients, anticoagulation should continue regardlessly to prevent the recurrence of embolism. [Level III] Pharmacist specialty trained in infectious diseases should assist with antibiotic selection and management. The nurses should coordinate care, assist with patient and family education, and arrange regular follow up reporting untoward events to the clinical team leader.

Patients with neurological sequelae to endocarditis require an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]