**3. Septic emboli to central nervous system**

neglected [14]. **Figure 1** summarizes the anatomic distribution of septic emboli in the setting of IE [1, 2, 4, 12–14]. Of note, anatomic distribution of septic emboli associated with infective endocarditis (48–65% cerebral, 35–52% noncerebral [1, 2, 4]) approximates that of valvular atrial fibrillation (56–63% cerebral, 38–44% noncerebral [15, 16]) suggesting that structural anatomic factors play a role in the pathophysiology of emboli originating from cardiac valves

Diagnosis of SE requires high index of clinical suspicion, combined with accurate identification and recognition of IE as a source. In the setting of native heart valves, trans-thoracic echocardiography (TTE) should be performed as an initial screening test [19]. If results of the TTE are negative, IE can usually be ruled out if Duke criteria suggest low probability [20, 21]. However, if Duke criteria suggest high suspicion of IE, or if TTE is positive or suspicious for IE, or the patient has a prosthetic valve, the next diagnostic step should be the performance of transesophageal echocardiography (TEE) [7, 19–21]. If the TEE is positive, the diagnosis is confirmed. However, if negative, the test can be repeated in 1–2 weeks if clinical suspicion continues to be high [19]. If the above diagnostic steps continue to produce negative results,

Multiple, repeated blood culture determinations are often required to identify the causative organism. Although microbiological studies provide critical information regarding targeted antibiotic therapy in IE, results are not always immediately available or universally accurate [22, 23]. Among more recent developments, real-time polymerase chain reaction (PCR) is more sensitive and specific in addition to providing clinically relevant results quickly [24]. Initial antimicrobial coverage should be broad, and once the involved microorganism is identified and antibiotic susceptibilities are known, the therapy can be appropriately narrowed to optimize long-term management. When SE is suspected, advanced imaging (CT and/or MRI)

Infective endocarditis complicated by SE requires a multidisciplinary, multimodality therapeutic approach. As outlined in previous sections, broad-spectrum antibiotic management is the most important initial step in management of both IE and SE. Once the offending microorganism is confirmed by microbiological testing, antibiotic coverage should be narrowed according to established sensitivity data. The decision to proceed with cardiac surgical therapy of IE is a complex one, most indications are not absolute, and pertinent decision-making is discussed elsewhere in this text. When cardiac surgery is indicated, early intervention has been associated with decreased all-cause mortality (including deaths following SE) due largely to the lower risk of subsequent systemic embolization [27]. When SE is present, the type and location of emboli guides the treatment strategy. Other surgical and interventional procedures may be utilized to treat complications resulting from SE, including vascular or endovascular interventions for arterial aneurysms [2, 28, 29], percutaneous drainage of abscesses [2], or organ

[16–18].

**2.4. Diagnostic considerations**

146 Contemporary Challenges in Endocarditis

alternative diagnosis should be entertained.

**2.5. Therapeutic considerations**

constitutes the cornerstone of confirmatory testing [2, 14, 25, 26].

Neurologic complications are a hallmark of left-sided IE and contribute to its unfavorable prognosis [32, 33]. The reported incidence of SE is likely underestimated [4, 34]. In the absence of abnormal intracardiac communication, neurological symptoms develop secondary to emboli originating from left-sided valvular vegetations (**Figure 2**) [1]. Less commonly, neurologic complications can also occur in cases of right-sided endocarditis with patent foramen ovale or other atrial septal defects [35]. A major risk factor for SE to the central nervous system is the delay or lack of appropriate antibiotic therapy [36]. In one study, the incidence of stroke decreased from 4.82 per 1000 patient-days to 1.71 per 1000 patient-days between the first and second weeks of appropriate antimicrobial therapy, respectively [37]. Other risk factors for septic cerebral embolism include vegetation size >10 mm, mobile and multiple vegetations, mitral and/or aortic valve endocarditis, preoperative empiric antibiotic therapy, annular abscess, anticoagulant therapy at the time of IE diagnosis, and the causative organism being *Staphylococcus aureus* [37–43]. Of note, SE to the spleen and kidneys commonly cooccur in patients with cerebral emboli [39].

**Figure 2.** Echocardiography showing large (1.8 × 1.6 cm) mitral valve vegetation (arrows).

Clinical manifestations may include ischemic stroke (**Figure 3**), transient ischemic attack (TIA), cerebral hemorrhage, meningitis, brain abscess, encephalopathy, and mycotic aneurysms [38, 39, 42, 44, 45]. Taken together, these complications often occur early (within the first 7 days of IE) and negatively impact patient outcomes [46]. Among all neurologic manifestations of IE, ischemic stroke and TIA are the most common (16–50% of all occurrences) [38, 39, 44, 45, 47– 49]. In approximately 70% of patients with SE of the central nervous system, the middle cerebral artery distribution is involved [38, 44]. Focal neurological symptoms (hemiparesis, facial droop, diplopia, aphasia, vertigo) are present in approximately 40% of affected patients, and nonfocal presentations (headaches, seizures, altered mental status) occur in approximately one-third of cases, with roughly one in five patients remaining asymptomatic [40]. Evaluation should include MRI with and without gadolinium, or CT with and without contrast if MRI is not possible. Vascular imaging should be performed routinely, and CTA or MRA is probably sufficient for screening, with catheter angiography reserved for cases where a mycotic aneurysm was noted and in those patients with an acute brain hemorrhage [50].

**Figure 3.** Magnetic resonance imaging (MRI) showing septic embolus to the brain. Source: Stawicki et al. [2]. Used under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A relatively less common manifestation of SE associated with IE is bacterial meningitis, usually presenting with fever, neck stiffness, and altered mental status [51]. The most common causative bacterial species are *Streptococcus pneumoniae* (54%) and *Staphylococcus aureus* (33%) [51]. The diagnosis is confirmed via cerebrospinal fluid analysis, and management requires long-term antibiotic administration and control of the septic source [44, 51].

Clinical manifestations may include ischemic stroke (**Figure 3**), transient ischemic attack (TIA), cerebral hemorrhage, meningitis, brain abscess, encephalopathy, and mycotic aneurysms [38, 39, 42, 44, 45]. Taken together, these complications often occur early (within the first 7 days of IE) and negatively impact patient outcomes [46]. Among all neurologic manifestations of IE, ischemic stroke and TIA are the most common (16–50% of all occurrences) [38, 39, 44, 45, 47– 49]. In approximately 70% of patients with SE of the central nervous system, the middle cerebral artery distribution is involved [38, 44]. Focal neurological symptoms (hemiparesis, facial droop, diplopia, aphasia, vertigo) are present in approximately 40% of affected patients, and nonfocal presentations (headaches, seizures, altered mental status) occur in approximately one-third of cases, with roughly one in five patients remaining asymptomatic [40]. Evaluation should include MRI with and without gadolinium, or CT with and without contrast if MRI is not possible. Vascular imaging should be performed routinely, and CTA or MRA is probably sufficient for screening, with catheter angiography reserved for cases where a mycotic

148 Contemporary Challenges in Endocarditis

aneurysm was noted and in those patients with an acute brain hemorrhage [50].

**Figure 3.** Magnetic resonance imaging (MRI) showing septic embolus to the brain. Source: Stawicki et al. [2]. Used under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unre-

A relatively less common manifestation of SE associated with IE is bacterial meningitis, usually presenting with fever, neck stiffness, and altered mental status [51]. The most common

stricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In addition to being associated with worse clinical outcomes, neurologic complications of SE often force the alteration in therapeutic plans for IE, including the timing/type of operative intervention and the duration of antibiotic treatment [42, 46–49]. Neurological complications negatively impact clinical outcomes, with mortality as high as 45% (compared to 24% in patients who did not experience neurologic sequelae) [43]. Cerebral hemorrhage and moderate-to-severe ischemic events are the main determinants of mortality [43]. Early and appropriate antibiotic therapy remains the cornerstone of IE management and a major preventive strategy to reduce SE to the brain [52]. Although thrombolysis has been traditionally contraindicated for ischemic stroke in the setting of IE due to the risk of massive cerebral hemorrhage [53], some authors have reported good outcomes with thrombolytic therapy in selected cases [44, 54]. Having said that, rates of intracerebral hemorrhage following thrombolysis in such circumstances may be as high as 20% [55].

The use anticoagulation may increase the risk of cerebral hemorrhage without appreciable reduction in the incidence of embolic events, and, as of now, there is no evidence to support this practice [43]. Likewise, antiplatelet agents (including aspirin) were not found to be beneficial in preventing the occurrence of embolic events in a double-blinded, placebo controlled trial [56]. It is recommended to discontinue anticoagulation for at least 2 weeks in patients with IE who develop central nervous system embolic complications regardless of the other indications for anticoagulation, including the presence of mechanical heart valves. The final decision regarding anticoagulation and antiplatelet therapy should be made by a multidisciplinary team including cardiologist, cardiac surgeon, and neurologist [57, 58].

Although uncommon, intracranial mycotic aneurysms are among the most dreaded complications of IE with mortality as high of 16–30% in unruptured cases and 49–80% in ruptured ones [58, 59]. The presentation is variable, with some patients remaining asymptomatic while others developing focal neurologic signs, meningitis, subarachnoid, or intraventricular hemorrhage [58]. Approximately one in five patients may have multiple aneurysmal lesions [60]. Unruptured mycotic aneurysms should be serially monitored and treated conservatively with antibiotic therapy [61]. The treatment of a ruptured cerebral mycotic aneurysm depends on its location, as well as the presence or absence of any associated mass effect [61, 62].

Indications for valvular surgical intervention include, but are not limited to: new severe valvular regurgitation, congestive heart failure, large vegetation (>10 mm), abscess formation, persistently positive blood cultures or emboli despite appropriate antibiotic therapy, prosthetic valve dehiscence, or the presence of highly resistant organisms [63, 64]. Although most patients continue to have an indication for valve surgery after a cerebral SE [47], the timing of cardiac surgery is controversial because the hemorrhagic conversion of an ischemic brain lesion in the setting of intraoperative anticoagulation can be devastating [65–67]. The traditional recommendation is to postpone cardiac surgery for at least 4 weeks [65–67]. The relatively uncommon nature of hemorrhagic conversion of preoperative brain lesions has led some to consider earlier operative therapy in acute IE, hoping to prevent deaths that otherwise would have occurred during the 1 month delay, as well as reducing further embolic events that can cause permanent disability [39]. As a result, evidence is emerging that early operative treatment for patients with nonhemorrhagic cerebral embolic events does not lead to worse outcomes. In a recent report, 198 patients undergoing valve replacement following cerebral infarction were analyzed with 58 undergoing early surgery (1–7 days) and 140 undergoing late surgery (>7 days). There was no survival benefit in delaying otherwise indicated surgery for IE among patients with cerebral SE [68]. Another retrospective study reviewed operative results of 308 patients with IE, finding no difference in key outcomes (postoperative stroke, 30-day mortality, long-term survival) when comparing patients with cerebral SE undergoing early surgery (<14 days) to patients undergoing surgery for IE without cerebral complications [40]. However, some authors report that early cardiac surgery is associated with neurological complications [43]. Both the American Heart Association and The Society of Thoracic Surgeons workforce on evidence-based surgery report that it is probably safe to proceed with an early operation in patients with small ischemic infarction, while delaying a surgery for 2–4 weeks might be preferred for those with a large ischemic infarction or a hemorrhagic event, respectively. In those with worsening cardiac function, recurrent stroke, uncontrolled infection or recurrent emboli, a delay of less than 4 weeks may be reasonable [50, 58].
