Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 6

Neurologic complications of valvular heart disease SALVADOR CRUZ-FLORES* Department of Neurology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

INTRODUCTION Cerebral embolism is the main neurologic complication related to valvular heart disease. In fact, as many as 10% of all patients with valvular heart disease have cardioembolic strokes (Cerebral Embolism Task Force, 1986). Platelet thrombi and red thrombi that result from the abnormalities in the valvular surfaces or from the anatomic and physiologic changes that follow valve dysfunction, including atrial or ventricular enlargement, intracardiac thrombi, and cardiac dysrhythmias in addition to prosthetic heart valves, explain the high frequency of embolism in valvular heart disease. Other neurologic complications arise from infection of the valvular system and from complications of anticoagulation used to decrease the risk of embolism. The prevention and management of these complications requires an understanding of their natural history in order to balance the risks posed by valvular disease itself against the risks and benefits associated with its treatment.

RHEUMATIC VALVULAR HEART DISEASE Valvular damage in rheumatic heart disease is the result of an abnormal immune response to Group A streptococcal infection. Rheumatic valvular heart disease (RVHD) is now fairly uncommon in developed countries but it continues to be a burden in developing nations given its association with social factors such as poverty, nutrition and access to medical care. RVHD is responsible for between 200 000 and 250 000 deaths every year (Carapetis et al., 2005) and is a major cause of cardiovascular death in children and young adults in developing countries. Furthermore, in 2004, RVHD was responsible for 5.2 million disability-adjusted life years worldwide

(Marijon et al., 2012). It is estimated that 15.6–19.6 million people worldwide have rheumatic heart disease, with the highest prevalence among adults aged 20–50 years (Carapetis et al., 2005). While the distribution of RVHD varies, the highest prevalence is among subSaharan Africans and indigenous Australians, in whom it can be as high as 20 per 1000 adults aged 35–44 years (Tibazarwa et al., 2008; Marijon et al., 2012). The use of echocardiography for screening has increased the detection of this disorder and therefore has challenged earlier epidemiologic data (Tubridy-Clark and Carapetis, 2007; Tibazarwa et al., 2008; Marijon et al., 2012; Remenyi et al., 2012). Clinical diagnosis of RVHD is primarily based on the identification of a heart murmur. The mitral valve is the most common cardiac valve involved followed by the combined involvement of the mitral and aortic valves. Mitral regurgitation is the most common valvular abnormality and may remain asymptomatic for as long as 10 years; mitral stenosis is the second most common valvular lesion and develops later in the disease course. RVHD often presents with symptoms of heart dysfunction. However, it may present as cerebral or systemic embolism with or without atrial fibrillation (AF), or infective endocarditis (Marijon et al., 2012). Rheumatic mitral valve disease conveys the highest risk of systemic embolization compared to other acquired valvular diseases. Mitral stenosis is not only the predominant lesion but also the lesion with higher risk for embolism(Carabello and Crawford, 1997; Carapetis et al., 2005). In a series of 500 patients, 66% had mitral stenosis and 21% had mitral regurgitation, with the rest having combined lesions. In this population, 125 patients suffered from systemic embolization (60% of which was to the brain); in 116, the predominant lesion was mitral

*Correspondence to: Salvador Cruz-Flores, Department of Neurology, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA. Tel: þ1-915-545-6703, x273, Fax: þ1-915-545-6705, E-mail: [email protected]

62

S. CRUZ-FLORES

stenosis; while only 10 patients had mitral regurgitation (Fleming and Bailey, 1971).The incidence of embolism is 1.5–4.7% per year prior to surgery in some reports (Fleming and Bailey, 1971; Adams et al., 1974). The prevalence of embolism is reported to be as high as 20%, with half to three-quarters of embolic events involving the brain. Embolic events occur in patients with mitral stenosis and normal sinus rhythm but AF greatly increases the risk. In fact, the incidence of embolism is seven times higher in patients with atrial fibrillation as compared to those in sinus rhythm (Szekely, 1964; Dewar and Weightman, 1983). Besides AF, other factors are associated with an increased risk of embolism and include older age, the presence of left atrial thrombus, left atrial enlargement, left atrial spontaneous contrast, and aortic regurgitation (Caplan et al., 1986; Stroke Prevention in Atrial Fibrillation Investigators, 1992a, b; Vigna et al., 1993; Atrial Fibrillation Investigators, 1998; Chiang et al., 1998; Goswami et al., 2000). Systemic or cerebral embolism explains 20–30% of deaths due to mitral stenosis (Szekely, 1964; Selzer and Cohn, 1972). AF and atrial flutter occur in 30–40% of patients with mitral stenosis (Szekely, 1964; Selzer and Cohn, 1972; Abernathy and Willis, 1973; Adams et al., 1974; Dewar and Weightman, 1983; Chiang et al., 1998). Atrial fibrillation tends to occur in older patients and is associated with worse prognosis. After AF develops, 30% of the embolic events occur within a month of the onset and 60% within a year. The recurrence rate of embolic events among patients with mitral stenosis and AF is reported at 15–40 events per 100 patient-months (Dewar and Weightman, 1983). Furthermore, recent evidence indicates that in patients with ischemic stroke classified as cryptogenic, the incidence of paroxysmal AF is 10–25% (Wallmann et al., 2007; Flint et al., 2012). Although patients in these studies did not have RVHD, it could be inferred that the incidence of paroxysmal AF may be even higher among patients with rheumatic valvular disease given the frequent occurrence of left atrial enlargement in this population. There are no randomized clinical trials assessing the efficacy of anticoagulation in preventing embolism in patients with rheumatic heart disease. However, retrospective observational studies show that anticoagulation reduces embolic events four- to 15-fold in patients with rheumatic valvular disease (Szekely, 1964). Szekely found a rate of embolism of 3.4% per year among patients on anticoagulation as compared with 9.6% per year among those not anticoagulated. Several randomized clinical trials and meta-analyses have conclusively shown that first and recurrent ischemic stroke and systemic embolization are lower in patients with nonvalvular atrial fibrillation (NVAF) treated with anticoagulation (Salem et al., 2004; Whitlock et al., 2012).

Warfarin anticoagulation has also resulted in the clearance of a left atrial thrombus in 62% of patients after of 34 months of treatment (Silaruks et al., 2002, 2004). More importantly, the disappearance of the thrombus was documented in 25% of patients treated for 6 months but the probability of thrombus clearance increased to 94% when the following factors were present: thrombus size < 1.6 cm2, New York Heart Association class < 2 (mild dyspnea or angina or mild limitation during ordinary activity), left atrial spontaneous contrast grade 1 (defined as dynamic clouds of echoes curling up slowly in a circular shape), and INR at least 2.5 (Silaruks et al., 2004). Therefore, it could be inferred that patients with RVHD and AF and/or left atrial thrombus may benefit from long-term anticoagulation. Most recently, long-term anticoagulation with warfarin has been recommended for patients with rheumatic mitral valvular disease when there is: 1. 2. 3.

normal sinus but the left atrial diameter is > 55 mm a left atrial thrombus AF or the presence of cerebral or systemic embolism.

CALCIFIC VALVE DISEASE Aortic stenosis Calcific aortic stenosis of a normal or a congenitally bicuspid valve is the most common cause of aortic valve disease in developed countries. The disease process resembles the natural course of atherosclerosis with lipid accumulation, inflammatory response, and calcification (Rajamannan et al., 2007; Bonow et al., 2008). Valve calcification is developed by the fourth or fifth decade in patients with bicuspid aortic valves, while calcific aortic stenosis in normal tricuspid valves usually occurs in the sixth through eighth decades (Carabello and Crawford, 1997). Clinical pathologic studies show that embolism from calcific aortic valve disease is not uncommon. In a series of 81 subjects with calcific aortic stenosis, 33% had emboli (Soulie et al., 1969). In another autopsy study of 165 subjects with calcific valve disease, 22% had emboli, 32 individuals had emboli in the coronary arteries, while emboli were found in the renal arteries in 11, the central retinal artery in one, and in the middle cerebral artery in another (Holley et al., 1963a, b). Calcium emboli have frequently been found in the retinal vessels where their appearance is as small white densities. Retinal calcium embolism is uncommon but is often associated with calcific aortic valve disease. In a small series of 24 patients with retinal calcium emboli, nine (38%) had calcific aortic valve stenosis (Ramakrishna et al., 2005). In another series of 103 patients with retinal artery

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE occlusions, 11 patients had aortic stenosis (Wilson et al., 1979). Aortic valve surgery, in particular percutaneous endovascular intervention, is associated with an incidence of embolism as high as 61% (Holley et al., 1963a). Despite the frequency of calcific emboli in the brain and retina found in autopsy studies, the frequency of symptomatic cerebral ischemia resulting from this type of emboli is rather low; the reason for this discrepancy is unclear, although some authors have hypothesized that the small size of the embolic particles is responsible. Therefore, in the absence of other indications such as AF or prosthetic heart valves, antithrombotic therapy is not recommended for stroke prevention in patients with calcified aortic valve disease. Antiplatelet agents should be used for secondary stroke prevention, as recommended for patients with noncardiogenc ischemic stroke (Whitlock et al., 2012).

Mitral annulus calcification Mitral annulus calcification (MAC) occurs most commonly among the elderly and is a degenerative disorder with calcification of the support system and mitral valve annulus. MAC was found in 27% of 100 elderly patients in an autopsy series (MsKeown, 1975; Lausier, 1987). MAC is associated with an increased risk of ischemic stroke. In a case control study of 151 patients with brain and retinal ischemia, eight had MAC compared with none of the age- and gender-matched controls (de Bono and Warlow, 1979). In the cohort of 1159 individuals in the Framingham study, 160 subjects had MAC; the incidence of ischemic stroke was 13.8% among those with MAC compared with 5.1% among those without MAC for a relative risk of 2.10 (CI 95% 1.24, 3.57) (Benjamin et al., 1992). Moreover, the frequency of stroke increased in correlation with the severity of MAC with each millimeter of thickness by echocardiogram, increasing the relative risk of stroke by 1.24. The embolic material causing stroke in MAC can be composed by calcium or by thrombus. The current recommendations for stroke prevention are to treat patients with MAC and embolism with antiplatelet agents. Long-term anticoagulation does not have a role in the secondary prevention of stroke in this condition. Mitral valve replacement should be considered in patients with recurrent embolism despite antiplatelet therapy (Fulkerson et al., 1979; Nestico et al., 1984; Kizer et al., 2005; Lansberg et al., 2012).

MITRAL VALVE PROLAPSE Mitral valve prolapse (MVP) is a condition that is defined by echocardiography as classic MVP when there is a superior displacement of the mitral leaflets of more than 2 mm during systole and a maximal leaflet thickness of at least 5 mm during diastasis; in comparison, nonclassic MVP is defined by a leaflet thickness < 5 mm. In the Framingham

63

study, which included 1845 women and 1646 men followed for over 10 years, the overall prevalence of MVP was 2.4% (1.3% classic and 1.1% nonclassic) (Freed et al., 1999). Patients with MVP often seek consultation for a variety of symptoms that occur as part of this syndrome; they include: atypical chest pain, dyspnea and or fatigue, and neuropsychiatric complaints that include panic attacks (Fontana et al., 1991; Bonow et al., 2008). Although early series suggested a causal association between MVP and stroke, more recently that association has not been supported. In a study of 213 patients 45 years or younger with cerebral ischemia and 263 matched controls, MVP was present in 1.9% of patients compared to 2.7% of controls, OR 0.70 (CI 95% 0.12, 2.5) (Gilon et al., 1999). Nevertheless, the Framingham study showed that MVP confers an excess risk of cerebral embolism with ischemia, which is 7% at 10 years compared with the expected rate of 3.2% (Avierinos et al., 2003). Thus, it is still unclear what the causal role of MVP is among patients with ischemic stroke. Considering this uncertainty and the lack of evidence of benefit of anticoagulation for the prevention of embolic events among patients with MVP, antiplatelet agents are the only recommended therapy for secondary stroke prevention (Whitlock et al., 2012).

PROSTHETIC HEART VALVES Cardiac valve prostheses were developed in the early 1960s. There are many different designs but they can be divided in two groups: bioprosthetic valves and mechanical valves. Bioprosthetic heart valves are usually heterografts from pig or cow pericardial or heart valve tissue which are then mounted on a mechanical frame; they have low thrombogenesis and therefore they have the advantage that they do not require anticoagulation with warfarin, but they tend to develop time-related structural failure. In contrast, mechanical heart valves are made of metal and carbon alloy which provide structural stability but they are particularly thrombogenic and require long-term anticoagulation with warfarin (Vongpatanasin et al., 1996; Chikwe et al., 2011). Prosthetic heart valves are associated with complications, some of which are considered of critical importance; they include: structural valve deterioration, nonstructural dysfunction, valve thrombosis, embolism, bleeding events, infection (endocarditis) (Chikwe et al., 2011). Although many of these complications may have an impact on the nervous system, the most common neurologic complications are thrombosis with cerebral embolism, hemorrhage related to anticoagulation, and infective endocarditis. Prosthetic heart valves can develop thrombosis leading to valve dysfunction but more importantly to systemic or cerebral thromboembolism. Thrombosis is more common in mechanical heart valves than in bioprosthetic heart

64

S. CRUZ-FLORES

valves, and more common in the mitral than the aortic valve. The estimated risk of valve thrombosis has been previously reported as as high as 5.7% per year (Metzdorff et al., 1984). However, more recent estimates are 0.2% per year for mechanical heart valves and less than 0.1% for bioprosthetic heart valves (Hammermeister et al., 2000; Chikwe et al., 2011). In a study of 575 patients undergoing aortic and mitral valve replacement in which patients were randomized to receive a mechanical heart valve (Bjork–Shiley) or a porcine heart valve (Hancock), they noted a valve thrombosis rate of 1–2%; more importantly, they did not find differences in the rate between valve type or location. No difference has been found in the rate of thrombosis between bileaflet and tilting disc valves (Bonow et al., 2008; Chikwe et al., 2011). The average risk of thromboembolism resulting from mechanical heart valves is estimated at 4% a year in the absence of anticoagulation treatment. The risk is decreased to 2% a year by antiplatelet agents and to 1% by warfarin anticoagulation (Cannegieter et al., 1994; Chikwe et al., 2011). Thromboembolism rates are associated to anticoagulation practices. In a study of 541 patients with a followup of 20 years, there were 158 embolic events in 121 patients (23%); the mean occurrence of embolism at 20 years was 24% for mechanical heart valves as compared to 39.2% for bioprosthetic heart valves in the aortic position; in contrast, the rate was 53.4% for mechanical versus 32% for bioprosthetic heart valves in the mitral position (Oxenham et al., 2003). In the Veterans Affairs Cooperative Study on Valvular Heart Disease, the embolism rates were comparable at 18% for either type of valve in the aortic position as compared to 18% for mechanical and 22% for bioprosthetic valves in the mitral position (Hammermeister et al., 2000). However, the thromboembolism rate in patients fully anticoagulated is in the range of 0.5% to 1% per year (Cannegieter et al., 1994; Grunkemeier et al., 2000).

AORTIC BIOPROSTHETIC VALVES Evidence to date suggests that anticoagulation does not decrease the risk of embolism and increases nonsignificantly the risk of hemorrhage. In a retrospective study of 185 patients (109 on anticoagulation and 76 with no anticoagulation) and followed for the first 3 months post valve implant, the risk of stroke was 7.4% among those anticoagulated compared to 6.5% among those not anticoagulated (RR 1.1 CI 95% 03.8, 3.28). The bleeding complication rate was the same in both groups (Moinuddeen et al., 1998). In another retrospective study of patients with aortic bioprosthetic heart valve implant, 103 patients were treated with warfarin, 509 were treated with aspirin, and 136 received no antithrombotic therapy; the rates of hemorrhage were 16.7%, 3.4%, and 3.1%, respectively. The risk of thromboembolism was 0.8% among those treated with aspirin compared to 2.9% and 1.5% in those treated with warfarin and on no antithrombotics, respectively (Blair et al., 1994). Two clinical trials compared antiplatelet therapy versus warfarin anticoagulation and showed no therapeutic effect of warfarin over trifusal in one, RR 1.98 (CI 95% 0.51, 7.68) (Aramendi et al., 2005), and over aspirin, RR 1.52 (CI 95% 0.28, 2.76), in the other (Aramendi et al., 1998; Colli et al., 2007). Although the quality of these studies is low, the current recommendation for patients with an aortic bioprosthetic heart valve replacement who have no other indication for anticoagulation is aspirin during the first 3 months postreplacement (Whitlock et al., 2012). With regards to endovascular aortic valve replacement with a bioprosthesis, the evidence is very limited; however, since this procedure is considered an extension of coronary artery stenting, the current antithrombotic prophylaxis for embolism is a combination of aspirin and clopidogrel (Whitlock et al., 2012).

MITRAL BIOPROSTHETIC VALVES

Bioprosthetic heart valves The risk of thromboembolism in patients with bioprosthetic heart valves and normal sinus rhythm is on average 0.7% per year. The risk is greater in patients with a valve in the mitral position than in the aortic position. The risk is generally greater early in the course after the implantation (first 3 months) before the valve is fully endothelialized (Bonow et al., 2008). Because of the high early risk, anticoagulation with unfractionated heparin is often used in the first few days, overlapping with warfarin until the INR is within therapeutic range. After the first 3 months, warfarin can be discontinued in as many as 60% of patients; the remainder often have to stay on warfarin owing to high risk factors such as AF or previous thromboembolism (Bonow et al., 2008).

The risk of thromboembolism after mitral valve bioprosthetic replacement is very high in the early postoperative period. The overall risk is 55% between days 1 and 10; 10% between days 11 and 90; and 2.4% per year thereafter. The risk is significantly decreased by anticoagulation. In fact, the risk of on and off anticoagulation is 50% versus 60% within the first 10 days, 10% versus 13% between days 11 and 90; and 2.5% versus 3.9% > 90 days (Heras et al., 1995). There is no randomized controlled trial supporting the use of anticoagulation in the first 3 months after mitral valve replacement. Despite the poor quality of the evidence, the current recommendation is for patients with bioprosthetic mitral valve replacement to be anticoagulated during the first 3 months post valve replacement (Whitlock et al., 2012).

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE The long-term risk of thromboembolism and stroke in patients with bioprosthetic valves is 0.2–2.6% per year, with the lowest risk among patients with aortic valve replacement; thus the current recommendation is to administer aspirin for patients with a bioprosthetic valve replacement (Cohn et al., 1981; Whitlock et al., 2012). It is important to note that when AF coexists with the valve replacement, the risk of embolism is as high as 16% at 36 months, and, therefore, anticoagulation with warfarin is indicated when atrial fibrillation coexists. Other associated factors potentially increasing the risk of thromboembolism include a low ejection fraction, an enlarged atrium, a hypercoagulable state, and a history of thromboembolism. Patients with any of these conditions, even in the absence of AF, should receive warfarin in addition to aspirin therapy (Cohn et al., 1981; Gonzalez-Lavin et al., 1984; Nunez et al., 1984; Goldsmith et al., 1998; Whitlock et al., 2012).

Mechanical heart valves The risk of thrombosis and embolism increases from the time of valve implantation. Prosthetic materials and injured perivalvular tissue lead to platelet aggregation. Dacron sewing rings are prime material for platelet activation. In a large systematic review including 46 studies between 1970 and 1992, looking at 13 088 patients with a total 53 647 patient-years of follow-up, the incidence of major embolism including stroke was 4 per 100 patientyears among patients not receiving antithrombotic therapy compared to 2.2 per 100 patient-years among those receiving antiplatelet therapy and 1 per 100 patient-years in patients receiving anticoagulation with coumarin (Cannegieter et al., 1994). In the same study, the risk was twice as high among patients with mitral valve prosthesis as compared to aortic valve prosthesis. In addition, bileaflet and disc tilting valves have a lower incidence than caged ball valves. Generally, all patients with mechanical heart valves require warfarin anticoagulation. Aspirin in addition to warfarin is recommended in all patients with mechanical prosthetic heart valves. For heart valves in the aortic position, the target INR is 2–3, although for disc valves and Starr–Edwards valves the recommended INR is 2.5–3.5. A target INR of 2.5–3.5 is also recommended for patients with mechanical heart valves in the aortic position and at high risk defined by the presence of AF, low ejection fraction, hypercoagulable state, and history of thromboembolism (Bonow et al., 2008; Whitlock et al., 2012). For mechanical prostheses in the mitral position, the recommended target INR is 2.5–3.5 for all valve types given the higher risk of thromboembolism (Bonow et al., 2008; Whitlock et al., 2012). The use of bridging therapy with either unfractionated heparin or low molecular weight heparin is rather controversial and based on observational studies.

65

Although the thromboembolic risk is certainly increased early after the implantation of the prosthetic heart valve, the reported risk of thromboembolism with bridging therapy with either agent is about 0.6–1.1% with a bleeding risk of 3.3–7.2%. Therefore, bridging therapy is recommended after valve implantation until the INR becomes therapeutic (Whitlock et al., 2012). Recently, a phase 2 dose-validation randomized clinical trial testing several doses of dabigatran vs warfarin in patients with mechanical valves in the aortic or mitral position or both was stopped prematurely after the enrollment of 252 patients due to the excess thromboembolic (5% vs 0%) and bleeding (27% vs 12%) events among patients receiving dabigatran (Eikelboom et al., 2013). For the long-term prevention of thrombosis and thromboembolic events it is recommended to treat patients with warfarin anticoagulation in addition to aspirin. For individuals allergic to aspirin, the addition of clopidogrel is appropriate (Bonow et al., 2008; Whitlock et al., 2012).

ANTICOAGULATION AND ITS COMPLICATIONS Since valvular thrombosis with systemic or cerebral embolism are important complications of valvular heart disease, antithrombotic therapy is an important aspect of the treatment. The current recommendations for antithrombotic therapy can be summarized as follows (Whitlock et al., 2012): 1.

Warfarin anticoagulation a. rheumatic mitral valve disease with normal sinus rhythm and a left atrial diameter > 55 mm. Target INR 2–3 b. rheumatic mitral valve disease associated with left atrial thrombus. Target INR 2–3 c. rheumatic valve disease associated with AF d. bioprosthetic mitral valve in the first 3 months from implantation e. mechanical heart valves. 2. Unfractionated heparin full dose or subcutaneous low molecular weight heparin a. nonbacterial thrombotic endocarditis and systemic or cerebral emboli b. mechanical valves and normal sinus rhythm until INR is therapeutic with warfarin therapy. 3. Antiplatelet agents a. rheumatic mitral valve disease and normal sinus rhythm with normal sized left atrium ( 5, the risk of hemorrhage is 2009). Prevention of early recurrent stroke was considgreatly increased. However, to avoid wide fluctuation in ered the primary indication for emergent anticoagulation INR from excessive anticoagulation to normalization, it as the risk of early recurrence was initially estimated to be 1% per day and as high as 14% in the first 2 weeks after a is possible to use small doses of vitamin K of 1–2.5 mg stroke (Cerebral Embolism Task Force, 1986). However, orally in addition to withholding warfarin and closely monitoring the INR (Weibert et al., 1997; Yiu et al., randomized clinical trials with anticoagulation showed 2006; Bonow et al., 2008). In an emergency situation that the risk of stroke early recurrence is much lower, fresh frozen plasma is used for correction. at 1.1% to 4.9%, among not anticoagulated patients with Interruption of warfarin therapy for invasive proa cardiac source of embolism (Adams, 2002). cedures. A frequent clinical scenario is the need for An important issue on the emergent use of anticoaguinvasive procedures among patients on long-term anticlation during ischemic stroke refers to its safety. Hemorrhagic transformation of an ischemic infarct is a oagulation, from dental procedures to noncardiac surknown potential complication, and all antithrombotics gery. The risks of bleeding during the procedure and the immediate perioperative period have to be weighed may be associated with it. Clinical trials testing unfracagainst the risk of thromboembolism. tionated heparin and a variety of low molecular weigh In general, antithrombotic therapy should not be heparin have shown that the risk of hemorrhagic transstopped for procedures during which the risk of bleeding formation ranges from 0.6% to 6.1%. Furthermore, the is negligible, such as skin surgery, dental cleaning, or a risk of symptomatic hemorrhagic transformation of simple caries procedure. For procedures with potential ischemic stroke is associated with stroke severity (National Institutes of Health Stroke Scale (NIHSS) for significant bleeding complications, the antithrombotic > 15) and high doses of anticoagulation. Although there treatment will have to be modified (Bonow et al., 2008). Since the risk of thromboembolic events in patients with is general agreement that large strokes are associated mechanical heart valves not taking warfarin is 10–20% with a higher risk of bleeding, there are no studies annually, the inference is that the risk for stopping anticlooking specifically at CT findings as predictive of oagulation for 3 days is about 0.08–0.16% (Bonow et al., hemorrhagic complications (Adams, 2002). Patients 2008). In patients with mechanical aortic valves and no with mechanical heart valves do have a higher risk of added risk factors for thromboembolism (AF, low ejecembolic events and therefore, early anticoagulation after an ischemic stroke may be necessary. In these cirtion fraction, history of thromboembolism) it is possible cumstances, it is recommended to repeat a CT scan in to stop warfarin for 2 or 3 days and restarted 24 hours after the procedure (Kearon and Hirsh, 1997; Chikwe the first 2–3 days and start anticoagulation provided et al., 2011). In contrast, patients at high risk of thrombothere is no evidence of hemorrhagic transformation. embolic events, such as those with mechanical heart valves After intracranial hemorrhage, anticoagulation may in the mitral position or with aortic valve prosthesis and need to be withheld for as long as 2 weeks (Adams, risk factors such as AF, low ejection fraction, history of 2002; Ferro, 2003).

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE

INFECTIVE ENDOCARDITIS Endocarditis is the inflammation of the endocardial surface of the heart and its valves. There are infective and noninfective causes of endocarditis. In infective endocarditis, bacteria continue to be the predominant microorganism, although fungi have rarely been reported. The noninfective variety occurs in conditions such as cancer and systemic lupus erythematosus (SLE). Endocarditis continues to have significant morbidity and mortality although there have been changes in its frequency and distribution since it was first described. There are a variety of neurologic complications in infective endocarditis, of which cerebral embolization with stroke is the most common. Other complications described include intracerebral and subarachnoid hemorrhage, mycotic aneurysm, abscess, meningoencephalitis, and encephalopathy. In contrast, the main neurologic complication in noninfective endocarditis is ischemic stroke (Hoen and Duval, 2013). Despite the changes in the distribution and epidemiology of infective endocarditis, the frequency of its neurologic complications has remained relatively stable. The frequency of neurologic complications ranges from 25% to 45% in most series before and after the introduction of antibiotics (Ziment, 1969; Jones and Siekert, 1989). In more recent international registries, stroke and systemic embolization occurred in 17% and 22% among patients with native valve endocarditis, while the rate was 18% and 15%, respectively, in prosthetic valve endocarditis (Wang et al., 2007; Murdoch et al., 2009). The presence of neurologic complications has remained a factor associated with an increased mortality (Pruitt et al., 1978; Jones and Siekert, 1989). In fact, the rupture of a mycotic aneurysm portends a mortality of about 80% if untreated (Bayer et al., 1998). Besides the impact in outcome, the presence of neurologic complications affects medical decision making as they may pose limits or restrictions on valve replacement surgery and the use of anticoagulation, and their timing. Infective endocarditis can also occur in patients with prosthetic heart valves. Mechanical valves have a slighter higher incidence than bioprosthetic heart valves at 1% overall. Prosthetic valve endocarditis can occur early after implantation ( < 60 days) or late. Early endocarditis usually results from seeding occurring intra- or perioperatively due to concurrent infections. The most common organisms include Staphylococcus aureus, S. epidermidis and Gram-negative bacteria. The overall risk of late endocarditis is in the range of 0.2–0.4% per patient year. Late endocarditis usually results from seeding from noncardiac sepsis or after invasive procedures; common bacteria include S. aureus and Streptococcus spp. Unfortunately, valve replacement is often needed

67

and common indications include perivalvular leak, partial dehiscence, new conduction deficits, abscess, and infection with organisms with high virulence such as S. aureus. (Hammermeister et al., 2000; Oxenham et al., 2003; Chikwe et al., 2011).

Cerebrovascular complications ISCHEMIC STROKE Brain embolism is the main mechanism of injury. Stroke in fact is the presenting symptom in 15–19% of all cases (Davenport and Hart, 1990; Hart et al., 1990; Thuny et al., 2007). It is estimated that strokes occurs in 21–39% of cases of infective endocarditis (Jones and Siekert, 1989; Salgado et al., 1989; Hart et al., 1990; Hoen and Duval, 2013). However, with the Duke criteria, the actual prevalence of stroke is lower at 9–22%. Most strokes are ischemic (Heiro et al., 2000; Anderson et al., 2003; Heiro et al., 2006; Thuny et al., 2007). As many as three-quarters of all ischemic strokes in patients with infective endocarditis occur at presentation (Hart et al., 1990; Anderson et al., 2003). About 8–10% of all embolic events present as transient ischemic attacks (TIA) (Jones and Siekert, 1989; Hart et al., 1990). While any cerebral vascular territory can be affected, most emboli involve the middle cerebral artery (MCA) distribution. However, more than 50% of patients have multiple vascular territories affected (Singhal et al., 2002; Anderson et al., 2003). Importantly, about 4% of patients may have asymptomatic brain infarctions (Thuny et al., 2007). Risk factors for embolism Factors increasing the risk of embolism include the time period, the virulence of the microorganism, which cardiac valve is affected, and the characteristics of the vegetation. The period of highest risk for neurologic complications is the time prior to diagnosis to the end of the first week of treatment. Neurologic complications usually occur at presentation or within a week from symptom onset and their rate declines very quickly to less than 10% after the first week of antibiotic treatment (Jones and Siekert, 1989; Davenport and Hart, 1990; Kanter and Hart, 1991; Heiro et al., 2000, 2006; Corral et al., 2007). The virulence of the causal organism is an important predictor. As many as 60% of cases of S. aureus endocarditis develop neurologic complications (Kanter and Hart, 1991; Corral et al., 2007). Fungal endocarditis also portends a high risk for neurologic complications. Candida and Aspergillus species endocarditis have rates of neurologic complications as high as 60%. Importantly, the size of embolic particles is larger in fungal

68

S. CRUZ-FLORES

endocarditis, which results in embolism in larger arteries (Jones and Siekert, 1989; Ellis et al., 2001). Anatomically, left-sided endocarditis carries a higher risk of brain embolism than right-sided endocarditis, although there are reports of paradoxical embolism (Jones and Siekert, 1989; Kanter and Hart, 1991). Mitral involvement carries a higher risk than aortic valve involvement (Pruitt et al., 1978; Vilacosta et al., 2002; Anderson et al., 2003). Native valve endocarditis conveys a higher risk of embolism than prosthetic heart valve endocarditis, and although the reasons are not completely understood, the larger vegetation size in native valve endocarditis and the frequent use of anticoagulation in prosthetic valve endocarditis may influence this distribution (Davenport and Hart, 1990). Some characteristics of the vegetation may impact the risk of embolism. Interestingly, the identification of a vegetation by echocardiography is not a factor increasing the embolic risk (Vilacosta et al., 2002). However, its size and mobility of the vegetation do increase it. Specifically, vegetations larger than 10 mm and mobile have the greatest embolic risk (Rohmann et al., 1992; Di Salvo et al., 2001). In summary, the factors associated with greater embolic risk are: 1. 2.

3. 4.

pretreatment period and the first week of antibiotic treatment virulence of the organism, such as S. aureus, Enterococcus spp., Aspergillus spp., Candida spp., coagulase-negative Staphylococcus spp. left-sided valves; mitral valve greater than aortic valve. Multiple valve involvement vegetations > 10 mm and mobile, or vegetations increasing in size during treatment

INTRACRANIAL HEMORRHAGE Intracranial hemorrhage occurs in 2–8%; however, it carries the highest mortality rate (Hart et al., 1990, Heiro et al., 2000). Most commonly, intracranial hemorrhage, either intracerebral or subarachnoid, results from septic endarteritis with erosion and vascular rupture or the hemorrhagic transformation of an infarction (Hart et al., 1987). Importantly, mycotic aneurysms are found in less than 3% of cases of intracranial hemorrhage.

MYCOTIC ANEURYSM Mycotic aneurysms result from septic microembolism to the vasa vasorum; they predominantly affect the MCA and are multiple in about 25% of patients (Peters et al., 2006). Their prevalence in patients with infective endocarditis is about 3% but is responsible for only 1% of all cerebrovascular complications. These aneurysms are

rarely responsible for intracerebral hemorrhage ( 3400 patients with cancer, about 15% had evidence of cerebral infarction, and NBTE was found in nearly 20% (Graus et al., 1985). In a clinical series of patients with stroke and cancer, cardioembolism explained 54% of cases of ischemic stroke, though NBTE was present in only 3% (Cestari et al., 2004). However, the prevalence of NTBE was 18% in case series of patients with stroke and cancer using transesophageal echocardiogram (TEE) as the diagnostic modality (Dutta et al., 2006). NBTE may present as a focal neurologic deficit characteristic of cerebral ischemia; however, multiple small embolic simultaneous events may lead to a picture of encephalopathy (Biller et al., 1982; Rogers et al., 1987; Singhal et al., 2002).

Libman–Sacks endocarditis The prevalence of this condition is as high as 75% among patients with systemic lupus erythematous (Roldan et al., 1992, 1996). It predominantly affects the valves in the left side. Macroscopically, the vegetations are small (usually < 4 mm) and nonmobile, and heterogeneous in quality, often with a verrucous appearance; they adhere to the base of the valve (Roldan et al., 1992, 1996, 2005). Arteritis, microangiopathy, and hypercoagulability are coexisting mechanisms of stroke in patients with NBTE; however, valvular disease independently predicts the presence of cerebral embolism (Roldan et al., 2007). Although there is a paucity of information and no randomized clinical trials, anticoagulation with unfractionated heparin or with low molecular weight heparinoids is recommended (Rogers et al., 1987; Mocchegiani and Nataloni, 2009; Whitlock et al., 2012). Patients with antiphospholipid antibody syndrome and evidence of systemic or cerebral embolism may also be treated with warfarin to a target INR of 2–3.

REFERENCES Abernathy WS, Willis PW 3rd (1973). Thromboembolic complications of rheumatic heart disease. Cardiovasc Clin 5: 131–175. Adams HP Jr (2002). Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke 33: 856–861. Adams GF, Merrett JD, Hutchinson WM et al. (1974). Cerebral embolism and mitral stenosis: survival with and without anticoagulants. J Neurol Neurosurg Psychiatry 37: 378–383.

Anderson DJ, Goldstein LB, Wilkinson WE et al. (2003). Stroke location characterization severity and outcome in mitral vs aortic valve endocarditis. Neurology 61: 1341–1346. Angstwurm K, Borges AC, Halle E et al. (2004). Timing the valve replacement in infective endocarditis involving the brain. J Neurol 251: 1220–1226. Aramendi JL, Agredo J, Llorente A et al. (1998). Prevention of thromboembolism with ticlopidine shortly after valve repair or replacement with a bioprosthesis. J Heart Valve Dis 7: 610–614. Aramendi JI, Mestres CA, Martinez-Leon J et al. (2005). Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (TRAC): prospective randomized co-operative trial. Eur J Cardiothorac Surg 27: 854–860. Atrial Fibrillation Investigators (1998). Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 158: 1316–1320. Avierinos JF, Brown RD, Foley DA et al. (2003). Cerebral ischemic events after diagnosis of mitral valve prolapse: a community-based study of incidence and predictive factors. Stroke 34: 1339–1344. Baddour LM, Wilson WR, Bayer AS et al. (2005). Infective endocarditis: diagnosis antimicrobial therapy and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever Endocarditis and Kawasaki Disease Council on Cardiovascular Disease in the Young and the Councils on Clinical Cardiology Stroke and Cardiovascular Surgery and Anesthesia American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111: e394–e434. Bayer AS, Bolger AF, Taubert KA et al. (1998). Diagnosis and management of infective endocarditis and its complications. Circulation 98: 2936–2948. Benjamin EJ, Plehn JF, D’Agostino RB et al. (1992). Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med 327: 374–379. Biller J, Challa VR, Toole JF et al. (1982). Nonbacterial thrombotic endocarditis. A neurologic perspective of clinicopathologic correlations of 99 patients. Arch Neurol 39: 95–98. Blair KL, Hatton AC, White WD et al. (1994). Comparison of anticoagulation regimens after Carpentier–Edwards aortic or mitral valve replacement. Circulation 90: II214–II219. Bonow RO, Carabello BA, Chatterjee K et al. (2008). 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions and Society of Thoracic Surgeons. Circulation 118: e523–e661.

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE Cannegieter SC, Rosendaal FR, Briet E (1994). Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 89: 635–641. Caplan LR, D’Cruz I, Hier DB et al. (1986). Atrial size atrial fibrillation and stroke. Ann Neurol 19: 158–161. Carabello BA, Crawford FA Jr (1997). Valvular heart disease. N Engl J Med 337: 32–41. Carapetis JR, McDonald M, Wilson NJ (2005). Acute rheumatic fever. Lancet 366: 155–168. Cerebral Embolism Task Force (1986). Cardiogenic brain embolism. Arch Neurol 43: 71–84. Cestari DM, Weine DM, Panageas KS et al. (2004). Stroke in patients with cancer: incidence and etiology. Neurology 62: 2025–2030. Chan KL, Dumesnil JG, Cujec B et al. (2003). A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 42: 775–780. Chiang CW, Lo SK, Ko YS et al. (1998). Predictors of systemic embolism in patients with mitral stenosis. A prospective study. Ann Intern Med 128: 885–889. Chikwe J, Filsoufi F, Carpentier A (2011). Prosthetic heart valves. In: RA Walsh, JC Wang, V Fuster (Eds.), Hurst’s the Heart, 13th edn. McGraw-Hill Education, New York, ch. 35. Cohn LH, Mudge GH, Pratter F et al. (1981). Five to eight-year follow-up of patients undergoing porcine heart-valve replacement. N Engl J Med 304: 258–262. Colli A, Mestres CA, Castella M et al. (2007). Comparing warfarin to aspirin (WoA) after aortic valve replacement with the St Jude Medical Epic heart valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis 16: 667–671. Corral I, Martin-Davila P, Fortun J et al. (2007). Trends in neurological complications of endocarditis. J Neurol 254: 1253–1259. Davenport J, Hart RG (1990). Prosthetic valve endocarditis 1976–1987. Antibiotics anticoagulation and stroke. Stroke 21: 993–999. De Bono DP, Warlow CP (1979). Mitral-annulus calcification and cerebral or retinal ischaemia. Lancet 2: 383–385. Dewar HA, Weightman D (1983). A study of embolism in mitral valve disease and atrial fibrillation. Br Heart J 49: 133–140. Di Salvo G, Habib G, Pergola V et al. (2001). Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol 37: 1069–1076. Ducruet AF, Hickman ZL, Zacharia BE et al. (2010). Intracranial infectious aneurysms: a comprehensive review. Neurosurg Rev 33: 37–46. Dutta T, Karas MG, Segal AZ et al. (2006). Yield of transesophageal echocardiography for nonbacterial thrombotic endocarditis and other cardiac sources of embolism in cancer patients with cerebral ischemia. Am J Cardiol 97: 894–898. Eikelboom JW, Connolly SJ, Brueckmann M et al. (2013). Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 369: 1206–1214.

71

Eishi K, Kawazoe K, Kuriyama Y et al. (1995). Surgical management of infective endocarditis associated with cerebral complications. Multi-center retrospective study in Japan. J Thorac Cardiovasc Surg 110: 1745–1755. Ellis ME, Al-Abdely H, Sandridge A et al. (2001). Fungal endocarditis: evidence in the world literature 1965–1995. Clin Infect Dis 32: 50–62. Ferro JM (2003). Cardioembolic stroke: an update. Lancet Neurol 2: 177–188. Fleming HA, Bailey SM (1971). Mitral valve disease systemic embolism and anticoagulants. Postgrad Med J 47: 599–604. Flint AC, Banki NM, Ren X et al. (2012). Detection of paroxysmal atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke: the Stroke and Monitoring for PAF in Real Time (SMART) Registry. Stroke 43: 2788–2790. Fontana ME, Sparks EA, Boudoulas H et al. (1991). Mitral valve prolapse and the mitral valve prolapse syndrome. Curr Probl Cardiol 16: 309–375. Fowler VG Jr, Miro JM, Hoen B et al. (2005). Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 293: 3012–3021. Freed LA, Levy D, Levine RA et al. (1999). Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 341: 1–7. Fulkerson PK, Beaver BM, Auseon JC et al. (1979). Calcification of the mitral annulus: etiology clinical associations complications and therapy. Am J Med 66: 967–977. Gilon D, Buonanno FS, Joffe MM et al. (1999). Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 341: 8–13. Goldsmith I, Lip GY, Mukundan S et al. (1998). Experience with low-dose aspirin as thromboprophylaxis for the Tissuemed porcine aortic bioprosthesis: a survey of five years’ experience. J Heart Valve Dis 7: 574–579. Gonzalez-Lavin L, Tandon AP, Chi S et al. (1984). The risk of thromboembolism and hemorrhage following mitral valve replacement. A comparative analysis between the porcine xenograft valve and Ionescu–Shiley bovine pericardial valve. J Thorac Cardiovasc Surg 87: 340–351. Goswami KC, Yadav R, Rao MB et al. (2000). Clinical and echocardiographic predictors of left atrial clot and spontaneous echo contrast in patients with severe rheumatic mitral stenosis: a prospective study in 200 patients by transesophageal echocardiography. Int J Cardiol 73: 273–279. Graus F, Rogers LR, Posner JB (1985). Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 64: 16–35. Grunkemeier GL, Li HH, Naftel DC et al. (2000). Long-term performance of heart valve prostheses. Curr Probl Cardiol 25: 73–154. Hammermeister K, Sethi GK, Henderson WG et al. (2000). Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 36: 1152–1158.

72

S. CRUZ-FLORES

Hart RG, Kagan-Hallet K, Joerns SE (1987). Mechanisms of intracranial hemorrhage in infective endocarditis. Stroke 18: 1048–1056. Hart RG, Foster JW, Luther MF et al. (1990). Stroke in infective endocarditis. Stroke 21: 695–700. Heiro M, Nikoskelainen J, Engblom E et al. (2000). Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med 160: 2781–2787. Heiro M, Helenius H, Makila S et al. (2006). Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980–2004. Heart 92: 1457–1462. Heras M, Chesebro JH, Fuster V et al. (1995). High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 25: 1111–1119. Hoen B, Duval X (2013). Clinical practice. Infective endocarditis. N Engl J Med 368: 1425–1433. Holley KE, Bahn RC, McGoon DC et al. (1963a). Calcific embolization associated with valvotomy for calcific aortic stenosis. Circulation 28: 175–181. Holley KE, Bahn RC, McGoon DC et al. (1963b). Spontaneous calcific embolization associated with calcific aortic stenosis. Circulation 27: 197–202. Jones HR Jr, Siekert RG (1989). Neurological manifestations of infective endocarditis. Review of clinical and therapeutic challenges. Brain 112: 1295–1315. Kanter MC, Hart RG (1991). Neurologic complications of infective endocarditis. Neurology 41: 1015–1020. Kearon C, Hirsh J (1997). Management of anticoagulation before and after elective surgery. N Engl J Med 336: 1506–1511. Kizer JR, Wiebers DO, Whisnant JP et al. (2005). Mitral annular calcification aortic valve sclerosis and incident stroke in adults free of clinical cardiovascular disease: the Strong Heart Study. Stroke 36: 2533–2537. Kovacs MJ, Kearon C, Rodger M et al. (2004). Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation 110: 1658–1663. Lansberg MG, O’Donnell MJ, Khatri P et al. (2012). Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141: e601S–e636S. Lausier S, B HJA (1987). Cerebral ischemia with mitral valve prolapse and mitral annular calcification. Springer Verlag, London. Lopez JA, Ross RS, Fishbein MC et al. (1987). Nonbacterial thrombotic endocarditis: a review. Am Heart J 113: 773–784. Marijon E, Mirabel M, Celermajer DS et al. (2012). Rheumatic heart disease. Lancet 379: 953–964. MsKeown EF (1975). De Senectute. The F. E. Williams lecture. J R Coll Physicians Lond 10: 79–99. No abstract available. PMID: 1202219. Metzdorff MT, Grunkemeier GL, Pinson CW et al. (1984). Thrombosis of mechanical cardiac valves: a qualitative

comparison of the silastic ball valve and the tilting disc valve. J Am Coll Cardiol 4: 50–53. Mocchegiani R, Nataloni M (2009). Complications of infective endocarditis. Cardiovasc Hematol Disord Drug Targets 9: 240–248. Moinuddeen K, Quin J, Shaw R et al. (1998). Anticoagulation is unnecessary after biological aortic valve replacement. Circulation 98: II95–II98, discussion II98–II99. Murdoch DR, Corey GR, Hoen B et al. (2009). Clinical presentation etiology and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med 169: 463–473. Nestico PF, Depace NL, Morganroth J et al. (1984). Mitral annular calcification: clinical pathophysiology and echocardiographic review. Am Heart J 107: 989–996. Nunez L, Gil Aguado M, Larrea JL et al. (1984). Prevention of thromboembolism using aspirin after mitral valve replacement with porcine bioprosthesis. Ann Thorac Surg 37: 84–87. Oxenham H, Bloomfield P, Wheatley DJ et al. (2003). Twenty year comparison of a Bjork–Shiley mechanical heart valve with porcine bioprostheses. Heart 89: 715–721. Paciaroni M, Agnelli G, Micheli S et al. (2007). Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 38: 423–430. Peters PJ, Harrison T, Lennox JL (2006). A dangerous dilemma: management of infectious intracranial aneurysms complicating endocarditis. Lancet Infect Dis 6: 742–748. Pruitt AA, Rubin RH, Karchmer AW et al. (1978). Neurologic complications of bacterial endocarditis. Medicine (Baltimore) 57: 329–343. Rajamannan NM, Bonow RO, Rahimtoola SH (2007). Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med 4: 254–262. Ramakrishna G, Malouf JF, Younge BR et al. (2005). Calcific retinal embolism as an indicator of severe unrecognised cardiovascular disease. Heart 91: 1154–1157. Remenyi B, Wilson N, Steer A et al. (2012). World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease – an evidence-based guideline. Nat Rev Cardiol 9: 297–309. Roder BL, Wandall DA, Espersen F et al. (1997). Neurologic manifestations in Staphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med 102: 379–386. Rogers LR, Cho ES, Kempin S et al. (1987). Cerebral infarction from non-bacterial thrombotic endocarditis. Clinical and pathological study including the effects of anticoagulation. Am J Med 83: 746–756. Rohmann S, Erbel R, Gorge G et al. (1992). Clinical relevance of vegetation localization by transoesophageal echocardiography in infective endocarditis. Eur Heart J 13: 446–452. Roldan CA, Shively BK, Lau CC et al. (1992). Systemic lupus erythematosus valve disease by transesophageal

NEUROLOGIC COMPLICATIONS OF VALVULAR HEART DISEASE echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol 20: 1127–1134. Roldan CA, Shively BK, Crawford MH (1996). An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med 335: 1424–1430. Roldan CA, Gelgand EA, Qualls CR et al. (2005). Valvular heart disease as a cause of cerebrovascular disease in patients with systemic lupus erythematosus. Am J Cardiol 95: 1441–1447. Roldan CA, Gelgand EA, Qualls CR et al. (2007). Valvular heart disease by transthoracic echocardiography is associated with focal brain injury and central neuropsychiatric systemic lupus erythematosus. Cardiology 108: 331–337. Salem DN, Stein PD, Al-Ahmad A et al. (2004). Antithrombotic therapy in valvular heart disease – native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 457S–482S. Salgado AV, Furlan AJ, Keys TF (1987). Mycotic aneurysm subarachnoid hemorrhage and indications for cerebral angiography in infective endocarditis. Stroke 18: 1057–1060. Salgado AV, Furlan AJ, Keys TF et al. (1989). Neurologic complications of endocarditis: a 12-year experience. Neurology 39: 173–178. Sandercock PA, Gibson LM, Liu M (2009). Anticoagulants for preventing recurrence following presumed noncardioembolic ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev CD000248. Selzer A, Cohn KE (1972). Natural history of mitral stenosis: a review. Circulation 45: 878–890. Silaruks S, Thinkhamrop B, Tantikosum W et al. (2002). A prognostic model for predicting the disappearance of left atrial thrombi among candidates for percutaneous transvenous mitral commissurotomy. J Am Coll Cardiol 39: 886–891. Silaruks S, Thinkhamrop B, Kiatchoosakun S et al. (2004). Resolution of left atrial thrombus after 6 months of anticoagulation in candidates for percutaneous transvenous mitral commissurotomy. Ann Intern Med 140: 101–105. Singhal AB, Topcuoglu MA, Buonanno FS (2002). Acute ischemic stroke patterns in infective and nonbacterial thrombotic endocarditis: a diffusion-weighted magnetic resonance imaging study. Stroke 33: 1267–1273. Soulie P, Caramanian M, Soulie J (1969). Calcified aortic stenosis; pathological anatomy. Arch Mal Coeur Vaiss 62: 1096–1118. Stroke Prevention in Atrial Fibrillation Investigators (1992a). Predictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk. Ann Intern Med 116: 1–5. Stroke Prevention in Atrial Fibrillation Investigators (1992b). Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 116: 6–12. Szekely P (1964). Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1: 1209–1212.

73

Thuny F, Avierinos JF, Tribouilloy C et al. (2007). Impact of cerebrovascular complications on mortality and neurologic outcome during infective endocarditis: a prospective multicentre study. Eur Heart J 28: 1155–1161. Tibazarwa KB, Volmink JA, Mayosi BM (2008). Incidence of acute rheumatic fever in the world: a systematic review of population-based studies. Heart 94: 1534–1540. Tleyjeh IM, Abdel-Latif A, Rahbi H et al. (2007). A systematic review of population-based studies of infective endocarditis. Chest 132: 1025–1035. Tornos P, Almirante B, Mirabet S et al. (1999). Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med 159: 473–475. Truskinovsky AM, Hutchins GM (2001). Association between nonbacterial thrombotic endocarditis and hypoxigenic pulmonary diseases. Virchows Arch 438: 357–361. Tubridy-Clark M, Carapetis JR (2007). Subclinical carditis in rheumatic fever: a systematic review. Int J Cardiol 119: 54–58. Vigna C, De Rito V, Criconia GM et al. (1993). Left atrial thrombus and spontaneous echo-contrast in nonanticoagulated mitral stenosis. A transesophageal echocardiographic study. Chest 103: 348–352. Vilacosta I, Graupner C, San Roman JA et al. (2002). Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 39: 1489–1495. Vongpatanasin W, Hillis LD, Lange RA (1996). Prosthetic heart valves. N Engl J Med 335: 407–416. Wallmann D, Tuller D, Wustmann K et al. (2007). Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: an opportunity for a new diagnostic strategy. Stroke 38: 2292–2294. Wang A, Athan E, Pappas PA et al. (2007). Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA 297: 1354–1361. Weibert RT, Le DT, Kayser SR et al. (1997). Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 126: 959–962. Whitlock RP, Sun JC, Fremes SE et al. (2012). Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 141 (2 Suppl): e576S–e600S. Wilson LA, Warlow CP, Russell RW (1979). Cardiovascular disease in patients with retinal arterial occlusion. Lancet 1: 292–294. Yiu KH, Siu CW, Jim MH et al. (2006). Comparison of the efficacy and safety profiles of intravenous vitamin K and fresh frozen plasma as treatment of warfarin-related over-anticoagulation in patients with mechanical heart valves. Am J Cardiol 97: 409–411. Ziment I (1969). Nervous system complications in bacterial endocarditis. Am J Med 47: 593–607.