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ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 43 (2013) 443–450

General review

Neurological complications of infective endocarditis: New breakthroughs in diagnosis and management Les complications neurologiques des endocardites infectieuses : dernières avancées dans le diagnostic et leurs modalités de prise en charge E. Novy a , R. Sonneville a,∗ , M. Mazighi b , I.F. Klein c , E. Mariotte a , B. Mourvillier a , L. Bouadma a , M. Wolff a a

Service de réanimation médicale et des maladies infectieuses, université Paris-Diderot, Sorbonne Paris-Cité, hôpital Bichat–Claude-Bernard, Assistance Publique–hôpitaux de Paris, 46, rue Henri-Huchard, 75877 Paris cedex 18, France b Service de neurologie, université Paris-Diderot, Sorbonne Paris-Cité, hôpital Bichat–Claude-Bernard, Assistance Publique–hôpitaux de Paris, 46, rue Henri-Huchard, 75877 Paris cedex 18, France c Service d’imagerie médicale, université Paris-Diderot, Sorbonne Paris-Cité, hôpital Bichat–Claude-Bernard, Assistance Publique–hôpitaux de Paris, 46, rue Henri-Huchard, 75877 Paris cedex 18, France Received 23 August 2013; received in revised form 5 September 2013; accepted 27 September 2013 Available online 9 November 2013

Abstract Neurological complications are frequent in infective endocarditis (IE) and increase morbidity and mortality rates. A wide spectrum of neurological disorders may be observed, including stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy. Most complications occur early during the course of IE and are a hallmark of left-sided abnormalities of native or prosthetic valves. Ischemic lesions account for 40% to 50% of IE central nervous system complications. Systematic brain MRI may reveal cerebral abnormalities in up to 80% of patients, including cerebral embolism in 50%, mostly asymptomatic. Neurological complications affect both medical and surgical treatment and should be managed by an experimented multidisciplinary team including cardiologists, neurologists, intensive care specialists, and cardiac surgeons. Oral anticoagulant therapy given to patients presenting with cerebral ischemic lesions should be replaced by unfractionated heparin for at least 2 weeks, with a close monitoring of coagulation tests. Recently published data suggest that after an ischemic stroke, surgery indicated for heart failure, uncontrolled infection, abscess, or persisting high emboli risk should not be delayed, provided that the patient is not comatose or has no severe deficit. Surgery should be postponed for 2 to 3 weeks for patients with intracranial hemorrhage. Endovascular treatment is recommended for cerebral mycotic aneurysms, if there is no severe mass effect. Recent data suggests that neurological failure, which is associated with the location and extension of brain injury, is a major determinant for short-term prognosis. © 2013 Published by Elsevier Masson SAS. Keywords: Endocarditis; Stroke; Magnetic resonance imagery; Mycotic aneurysm

Résumé Les complications neurologiques des endocardites infectieuses sont fréquentes et aggravent la morbi-mortalité. Elles sont souvent inaugurales et constituent le principal motif d’admission en réanimation. Elles doivent être recherchées devant tout signe neurologique focal ou trouble de conscience inexpliqué. Les accidents vasculaires ischémiques par embolie d’une végétation représentent 40 à 50 % des complications neurologiques des endocardites. L’utilisation de plus en plus systématique de l’imagerie cérébrale par résonance magnétique avec injection révèle la présence de complications neurologiques dans plus de 80 % des cas dont 50 % sont asymptomatiques. Les complications neurologiques affectent le traitement médical et chirurgical. La prise en charge doit être confiée à une équipe multidisciplinaire (réanimateur, cardiologue, neurologue, chirurgien cardiaque) expérimentée. En cas de complication neurologique et d’indication chirurgicale urgente au cours d’une endocardite infectieuse, plusieurs études récentes ont rapporté que la chirurgie de remplacement valvulaire précoce est réalisable sans affecter le pronostic vital et fonctionnel.

∗

Corresponding author. E-mail addresses: [email protected], [email protected] (R. Sonneville).

0399-077X/$ – see front matter © 2013 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.medmal.2013.09.010

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Les seules exceptions sont : le coma ou déficit focal majeur préopératoire. En cas d’accident hémorragique, il est clairement démontré que la chirurgie doit être reportée de 2 à 3 semaines. Concernant la prise en charge des anévrismes mycotiques, le traitement endovasculaire prend une place croissante en l’absence d’effet de masse. Des données récentes suggèrent que la défaillance neurologique, qui est associée à la localisation et la taille des lésions cérébrales, est un facteur déterminant le pronostic à court terme des patients. © 2013 Publié par Elsevier Masson SAS. Mots clés : Endocardites ; Accident vasculaire cérébral ; IRM ; Anévrismes mycotiques

1. Introduction

2.1. Ischemic stroke

The estimated yearly incidence of infective endocarditis (IE) is 3 to 9 cases per 100,000 individuals in industrialized countries [1,2]. In the early 21st century, IE is more often an acute presentation, characterized by a high rate of S. aureus infection, and more frequent health care-associated infections [3,4]. Neurological complications are the most severe extra cardiac complications of left-sided IE, occurring in 15 to 20% of patients [5,6]. They can be due to various mechanisms: ischemic stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy [7,8]. Most of theses occur early in the course of IE and are considered as major risk factors for increased morbidity and mortality [3,9]. Furthermore, neurological complications may affect both medical therapy [2] and the optimal timing for surgery [10]. Noninfective endocarditis (including thrombotic endocarditis and Libman-Sacks endocarditis) is a rare complication of cancer or immune-mediated disorders and will not be discussed in this review. We propose an updated review for the diagnosis and management of major neurological complications of IE.

Cerebral embolic events, stroke or transient ischemic attack, account for 40% to 50% of neurological complications of IE [15]. Most of these are asymptomatic, as demonstrated by recent studies on the contribution of brain magnetic resonance imaging (MRI) [16–19]. The authors of a cohort study including 130 patients presenting with IE systematically investigated by brain MRI reported that 82% presented with neurological lesions, but only 12% with neurological symptoms [17]. The authors of another study reported that “silent” cerebral embolism was detected on brain MRI in 30% of patients with mitral or aortic valve IE [16]. These findings were confirmed by another study in which occult ischemic lesions were identified in up to 37% of IE patients with a normal neurological examination [18]. Acute ischemic lesions mostly appear on brain MRI as multiple small infarcts, disseminated in watershed territories, and as lesions of various ages (Fig. 1).

2. Mechanisms of neurologicalal complications Neurological complications of IE arise from central nervous system embolization of valvular vegetation(s) and are a hallmark of left-sided IE. One or more of the following manifestations can be observed in the same patient: • ischemic stroke, following occlusion of cerebral arteries by emboli from vegetation; • cerebral hemorrhage, resulting from hemorrhagic infarction, cerebral vasculitis and/or ruptured mycotic aneurysm; • meningitis; • brain abscess; • mycotic aneurysms. Sepsis-related encephalopathy, defined by an acute confusion or delirium, with varying levels of consciousness, may also contribute to neurological manifestations of IE [11]. Risk factors for CNS embolization are well-known and include vegetation size and mobility [7,11–13], Staphylococcus aureus infection [14], mitral valve involvement [12]. But the risk of CNS embolic events in IE decreases dramatically, after the initiation of effective antimicrobial therapy, to less than 1.71/1000 patient days in the second week [8].

Fig. 1. Axial T2*-weighted gradient echo image showing multiple cerebral microbleeds preferentially located in cortical regions, in a patient with left-sided Staphylococcus aureus infective endocarditis. Endocardite mitrale à Staphylococcus aureus, IRM cérébrale, séquence T2* avec écho de gradient. Hyposignaux multiples juxta-corticaux évocateurs de lésions micro-hémorragiques.

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Table 1 Diagnostic criteria for intracranial mycotic aneurysm (ICMA) [25]. Presence or recent (within past 8 weeks) history of a predisposing infection Infective endocarditis Meningitis Orbital cellulitis Cavernous sinus thrombophlebitis Angiographic features Multiplicity Distal location Fusiform shape Change in size or appearance of new aneurysm on follow-up angiogram Other contributory features Age less than 45 years Fever/recent history of fever > 7 days Recent lumbar puncture Intraparenchymal haemorrhage in CT/MRI scan Clinically definite ICMA If mandatory criterion and any three or more of the supportive criteria are satisfied. (Sensitivity 96%, specificity 100%, positive predictive value 100%, negative predictive value 99.4%)

Fig. 2. Diffusion-weighted magnetic resonance imaging showing acute hyperintense ischemic strokes disseminated in both cortical and subcortical areas in a patient with left-sided Staphylococcus aureus endocarditis. Endocardite mitrale à Staphylococcus aureus, IRM cérébrale, séquence de diffusion. Hypersignaux diffus dans les régions corticales et sous-corticales traduisant de multiples accidents vasculaires cérébraux ischémiques.

Clinically probable ICMA Mandatory criterion and any two of the supportive criteria are satisfied. (Sensitivity 100%, specificity 87.4%) Clinically possible ICMA Mandatory criterion and any one supportive criterion. (Sensitivity 100%, specificity 39.6%) Mandatory criterion: demonstration of an intracranial aneurysm by neuroimaging; 12 supportive criteria: each positive supportive criterion is given 1 point.

2.2. Cerebral hemorrhage Cerebral hemorrhage accounts for 12% to 30% of neurological complications of IE [13,15], the highest prevalence being observed in critically ill patients presenting with IE [12]. One third of cerebral bleeding in patients presenting with endocarditis is due to the evolution of ischemic infarcts caused by septic emboli, either at the early phase of embolism or later [20]. Cerebral microbleeds have been observed at the acute phase of IE by using MRI, [17,21,22]. These lesions were observed in 57% of the 130 patients included in the IMAGE group prospective study of [17] and could be the most frequent cerebrovascular lesions in patients without neurological symptoms [18]. They are preferentially distributed in cortical areas with lesions of various ages. Microbleeds may be explained by a subacute microvascular process, either due to an immunologic vasculitis and/or an embolic process in the vasa vasorum (Fig. 2). However, the pathophysiological processes involved in microbleed genesis remain to be elucidated. The prognostic value of cerebral microbleeds has been addressed in a recent study, in which the presence of more than 2 or 3 lesions was independently associated with the development of intracranial hemorrhage [23]. 2.3. Intracranial mycotic aneurysms (ICMA) Intracranial mycotic aneurysms are relatively rare, less than 10% of neurological complications of IE [24,25]. They are

usually due to septic embolization in the vasa vasorum or in the intraluminal space of the vessel itself. Septic emboli are responsible for an inflammatory lesion starting at the adventitia surface and ultimately destroying the intima. Multiple ICMA are found in 25% of cases and are mostly located in the distal branches of the middle cerebral artery [26]. Streptococci, and to a lesser extent S. aureus are the pathogens most frequently implicated in ICMA [24]. Patients with non-ruptured ICMA may present with fever, headache, seizures, and/or focal deficit(s). Patients with ruptured ICMA present with sudden subarachnoid or intracerebral hemorrhage, with decreased level of consciousness, symptoms of intracranial hypertension, and/or focal deficit(s) [26]. Rupture generally occurs at the early phase of IE, but in some patients, especially those with streptococcal IE, the rupture may occur during or even after the end of antibiotic therapy [27]. Diagnostic criteria have been proposed by various authors and are listed in Table 1 [25]. CT-scan angiography and MR angiography are of equal value for the detection of ICMA [24,26]. The authors of a previous study reported that the sensitivity of CT-scanning and MR angiography was 94% and 86%, respectively for the detection of ICMA 5 mm in diameter or more, but only 57% and 35%, respectively for ICMA < 5 mm [28]. 4-vessel conventional angiogram remains the gold standard diagnosis of ICMAs because of its frequently distal locations [24]. However, the sensitivity of non-invasive MRI detection is good and particularly useful for patient follow-up [29] (Fig. 3A and B).

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that 24 patients presented with IE, mainly due to Streptococcus species and S. aureus. The outcomes were bad (death or severe complications) for 63% of patients [32]. S. aureus meningitis almost always presents with a primary infection focus, most commonly pneumonia or endocarditis [33]. This suggests that, in case of S. aureus infection, endocarditis precedes bacterial meningitis and is caused by septic emboli originating from cardiac valve vegetations. Early detection of endocarditis in patients with pneumococcal meningitis patients may lower the rate of complications and of unfavorable outcome. This is why IE should always be ruled out in the presence of unexplained staphylococcal or streptococcal meningitis. The association of endocarditis and meningitis may also significantly affect the duration of antibiotic therapy. The course of antibiotic therapy should last 4 to 6 weeks in patients presenting with endocarditis and meningitis, which is substantially longer than the standard 10 to 14 days for patients presenting with meningitis without endocarditis. Brain abscesses are rare and occur in 5% of patients presenting with IE [34]. They are mostly observed in IE and are caused by S. aureus. Abscesses are often multiple and result from septic embolism. IE should always be ruled out for patients presenting with multiple abscesses, when no obvious source can be identified [34]. 3. Impact of systematic neuroimaging on clinical decisions

Fig. 3. T2* cerebral magnetic resonance imaging showing left occipital cortical hemorrhage (A). At the corresponding site, axial magnetic resonance angiography revealed the presence of a sacciform mycotic pseudo-aneurysm. IRM cérébrale, séquence T2* (A) montrant un accident vasculaire hémorragique dans le territoire occipital gauche. L’angio-IRM cérébrale (B) révèle dans le même territoire la présence d’un anévrisme mycotique sacciforme.

2.4. Meningitis and brain abscess Meningitis, sterile inflammatory reaction to infection, brain ischemia, or hemorrhage occurs in 2% to 20% of patients presenting with IE [15,30,31]. The cerebrospinal fluid is not purulent and the presence of pathogens is very transient in most cases, except in the rare cases of Streptococcus pneumoniae IE. The authors of a recent study, assessing the incidence and clinical characteristics of 1025 episodes of bacterial meningitis, reported

The authors of previous studies suggested that systematic computed tomography (CT) should be performed at the acute phase of IE to thoroughly search for asymptomatic embolisms [35]. MRI is a more sensitive and specific method of detecting neurological event in IE [16,17,36]. Early brain MRI led to modifications of diagnosis or therapeutic scheme in up to 28% of cases in the IMAGE study. Furthermore, MRI revealed an extended involvement of the brain (type and number of lesions), compared to clinical signs and/or CT-scan [19]. However, current European guidelines do not explicitly recommend systematically using brain MRI imaging during acute IE, and the management of IE patients with neurological symptoms is still based on use of brain CT-scan [37]. Brain MRI should be chosen rather than CT-scan because of a better sensitivity for the detection of small cerebral infarctions and hemorrhages, without ionizing radiation or injection of nephrotoxic contrast products [38], and better sensitivity for the detection of clinically symptomatic cerebral lesions and additional asymptomatic lesions [19]. 4. Management of IE patients with neurological complications 4.1. Non-specific management Early appropriate antibiotic therapy decreases the risk of (neurological) embolic events and is the cornerstone of IE management (Fig. 4) [8,37]. A management-based approach with a multidisciplinary team has recently resulted in a reduction of mortality in IE with or without neurological complications [39].

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Fig. 4. Management of patients with IE and neurologic complications, adapted from [37]. Prise en charge des endocardites infectieuses avec complications neurologiques d’après [37].

High risk IE patients with acute cerebrovascular complications (ischemic stroke, hemorrhage) should be identified rapidly and transferred to the intensive care unit [40]. The key-points of management include: • airway control and intubation to prevent aspiration pneumonia; • avoiding hypotensive episodes and/or excessive hypertension in case of cerebral hemorrhage (BP ≤ 180/120 mmHg in case of chronic hypertension, BP ≤ 160/85 mmHg if none); • glycemic control (glycemia ≤ 10 mmol/l); • venous thromboembolism prevention (ischemic stroke: low molecular weight heparin 4000 unit per day; cerebral hemorrhage: elastic venous compression in the first 24 hours and then low molecular weight heparin at 4000 unit per day) [41]. 4.2. Antithrombotic therapy, anticoagulation Thrombolysis for acute ischemic stroke related to IE remains a controversial therapy. Some authors of case series have reported a good outcome following thrombolysis [42–44]. The rationale for thrombolytic therapy in this setting is related to the assumption that thrombolysis may lead to thrombus resolution by its action on the fibrin present in the vegetation itself, or on the new fibrin that may develop after embolization in the cerebral arteries. There is a risk of major intracerebral hemorrhagic complications, including hemorrhagic transformation of cerebral infarction or rupture of an ICMA [10]. The current published data suggests that thrombolysis cannot be recommended when IE is suspected as the cause of ischemic stroke [44]. Anticoagulant therapy may be an independent risk factor for the occurrence of neurological complications, mostly related to a

greater incidence of hemorrhagic events [13]. Observational data suggests an increased risk of fatal cerebral hemorrhage, with no reduction in the risk of embolic events for patients with S. aureus prosthetic valve IE receiving oral anticoagulant agents [45]. In such cases, anticoagulation therapy should be stopped for at least 15 days. The European Society of Cardiology guidelines currently recommend that the oral anticoagulant agent be replaced with heparin for 2 weeks, in patients already receiving oral anticoagulant therapy, presenting with IE complicated by ischemic and non-hemorrhagic stroke. However, the authors acknowledge the low level of evidence supporting this recommendation [45]. Interruption of all anticoagulation is recommended in case of cerebral hemorrhage, but unfractionated heparin should be reinitiated as soon as possible in patients with a mechanical valve, depending on the evolution of bleeding monitored by repeated CT imaging [37]. Antiplatelet agents are not recommended for patients with IE [46]. There was no significant decrease in the incidence of embolic events, in a double-blinded, placebo-controlled trial, in which patients with IE were randomly assigned to receive aspirin at a dose of 325 mg per day for 4 weeks [47]. The authors of a retrospective cohort study on adult IE patients reported that the risk of symptomatic embolism associated with IE was reduced in patients receiving continuous antiplatelet therapy daily before the onset of IE [48]. It is not necessary to discontinue aspirin treatment taken for other indications when there is no bleeding [37]. 4.3. Management of ICMA The routine use of systematic MRI in case of IE has recently changed the therapeutic approach of ICMA [49].

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Hypointense spots (black dots) on T2*-weighted imaging have been observed in many IE patients and considered as signaling the presence of ICMA [17,21,49]. Blacks dots are a feature of thrombosed ICMA [49]. They are frequently associated with inflammation, such as encephalitis or meningitis, confirmed by contrast enhancement on gadolinium contrast imaging [49]. The presence of blacks dots was correlated to an increased risk for symptomatic cerebral and subarachnoid hemorrhage after surgery and even more if inflammation was confirmed by contrast imaging [23,49,50] Therefore, conservative treatment with appropriate antibiotics should be proposed in case of unruptured ICMA or blacks dots identified on MRI. They should be monitored by repeated imaging (MRI if possible), because most will disappear with antibiotic therapy [51]. The mortality rate is higher and may reach 80% in case of ruptured ICMA [26]. The treatment of ruptured ICMA or very large ICMA depends on its location and the presence or not of any mass effect. Endovascular therapy should be considered when there is no mass effect and if the ICMA is located in a non-eloquent neural territory [52]. But neurosurgery is probably the best choice when there is any mass effect or if the ICMA is located in an eloquent neural territory [24]. The authors of a recent study suggested that the endovascular treatment of ruptured, symptomatic or enlarging ICMA was an excellent treatment modality with a high rate of occlusion (96%) and a low rate of procedure-related complications (5%) [51]. In the same study, the authors recommended endovascular procedures for unruptured large ICMA or for small ICMA enlarging, despite appropriates antibiotic treatment. 4.4. Meningitis and brain abscesses Presenting with meningitis should not lead to modifying recommended antibiotic regimens because the primary goal is to obtain the clearance of pathogens in blood cultures. Adding to the standard regimen a molecule penetrating brain parenchyma, such as a fluoroquinolone or rifampin, may be justified for patients with S. aureus brain abscesses [53]. In most cases, patients have small (< 3 cm) and multiple abscesses that do not require surgery. The presence of intracerebral abscess requires extending the antibiotic therapy to more than 6 weeks. 4.5. What is the optimal timing for cardiac surgery? Most patients still have an indication for valvular surgery after a cerebral embolic event [3]. The optimal timing of surgery for IE with cerebrovascular complications remains controversial, since the decision to proceed with surgery must take into account various risks, including the risk of recurrent embolism and the risk associated with surgery. For example, using anticoagulation during cardiopulmonary bypass might exacerbate the risk of ischemic cerebral hemorrhage. Moreover, recurrent hypotensive events may also worsen cerebral ischemic penumbra. The incidence of stroke decreases with the introduction of an appropriate antimicrobial therapy [8,14]. A history of embolic stroke or transient ischemic attack is not in itself a contraindication for surgery [5]. Postoperative neurological deterioration

is infrequent after a silent cerebral embolism or a transient ischemic attack [16]. The risk associated with surgery depends on the neurological condition of the patient after an ischemic stroke [6]. Usually, surgery is performed if the patient does not present with severe neurological damage, as long as cerebral hemorrhage has been ruled out by cerebral imaging [37]. The authors of a recent study performed on 857 patients presenting with IE complicated by ischemic stroke, 198 of whom underwent early (58 cases) or late (140 cases) surgery, suggested that there was no apparent benefit in survival by delaying surgery when indicated. This was recently confirmed by the authors of a recent study performed on critically ill patients presenting with IE, for whom surgical timing was not independently associated with postoperative outcome [54]. However, complementary studies that include detailed pre- and postoperative clinical neurological findings and advanced imaging data (e.g., ischemic stroke size), may allow for more refined recommendations on the optimal timing of valvular surgery in patients presenting with IE and recent stroke syndromes [55]. European guidelines suggest postponing surgery for at least one month after cerebral hemorrhage proved by CT [37]. These recommendations were confirmed in a recent study, in which the authors suggested that mortality was higher when surgery was performed within 4 weeks after the hemorrhagic event (75% vs 40% for delayed surgery) [13]. The authors of many observational studies are in favor of early surgery in patients with neurological complications [50,55,56], but the absence of high-level recommendation is due to the lack of controlled studies. Surgery for acute IE provided excellent long-term results concerning reinfection and reintervention rates, despite a high early mortality rate during the first year [57]. Late mortality remains high, as attested by the results of a recent multicenter study performed on critically ill patients, with an overall mortality of 69% at 5 years [54]. In this study, the severity of multiorgan failure (as measured by the SOFA score) [58] was a major prognostic factor. Interestingly, neurological complications, which were identified in 40% of cases, were not independently associated with long-term outcomes.

5. Conclusion Cerebral complications are the most frequent and severe extra cardiac complications of IE. Diagnosis and therapeutic approaches have been changing with the use of systematic brain MRI. Recently published data suggest that after an ischemic stroke, surgery indicated for heart failure, uncontrolled infection, abscess, or persisting high risk of embolism should not be delayed, provided that the patient is not comatose, has no severe deficit or hemorrhagic lesion. The authors of recent studies suggest that neurological failure, associated with the location and extension of brain injury, is a major determinant of short-term outcomes. Further studies are needed to definitely validate this strategy in patients presenting with symptomatic neurological complications, despite the results of a recent randomized controlled study supporting early surgery in patients presenting with complicated IE [59].

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Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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