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 15

Neurologic complications of cardiac tumors DAVID ROELTGEN1* AND CHELSEA S. KIDWELL2 Cape Physicians Associates, Cape May Court House, NJ, USA

1 2

Department of Neurology, Georgetown University Medical Center, Washington, DC, USA

INTRODUCTION The complications of intracardiac tumors can be neurologically devastating or life-threatening, and usually represent embolic phenomena or the sequelae of cardiac dysfunction. Despite the clinical significance of these disorders, until the last five decades they have been underdiagnosed and rarely reported. Advances in both cerebral and cardiac imaging have increased the ease as well as the frequency of these diagnoses. The incidence of primary cardiac tumors in autopsy series ranges from 0.001% to 0.03% (Butany et al., 2005). Three-fourths are benign and half of these are atrial myxomas, with 75% located in the left atrium. Metastatic neoplasms, papillary fibroelastomas, rhabdomyomas, and fibromas comprise the majority of the remaining tumors (Table 15.1) (Molina et al., 1990; Endo et al., 1997; Roberts, 1997; Butany et al., 2005). Embolization is common, especially with atrial myxomas and fibroelastomas, and in some series the rate is as high as 50% (Yufe et al., 1976), and half of the emboli are to the brain (Pinede et al., 2001; Sun et al., 2001). Some series report higher or lower frequencies of embolization (Dein et al., 1987; Tschirkov et al., 1990; Endo et al., 1997). Almost any malignant neoplasm can metastasize to the heart (excluding primary central nervous system (CNS) tumors), and carcinomas are more common than sarcomas (Roberts, 1997). The most common are breast and lung carcinomas, followed by malignant melanoma, lymphoma, leukemias, and sarcomas (Hanfling, 1960; Heath, 1968; Kutalek et al., 1985). Cerebral metastasis in malignant melanoma is well documented and this may be related to this particular neoplasm having a propensity for intracardiac metastasis (Glancy and Roberts, 1968). Neoplastic metastases to the heart appear to have

less tendency to cause neurologic sequelae than do primary cardiac neoplasias, but this is perhaps related to the general seriousness of the disease by the time tumors metastasize to the heart (Dein et al., 1987; McFadden and Lacy, 1987; Flipse et al., 1990). Presenting neurologic symptoms and signs can be quite varied and may not immediately suggest a cardiac lesion, but the common use of echocardiography and other noninvasive imaging has made this less of a concern (Roberts, 1997). Prior to echocardiography, diagnosis was difficult and usually made at autopsy. A clinical triad of cardiac dysfunction, nonspecific constitutional symptoms, and embolic phenomena is the commonly described presentation (Butany et al., 2005), but patients rarely present with all three components. Once an intracardiac tumor is suspected, echocardiography can provide an early and reliable noninvasive diagnosis (Yufe et al., 1976; Fueredi et al., 1989; Molina et al., 1990; Roberts, 1997; Butany et al., 2005). The purpose of this chapter is to review the clinical presentations, neurologic complications, clinicopathologic characteristics, diagnostic evaluation, and therapeutic approach to primary and secondary cardiac tumors. The variable clinical presentation is emphasized and the need to maintain a high index of suspicion within the appropriate clinical setting is encouraged.

THE CLINICAL TRIAD Cardiac dysfunction Impairment of cardiac function can occur from mechanical obstruction of the chamber or valves (the most common etiology) (Pinede et al., 2001), arrhythmias, or myocardial dysfunction secondary to tumor infiltration of the myocardial wall itself. Dysfunction may occur

*Correspondence to: David Roeltgen, M.D., Cape Physicians Associates, 11 Village Dr., Cape May Court House, NJ 08246, USA. Tel: þ1-609-465-2273, Fax: þ1-609-463-0235, E-mail: [email protected]

210

D. ROELTGEN AND C.S. KIDWELL

Table 15.1 Primary cardiac tumors in order of frequency (reproduced from Molina et al., 1990, with permission) Number Myxoma Rhabdomyoma Papillary fibroelastoma Fibroma Rhabdomyosarcoma Angiosarcoma Hamartoma Myxosarcoma Others Total

51 14 12 9 6 4 4 3 21 124

% 42 12 10 7 5 3 3 2 17 100

despite the tremendous capacity of the heart to preserve function when faced with a large tumor burden (Glancy and Roberts, 1968; Kutalek et al., 1985). In patients with neurologic complications of intracardiac tumor, the history and physical examination may be helpful in identifying an intracardiac source. Dyspnea, followed by peripheral edema and precordial murmurs. were the most common clinical manifestations in a series of 70 patients with metastatic intracardiac malignant melanoma (Glancy and Roberts, 1968). Flipse et al. indicate that dyspnea may either be the presenting manifestation of intracardiac metastasis in a patient with a remote history of systemic malignant disease, or a sign of chemotherapeutic toxicity (Flipse et al., 1990). The classic precordial manifestation of atrial myxoma or cardiac tumor is the ‘precordial plop.’ However, a ‘tumor plop’ was heard in only one of 42 patients described by Dein et al. (1987) and in 17 of 72 described by Pinede et al. (2001). Systolic or diastolic murmurs often simulating mitral stenosis are more frequent findings upon auscultation (Harvey, 1968; Pinede et al., 2001). A widened pulse pressure, signs of a superior or inferior vena cava syndrome, or evidence of right or left heart failure may be apparent on the general physical examination, suggesting an intracardic source in association with the patient’s neurologic manifestation. Some presenting neurologic sequelae are caused by direct cardiac dysfunction, including sudden death and arrhythmia (Goodwin, 1968; Harvey, 1968; Kandt et al., 1985; Acebo et al., 2003). The most common cardiac tumor etiology for this is fibroma, but rhabdomyomas, large myxomas. and metastatic lesions may also be the cause. Clay and Shorter reported two infantile cases of intramural fibroma and reviewed 10 more (Clay and Shorter, 1957). Ten of the infants presented with sudden death. Five infants were noted to have convulsions just

prior to expiration. Burke et al. reported patients presenting with fibroma-related sudden death (Burke et al., 1994). James and Starfield described an infant with an intramural fibroma who presented with a paroxysmal tachyarrhythmia prior to sudden expiration (James and Stanfield, 1955). Glancy and Roberts describe a high percentage of tachyarrythmias (superventricular tachycardia being the most common), bradyarrhythmias, and conduction disturbances in 60 cases of intracardiac malignant melanoma (Glancy and Roberts, 1968). However, only one patient was thought to expire suddenly as a result of cardiac disease. Arrhythmias and valvular obstruction may account for the high percentage of syncopal episodes among those patients with neurologic complaints referable to intracardiac tumors. In some studies, syncope has been reported to occur in up to 56% of symptomatic surgical candidates (Tschirkov et al., 1990). Syncope may present as a Stokes–Adams attack and may lead to generalized convulsions. (Harvey, 1968). A restrictive pericarditis or effusion secondary to metastatic cardiac disease may also produce syncopal episodes. A pericardial friction rub on auscultation may suggest this diagnosis (Harvey, 1968; Mugge et al., 1991). Abrupt cerebral hypoperfusion probably accounts for the convulsions associated with cardiac fibromas discussed above (Clay and Shorter, 1957). Cardiac rhabdomyoma, associated with tuberous sclerosis, has also been noted to cause arrhythmias and circulatory obstruction, although epilepsy in tuberous sclerosis is usually due to the primary derangements of cerebral architecture (Heath, 1968; Kandt et al., 1985; Gold, 1989).

Nonspecific constitutional symptoms Constitutional symptoms in association with cardiac neoplasia may be particularly misleading as they may direct the diagnostic process away from a primary cardiac source towards an infectious, collagen vascular, rheumatologic, or malignant disorder (Levine and Swanson, 1969; Yufe et al., 1976; Gindea et al., 1987; Reynen, 1995). Fever, rash, arthralgia, myalgia, and cachexia are often reported in association with malignant intracardiac tumors but are also common in atrial myxoma, seen in some series in up to 89% of patients (Goodwin, 1968; Yufe et al., 1976). The pathogenicity of the autoreactivity in patients with atrial myxoma will be discussed later. However, these symptoms and associated laboratory findings such as elevated sedimentation rate and C-reactive protein, leukocytosis, anemia, thrombocytosis, elevated transaminase (perhaps from cardiac failure) (Pinede et al., 2001), and gammopathies are also seen in endocarditis and malignant intracardiac tumors such as spindle cell carcinoma (Maisch, 1990)

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS and primary cardiac sarcoma (Harvey, 1968). The clinical relevance of these symptoms and findings, beyond the patient’s discomfort, is the confusing clinical and laboratory picture that results. However, prior to use of echocardiography, these findings were helpful in making the diagnosis of cardiac tumor (Pinede et al., 2001). In myxoma, the laboratory abnormalities and the patient’s discomfort often resolve after surgical resection (Goodwin, 1968).

Embolic phenomena Embolic complications of intracardiac tumors may be either systemic or neurologic and appear to be most common from myxoma and fibroelastoma (Endo et al., 1997; Roberts, 1997; Ngaage et al., 2005; Sun et al., 2001). These embolic events comprise the majority of the neurologic complications of cardiac tumors. Embolic phenomena may be the presenting feature of the patient’s illness (Harvey, 1968; Kasarskis et al., 1988; Limper et al., 1988). Embolic material may be thrombus from the tumor surface or tumor material itself (Alessi et al., 2001). Ventricular or atrial tumor involvement from endocardial implantation, or extension into the chamber from myocardial rests can result in tumor thrombosis yielding embolic material (Hanfling, 1960). Tumor cells may be intermixed within the thrombus (Hanfling, 1960), so that pathologic evaluation of material from a systemic vascular thrombectomy is a diagnostic necessity (Harvey, 1968; Yufe et al., 1976). A patient presenting with isolated or recurrent central embolic phenomena, evanescent neurologic symptoms, syncope or convulsive syncope, arrhythmia or other features of the clinical triad should have a complete cardiovascular examination. The presence of electrocardiographic abnormalities, or evidence of peripheral embolization on physical examination or laboratory analysis, should prompt an immediate diagnostic evaluation. Considering the variety of neurologic sequelae from embolization or cardiac dysfunction, and the complicated constellation of constitutional symptoms and signs, the clinician should have little hesitation in obtaining noninvasive cardiac visualization and considering surgical intervention, especially for the benign primary cardiac tumors (Reynen, 1995; Ngaage et al., 2005).

SPECIFIC CARDIAC TUMORS Myxoma Myxomas are the most common benign tumors of the heart (Molina et al., 1990; Endo et al., 1997; Roberts, 1997). Among primary cardiac neoplasms, atrial myxoma is the most common, accounting for approximately 40–80% (Prichard, 1951; Molina et al., 1990; Tschirkov

211

et al., 1990). Rarely, they may present as an autosomal dominant disorder, Carney’s complex (cardiac myxoma, endocrine, cutaneous and neural tumors and spotty pigmentation of the skin) (Guenther, 2011). Molecular studies have shown a relationship between this disorder and the PRKAR1A gene (Stratakis et al., 2001; Horvath et al., 2008). Atrial myxomas can arise in the ventricles or atria, are far more common in the latter, and more common in the left than the right atrium. Neurologic complications most commonly occur from lesions in the left atrium. Only since the advent of noninvasive cardiac imaging have the majority of left atrial myxomas been diagnosed prior to death. Roeltgen et al. reviewed 47 previously described patients with neurologic complications of atrial myxoma and added two more (Roeltgen et al., 1981). Among those, 24 died from neurologic complications. In contrast, more recent studies show excellent survival (Roberts, 1997). The age distribution of atrial myxoma varies, but most have been reported in the 40–80-year-old age group (Table 15.2) (Molina et al., 1990; Roberts, 1997). Familial myxoma has been reported and tends to occur in younger patients (Reynen, 1995). One inherited form, the Carney syndrome, is autosomal dominant, inherited on chromosome 17q2, and associated with cutaneous hyperpigmentation (Casey et al., 1998). There is disagreement among studies as to whether atrial myxoma is more common in women. Prichard described an equal gender distribution (Prichard, 1951) but more recent studies suggest a female predominance (Roberts, 1997; Pinede et al., 2001; Lee et al., 2007). In the review by Roeltgen et al. (1981), the neurologic manifestations of left atrial myxoma appeared to be more severe in women than in men. The mortality for women was 72% and for men 25%, a difference that was statistically significant. Similarly, the duration of neurologic symptoms and signs as well as the total duration of illness was significantly shorter in women than in men. There are many ways in which atrial myxoma can present clinically. The cardiac and peripheral embolic Table 15.2 Distribution of myxoma (51 cases) by age (reproduced from Molina et al., 1990, with permission) Years of age

Number

80 Total

8 6 22 12 3 51

212 D. ROELTGEN AND C.S. KIDWELL presentations, similar to those seen with other tumors, complexes. These data suggested an immunologic comare described later in this chapter. However, other preponent involved in the systemic manifestations of atrial sentations including apparent ‘metastatic’ lesions, sysmyxoma. More recently, Mendoza et al. found evidence temic abnormalities, and focal neurologic dysfunction in a series of eight patients to implicate interleukin-6 as the also occur. etiology of the systemic symptoms and signs (Mendoza et al., 2001). However, studies do not find an association between IL-6 and the systemic symptoms (Acebo et al., SYSTEMIC EFFECTS 2003). Independent of the cause, in general, systemic Although atrial myxoma is generally a benign neoplasm, and cutaneous abnormalities resolve with excision of embolic fragments from the tumor may be distributed the myxoma (Reynen, 1995; Acebo et al., 2003; Yuehua throughout the vascular system and cause infarctions; et al., 2003). rarely metastatic tumor lesions have been described, parSTRUCTURAL NEUROLOGIC COMPLICATIONS ticularly in bones and the brain (Kimbrell and Kaasa, 1973; Read et al., 1974; Rankin and DeSousa, 1978). Bony From a series of six studies spanning 1970 to 1990, the lesions may be asymptomatic or associated with local frequency of structural neurologic manifestations from pain and fractures. left atrial myxoma ranged from approximately 18% to Constitutional symptoms in patients with cardiac 67%. From these studies, 22 of 80 patients (28%) with left myxoma are common, but rates vary. In reviews reflectatrial myxoma have had neurologic complications ing experience before noninvasive cardiac testing, (Croxson et al., 1972; Yufe et al., 1976; Bulkley and including one with 23 patients (Steinke et al., 1972), Hutchins, 1979; Sandok et al., 1980; Marvasti et al., 50% or more of patients with atrial myxoma had consti1984; Knepper et al., 1988), a percentage that is higher than tutional symptoms or serologic abnormalities including that found by Lee et al. (2007). However, unlike the results fever, fatigue, weight loss, generalized aching, leukocyfor systemic abnormalities, Pinede et al. (2001) did not tosis, elevated sedimentation rate, and anemia. In confind a difference in neurologic signs when comparing trast, more recent studies include a lower frequency of pre- (14%) and postechocardiographic results. these findings (Fernandes et al., 2001). Pinede et al. The most common neurologic manifestation is divided their subjects into pre- and postechocardioembolic infarction or transient ischemic attack (TIA). graphic testing and also found fewer of these findings Until the 1990s, the literature was dominated by single in the latter group (Pinede et al., 2001). Occasional case studies or literature reviews (Silverman et al., 1962; patients have presented with a clinical picture resembling Yarnell et al., 1971; Albers et al., 1987). However, in the immune disease, with multiple joint pains (Currey et al., last two decades, group studies, usually retrospective, 1967), or a rash (Yufe et al., 1976; Huston et al., 1978; have included larger numbers of subjects ranging from Feldman and Keeling, 1989; Yuehua et al., 2003) that the 20s to greater than 100 (Grande et al., 1993; Endo has been mistaken for peripheral vasculitis with Rayet al., 1997; Alvarez-Sabin et al., 2001; Fernandes et al., naud’s phenomena. Tissue biopsy including muscle or 2001; Pinede et al., 2001; Swartz et al., 2006). Cerebral vasskin may reveal no specific diagnosis (Huston et al., cular abnormalities from myxoma may be bilateral; how1978) or may show myxomatous cells (Feldman and ever, in the review by Roeltgen et al. (1981) there was a 2:1 Keeling, 1989). Laboratory assessment in patients with predominance of left-sided abnormalities. A similar findatrial myxoma frequently includes an increased gammaing was made by Jampol et al. (1973), who found predomglobulin ratio, increased erythrocyte sedimentation rate, inance of left ocular embolization over right. Additional and anemia. However, other tests of immunologic disease studies have described left to right ratios of cerebral including rheumatoid factor, lupus antibody tests and involvement ranging from 3:1 to 9:1 (Marvasti et al., other specific immunologic assessments are usually 1984; Knepper et al., 1988; Larsson et al., 1989). normal. Curry et al. suggested that some patients might have an Embolic disease autoimmune dysfunction that was in response to the Although overall neurologic complications of atrial tumor (Currey et al., 1967). Consistent with such an explamyxoma are uncommon as a cause of stroke or TIA, nation is the improvement in the constitutional symptoms embolic complications are the most frequent focal neuand the return to normal of the laboratory values when the rologic presentation of this disorder. Overall, embolic cardiac tumor is surgically removed. Maish showed antidisease occurs in 30–40% of patients with myxoma myolemmal antibodies in patients with cardiac myxoma (Reynen, 1995). However, the type of emboli appear to (Maisch, 1990). Six of seven patients with cardiac myxbe dependent on the pathology of myxoma. Myxomaoma had antibody elevation, the presence of antiendothetous emboli are associated with villus surface myxoma. lial antibodies of the IgG type, and circulating immune

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS 213 In contrast, large solid myxomas are associated with multiple infarctions of the brain. Hirose et al. described atrial fibrillation and possible emboli. Small solid myxoa patient with a sudden onset of transverse myelopathy mas uncommonly cause neurologic dysfunction and (Hirose et al., 1979). The diagnosis of embolic disease more typically present with congestive heart failure was made after aortic angiography disclosed multiple (Acebo et al., 2003; Swartz et al., 2006). In general, emboli. After removal of a left atrial myxoma, the the clinical presentation of atrial myxoma embolic dispatient made an uneventful recovery. Lee described ease is no different from that of other cardioembolic disone patient with aortic embolus that was associated with eases. However, the pathophysiology may vary. Tumor paraplegia (Lee et al., 2007). emboli are probably most common. However, up to 41% of atrial myxomas may have surface thrombosis, Cerebral aneurysms and emboli may also contain this thrombotic material (Burke and Virmani, 1993; da Silva and de Freitas, Aneurysms of the cerebral arteries, with or without hem2012). Additionally, though embolic disease is episodic orrhage, in patients with atrial myxoma are also rare. In a rather than continuous, it is likely that there are frequent review, Sabolek et al. (2005) described 33 previously pubmicroemboli that are not detected clinically (Telman lished cases and added an additional case. Most studies et al., 2010). (91% according to Sabolek et al. (2005)) have described Multiple strokes secondary to myxoma could potenfusiform aneurysms. Occasionally, saccular aneurysms tially present as a progressive dementia. At least two have been reported (New, 1970; Damasio et al., 1975). patients with a progressive dementia have been reported Longitudinal angiographic data from New et al. (1970) (Hutton, 1981; Bonnefoi et al., 1990; Browne et al., 1993; indicate that the saccular aneurysms in their patient folMattle et al., 1995). One of these patients (Hutton, 1981) lowed embolic occlusion of the arteries and were therewas an elderly man with a history of hypertension and fore not present on a developmental basis. In addition to coronary artery disease, who presented with a clinical fusiform and saccular aneurysms, Stoane et al. (1966) picture of multi-infarct dementia, but without any sympdescribed the appearance of a “beaded” artery that toms or signs suggestive of atrial myxoma. No evaluawas interpreted as being consistent with an aneurysm. tion was done for a cardiac cause of stroke and the Under other circumstances, without a clear diagnosis patient expired from complications of a perforated duoof myxoma, such an angiogram might be interpreted denal ulcer. Multiple cerebral ischemic infarctions were as indicative of arteritis. The cerebral aneurysms from found, and several vessels contained myxomatous mateatrial myxoma may occur in distal branches(Leonhardt rial. Such patients are very rare, usually because from and Kullenberg, 1977), proximal branches, or both. They the onset of the symptoms to the diagnosis is within a may also occur in the ophthalmic and retinal arteries few months (Pinede et al., 2001). (Herbst et al., 2005). In addition to cerebral artery emboli, retinal artery emboli have been attributed to atrial myxoma Metastatic disease (Anderson and Lubow, 1973; Jampol et al., 1973; Campbell, 1974; Cogan and Wray, 1975; Tonz et al., Although most embolic phenomena associated with 1992; Reynen, 1995). The diagnosis of retinal artery myxoma lead to ischemic infarction, there have been occlusion from atrial myxoma has primarily been made rare reports of apparent cerebral metastatic atrial myxin patients who have recurrent neurologic involvement, oma. Rankin and DeSousa (Desousa et al., 1978) and or occasionally in patients with noncerebral systemic Desousa et al. (Desousa et al., 1978) described a patient embolization (Jampol et al., 1973; Cogan and Wray, with a known atrial myxoma and a mass in the choroid 1975). Fundoscopic examination usually reveals central plexus that consisted of myxomatous tissue. Their retinal artery occlusion; only rarely has embolic material patient also had multiple bony lytic lesions, but one been identified. Cogan and Wray have suggested that the biopsy only revealed aseptic necrosis without evidence combination of central retinal artery occlusion, ischemic of metastatic tumor. Kimbrell and Kaasa (1973) optic neuropathy, and juxtapapillary choroidal involvedescribed a patient with aortic myxoma who had eviment in one eye is sufficiently rare that, when it is predence of myxomatous infiltration of the thoracic vertesent, atrial myxoma is a likely etiology (Cogan and brae. In the cases described by Rankin and DeSousa Wray, 1975). (Desousa et al., 1978) and Kimbrell and Kaasa (1973), Spinal cord ischemia and infarction from atrial myxthe histologic appearance of the tumor was consistent oma are rare and most series report no cases (Pinede with atrial myxoma. Altundag et al. (2005) described et al., 2001). The second case of spinal cord embolism hemorrhagic lesions that contained myxoma cells when described by Wolman and Bradshaw (1967) had apparent biopsied. Their review of the literature included a total infarction from atrial myxoma in association with of 16 cases of metastatic myxoma (including the case

214

D. ROELTGEN AND C.S. KIDWELL

A

B

Fig. 15.1. (A). Right internal carotid angiogram showing occlusions of the middle cerebral artery and pericallosal artery (arrow). following embolization of a left atrial myxoma. (B). Repeat angiogram showing an aneurysm of the proximal segment of the right middle cerebral artery and the right pericallosal artery.

of Rankin and DeSousa (Desousa et al., 1978), but not the case of Kimbrell and Kaasa (1973)). Other Rubens et al. (1989) described a patient with a large left atrial myxoma that displaced the left pulmonary artery in such a way that it compressed the recurrent laryngeal nerve. Their patient presented with a long history of hoarseness and, on examination, had findings consistent with left recurrent laryngeal nerve palsy. After the myxoma was removed, the hoarseness improved, and the patient was again able to adduct the left vocal cord during phonation.

NATURAL HISTORY Roeltgen et al. (1981) formulated the probable natural history of the acute and delayed neurologic manifestations of left atrial myxoma. The neurologic disorder typically begins with embolization from the primary tumor. Some patients have symptoms of acute cerebral infarction with or without embolization to other organs. Failure to diagnose and resect the cardiac tumor leaves a definite risk of repeated embolization. However, complete surgical resection has failed to protect some patients (New, 1970; Roeltgen et al., 1981; Jean et al., 2001; Oguz et al., 2001) from later delayed complications of the original embolization, suggesting a continuing intracerebral process. After embolization, several outcomes are possible. Roeltgen et al. (1981) described a patient who initially had evidence of embolic disease to a large cerebral vessel. Repeat angiographic studies first showed resolution of the arterial obstruction, followed by the development

of a fusiform aneurysm at the previous site of obstruction (Fig. 15.1). Aneurysm formation in the context of previous embolic disease has also been shown in other studies (Stoane et al., 1966; Burton and Johnston, 1970). Aneurysm formation from myxoma is in contrast to bland embolization from other etiologies. Most emboli do not result in aneurysm formation in either clinical or experimental studies. The true incidence of myxomatous aneurysm formation after emboli is unknown. Longitudinal data of patients with embolic cerebral vascular disease are limited, but clearly indicate the relationship between embolism and aneurysm formation (New, 1970; Damasio et al., 1975; Roeltgen et al., 1981; Rodriguez et al., 2006). Burton and Johnston (1970) proposed that embolic occlusion of the artery first weakens the wall and that myxoma cells penetrate the damaged endothelium. Myxoma cells have been identified in vessel walls at the sites of cerebral infarction (Steinmetz et al., 1973; Frank et al., 1979) or in the wall of an aneurysm at the site of an old infarction (Burton and Johnston, 1970). Other support for myxomatous embolization as an etiology is the report by Rodriguez et al. (2006), whose patient initially had probable embolic infarction and later had a large hemorrhage that was surgically removed. On pathologic analysis there was intraluminal myxoma that appeared to disrupt the vascular walls with aneurysm formation and hemorrhage. New et al. (New, 1970) proposed that after invasion of the vessel wall, tumor cells continue to spread causing fibroblastic proliferation that further weakens the media and leads to aneurysmal dilatation. This theorized pathophysiology resembles one postulated for mycotic aneurysms (Moskowitz et al., 1974; Olmsted and McGee, 1977).

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS 215 However, many patients develop fusiform aneucardiac thrombosis (Prichard, 1951). Myxoma and thromrysms without prior symptomatic cerebral embolization bus frequently coexist and there are similarities between (New et al. (New, 1970) (third patient); Roeltgen et al., myxoma and thrombus on gross and microscopic analysis. 1981 (second patient); Furuya et al., 1995; Jean et al., In 1968, in a detailed description of the pathology of myx2001; Walker et al., 2003; Sabolek et al., 2005), and some oma, Heath stressed that it was important and possible to after surgical resection of the primary myxoma (New, distinguish a myxoma from a thrombus (Heath, 1968). 1970; Roeltgen et al., 1981; Michael et al., 1989; Liou Cardiac myxomas are usually single, but may be mulet al., 1990; Furuya et al., 1995; Ho et al., 1995; Jean tiple (Heath, 1968; Reynen, 1995; Butany et al., 2005). et al., 2001; Walker et al., 2003; Sabolek et al., 2005). Although myxomas are more common in the atria Despite the lack of embolic signs or symptoms, the path(Prichard, 1951; Heath, 1968; Bulkley and Hutchins, ogenesis of these aneurysms is also probably embolic. 1979), they have also been found in the ventricles (Stoane It is possible that prior to resection there were small et al., 1966; Greenwood, 1968; Heath, 1968; Mandel and asymptomatic embolic occlusions, leading to vessel wall Strimel, 1970; Reynen, 1995; Butany et al., 2005). Atrial infiltration and gradual aneurysm formation. The study myxomas are at least three times more common in the by Furuya et al. supports this hypothesis (Furuya et al., left atrium than in the right (Prichard, 1951; Heath, 1995). They resected aneurysms from a patient with a 1968; Bulkley and Hutchins, 1979; Reynen, 1995). Venpreviously removed atrial myxoma and showed that tricular myxomas frequently arise next to or on the the excised aneurysms had nests of myxoma in the mitral valve. Occasionally, when the myxoma arises on lumen invading the endothelial space. A third hypothesis the mitral valve, significant portions of the tumor may is that there are myxomatous emboli to the vasa vasorum project into both the left atrium and the left ventricle with subsequent invasion and weakening of the vessel (Joynt et al., 1965). Even rarer than the occurrence of wall (Sabolek et al., 2005). However, vasa vasora are ventricular myxoma is the occurrence of myxoma in rarely found in cerebral vessels of experimental animals the aorta (Kimbrell and Kaasa, 1973). However, the neu(Molinari et al., 1973) or man (Stehbens, 1972). rologic complications from myxomas in the left ventricle As indicated, there are multiple case reports of cereand aorta are similar to those found with myxomas in the bral complications of atrial myxoma occurring months left atrium. to years after the tumor has been resected. However, As indicated previously, there are two basic types of although reported, reviews of groups of subjects with cardiac myxoma. The solid and ovoid tumors, which atrial myxoma suggest that such complications are embolize infrequently, appear to be slightly more comuncommon (Sandok et al., 1980; Mattle et al., 1995). mon than the soft papillary myxomas, which embolize Myxomatous cerebral aneurysms have an unpredictmore commonly (Shimono et al., 1995; Swartz et al., able natural history. Many stabilize (Roeltgen et al., 1981 2006). The former are thought to embolize from cracking (second patient); Branch et al., 1985 (first patient); Oguz of the surface, fractured from turbulent flow, and the latet al., 2001). Some may symptomatically thrombose ter from their friable surface. The mass almost always has (Jean et al., 2001). Some may resolve by occlusion of a pedicle that attaches to the atrial wall, most commonly the affected vessel (Roeltgen et al., 1981) or recanalizaonto the intra-atrial septum near the margin of the fossa tion leading to angiographically determined normal vesovalis. Their general consistency varies with the collagen sel diameter (Branch et al., 1985). Some may also content and the gross color is also variable (Prichard, 1951; progress with or without hemorrhage (Furuya et al., Heath, 1968; Bulkley and Hutchins, 1979). 1995; Rodriguez et al., 2006). Microscopically the solid and papillary myxomas are In addition to aneurysm rupture as an etiology for very similar. The bulk of the tumor consists of an amorhemorrhage, some patients have had intracerebral hemphous matrix of interstitial ground substance, predomiorrhage without angiographic or pathologic evidence of nantly an acid mucopolysaccharide (Heath, 1968). The aneurysm (Frank et al., 1979; Roeltgen et al., 1981). Aneucellular content consists of ovoid or elongated cells that rysms may escape detection after rupture, or hemormay occur singly or in small groups of 3–6 cells rhages might result from destruction and rupture of (Tschirkov et al., 1990). The groups of cells are usually small vessels without aneurysm formation, as suggested associated with thin-walled capillary-type blood vessels. by the finding of myxoma tissue in the muscularis of Larger, thick-walled blood vessels are found in the pedsmall cerebral vessels (Price et al., 1970). icle. Fibroelastic tissue is found throughout the tumor but is most prominent in the pedicle (Prichard, 1951; Heath, 1968). Microscopic hemorrhage is more common PATHOLOGY in the solid than the papillary myxomas (Shimono As late as 1951, Pritchard described controversy regarding et al., 1995; Swartz et al., 2006). Electron microscopic whether myxoma was a true neoplasm or represented examination of the cells indicates only one basic cell

216

D. ROELTGEN AND C.S. KIDWELL

type. These cells contain fusiform densities along their course, similar to the attachment bodies of smooth muscle cells. According to Tschirkov et al., the common tumor cells correspond to smooth muscle cells of synthetic phenotype (Tschirkov et al., 1990). This group indicates that other cell types, including fibroblasts, macrophages, mast cells, lymphocytes and plasma cells, may occur within the tumor.

Other benign primary tumors Atrial myxoma is the most common primary cardiac neoplasm, but other rare tumors also occur. Although any tumor may give rise to emboli, neurologic complications from cardiac tumors are uncommon with most tumor types except papillary fibroelastoma.

PAPILLARY FIBROELASTOMA Papillary fibroelastomas (sometimes called papillomas) account for only 20% of nonmyxomatous benign cardiac tumors. However, they cause almost all of the neurologic complications of nonmyxomatous cardiac tumors. With the advent of echocardiography the diagnosis is more common than in the past. Sun et al. (2001) described 162 patients with fibroelastoma and Ngaage et al. (2005) described 88 patients having this diagnosis. These studies suggest this diagnosis is more common than was previously thought. For both studies the mean age was early 60s and there is probably no gender predilection. Neurologic involvement occurs in approximately half of the patients, all with presumed embolism. Papillary fibroelastoma presents neurologically as single or multiple TIAs or strokes and may occur in any age group. Because of their small size, these tumors frequently do not produce any cardiac symptoms or signs. Fibroelastomas are thought to arise from valvular connective tissue (Kasarskis et al., 1988) and are found most commonly on valvular endocardium of the aortic and mitral valves (Butany et al., 2005). However, they may arise from any endocardial surface (Gorton and Soltanzadeh, 1989). Histologically these tumors consist of nonvascularized cores of fibroelastic tissue covered with a loose myxoid layer of mucopolysaccharide and endocardial lining cells and are said to be related to cardiac myxomas (Kasarskis et al., 1988; Gorton and Soltanzadeh, 1989; Sun et al., 2001). Based on the papillary structure and a correlation of neurologic events and the finding of thrombus when the elastoma was studied pathologically, it has been suggested that the configuration of these tumors is likely to lead to surface thrombosis and subsequent emboli (Grandmougin et al., 2000). However, most pathologic reports of papillary fibroelastoma have not described associated thrombosis (McFadden and Lacy, 1987;

Kasarskis et al., 1988; Gorton and Soltanzadeh, 1989; Sun et al., 2001; Ngaage et al., 2005). An alternative explanation for the occurrence of embolization is the villous nature of the tumor. It is likely that at least some emboli from this tumor are actual tumor fragments, rather than embolic thrombus material, but the absence of appropriate pathologic studies does not allow confirmation of this hypothesis. Grandmougin et al. (2000) proposed an additional hypothesis regarding this disorder. They found remnants of cytomegalovirus in the pathologic specimens and suggested that this may be a virus-induced tumor and therefore is an example of a chronic form of viral endocarditis.

RHABDOMYOMA Rhabdomyomas are rare in adults but more common in children. They are the second most common benign primary cardiac tumor after myxomas (Molina et al., 1990; Butany et al., 2005). They are usually associated with cardiac abnormalities and may be multicentric. They are of interest to neurologists because of their association with tuberous sclerosis (Gomez, 1989; Harding and Pagon, 1990). Harding and Pagon (1990) suggest that 50–86% of rhabdomyomas are associated with tuberous sclerosis. Gomez (1989) found no evidence that embolization from the rhabdomyoma had a role in the higher incidence of stroke in tuberous sclerosis. He suggested that the higher incidence of stroke in tuberous sclerosis is due to abnormalities of the cerebral arteries and the aorta, a problem more common in patients with tuberous sclerosis than in the rest of the population.

Primary malignant cardiac tumors Myxosarcoma can be described as a malignant version of myxoma (Read et al., 1974). This tumor is more common in infants and children than adults and tends to metastasize to the vertebral column or soft tissue organs (Heath, 1968), including the brain (Mahar et al., 1979; Roh et al., 2001), and thus has been associated with neurologic complications.

Secondary tumors Secondary tumors in the heart are more common than primary tumors (Heath, 1968; Butany et al., 2005). Tumors that commonly metastasize to the heart include bronchial carcinoma, carcinoma of the breast, malignant reticulosis, renal cell carcinoma, and malignant melanoma. Despite the higher frequency of metastatic tumors in the heart compared to primary tumors, cerebral manifestations from these neoplasms are rare (Reynen, 1995), possibly because tumor involvement of the cardiac chambers is rare (Hanfling, 1960). In

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS addition, not all tumors that are metastatic to the cardiac chambers result in cerebral emboli. However, emboli with multiple strokes have been described in some patients who have had tumors metastatic to the heart. The tumor types described include endometrial stromal sarcoma, osteogenic sarcoma, and synovial-cell sarcoma (Lefkovitz et al., 1986; Chalmers and Campbell, 1987; Limper et al., 1988). Choriocarcinoma may also produce neurologic complications and an interesting set of features may occur in patients with this tumor. In a case report and review, Seigle et al. described a 28-year-old woman who presented with two intracranial hemorrhages (Seigle et al., 1987). On echocardiogram she was found to have a mass in the left ventricle. A cerebral angiogram indicated multiple aneurysms and a suggestion of multiple emboli. An autopsy disclosed metastatic choriocarcinoma in the heart as well as other organs. In addition, arterial emboli consisting of choriocarcinoma were found in cerebral vessels. Choriocarcinoma was present at the site of the aneurysms. In addition to their patient, Seigle et al. reviewed the results from 10 previously reported patients with aneurysms secondary to metastatic choriocarcinoma (Seigle et al., 1987). They indicated that this presentation mimics that of atrial myxoma and should be included in the differential diagnosis when atrial myxoma is considered. However, metastatic choriocarcinoma presenting with cerebral involvement, including aneurysm, may occur without evidence of cardiac involvement (Semple et al., 2004).

DIAGNOSIS Echocardiography Advances in imaging techniques have led to increased detection of cardiac tumors. Echocardiography is the first-line imaging technique for diagnosis of intracardiac tumors (Sheppard and Mohiaddin, 2010). It is noninvasive and relatively inexpensive. Two-dimensional (2D) transthoracic echocardiography (TTE) is typically capable of identifying a mass lesion in the majority of cases and can usually characterize the location, size, and mobility of the mass. An important distinction is between left atrial thrombus and atrial myxoma (a myxoma is more likely to have a stalk and be mobile). However, TTE has limited ability to detect lesions in the atrial appendages or those with extracardiac extension. Transesophageal echocardiography (TEE), although more invasive, allows better visualization of the left atrium, lesions with extracardiac involvement, and small masses. Doppler echocardiography can demonstrate hemodynamic effects caused by the mass (e.g., mitral stenosis or regurgitation).

217

Other cardiac imaging Both cardiac MRI and cardiac CT are often useful as adjunctive techniques in the diagnosis and characterization of cardiac tumors (Gupta et al., 2010). MRI is particularly helpful when echocardiography is equivocal. It has proven useful in delineating the degree of intra- and extracardiac extension including involvement of the great vessels and mediastinum, and in differentiating tumor from thrombus. Certain tumors such as lipomas and fibromas may be diagnosed by MRI signal characteristics (Sheppard and Mohiaddin, 2010). Malignant tumors are more frequently characterized by their size, involvement of more than one cardiac chamber or extracardiac extension, and wide points of attachment. Use of a gadolinium-based contrast agent may be useful in tissue characterization and in identifying tumors with contrast enhancement (e.g., angiosarcomas and hemangiomas) (Sheppard and Mohiaddin, 2010). Gated cine-loop sequences are useful in characterizing the hemodynamic and pathophysiologic effects of the tumor as well as tumor mobility. MRI is often the preferred approach for preoperative evaluation of the surgical candidate and post-treatment follow-up. Cardiac CT may also be useful in the diagnosis, tissue characterization, and ongoing evaluation of patients with cardiac tumors. CT is superior to MRI in detecting calcified lesions and fat. Multidetector computed tomography provides a noninvasive means to assess the coronary vasculature as well as the blood supply to the tumor (Gupta et al., 2010). Cardiac angiography provides an assessment of hemodynamic status; however, it gives relatively little insight into tissue characterization or anatomic detail. The adverse effects of contrast and intra-arterial manipulation, with the associated increased risk of embolus, may be potential complications. Cardiac angiography may be useful in identifiying pre-existing coronary artery disease, demonstrating tumor blood supply, and visualizing aneurysms.

Cerebral imaging Findings on cerebral angiography and CT are varied. Embolic strokes have been reported in all vascular distributions and may be ischemic or hemorrhagic. Lobar hemorrhages or subarachnoid hemorrhages secondary to oncotic aneurysms may also be visualized. Vascular occlusions as well as fusiform aneurysms may be found on cerebral angiography, magnetic resonance angiography (MRA), and computed tomographic angiography (CTA). Cerebral angiography at this time remains the first choice for the diagnosis of intracerebral oncotic aneurysm.

218

D. ROELTGEN AND C.S. KIDWELL

Pathology Tissue diagnosis involves pathologic evaluation of thromboembolic material removed surgically, endomyocardial biopsy, or pathologic evaluation of the surgically resected tumor (Flipse et al., 1990). Percutaneous endomyocardial biopsy is increasingly being used to provide a pathologic diagnosis prior to surgical resection or other treatments and has a low complication rate. A transvenous approach is used for rightsided lesions and a trans-septal approach for left-sided masses.

TREATMENT AND PROGNOSIS Atrial myxoma The onset of complications and the rate of progression of cardiac tumors are unpredictable. Medical supportive care should be provided for complications such as heart failure or arrhythimias. The treatment of choice is prompt surgical resection both for symptomatic improvement and to avoid complications (Markel et al., 1987). With surgical resection, improvement in systemic symptoms, cardiac symptoms, and immunologic abnormalities is likely (Damasio et al., 1975; Huston et al., 1978; Markel et al., 1987). In addition, there is some evidence to suggest that cerebral aneurysms may also improve with resection of the primary cardiac tumor (Roeltgen et al., 1981; Knepper et al., 1988). The operative mortality from surgery for atrial myxoma has improved dramatically in the last decade, from 18% to less than 2.5% (Markel et al., 1987; Tschirkov et al., 1990). Since prompt surgical intervention is recommended for this disorder, and because patients frequently present with recent neurologic events, concern may be raised regarding potential difficulties of surgery in a patient with a recent stroke. However, Zisbrod et al. describe the results of open heart surgery in 15 patients with recent cardiogenic embolic stroke (2–28 days, with a mean of 121 =2 days from the onset of neurologic injury until surgery) (Zisbrod et al., 1987). Fourteen of their patients had left atrial myxoma. One patient died in the postoperative period and the remaining patients had improvement in their neurologic symptoms. Eight patients had complete neurologic recovery. Such results suggest that prompt surgical resection should be performed in patients with and without recent neurologic injury. The operative technique is described in some detail by Marvasti et al. (1984). Long-term prognosis following surgical resection is very good with a recurrence rate of 1–5% (Larsson et al., 1989; Pinede et al., 2001). Pretumorous cells around the stalk should be destroyed by wider resection or photocoagulation. Deshpande has reported successful results with endoscopic resection

as a less invasive alternative (Deshpande et al., 2007). In general, follow-up imaging (typically echocardiography) should be performed biannually following resection. Treatment of the neurologic complications of atrial myxoma is uncertain. Results of thrombolytic therapy in embolic stroke from atrial myxoma have been mixed. A few case reports have described successful treatment of stroke from probable embolic disease using intravenous thrombolysis (Nagy et al., 2009; Abe et al., 2011; Malijevic et al., 2011; Ong and Chang, 2011) and intraarterial thrombolysis (Gassanov et al., 2011). Other authors have described lack of success or intracranial hemorrhage from both intravenous and interarterial thrombolysis in similar patients (Bekavac et al., 1997; Chong et al., 2005; Acampa et al., 2011; Kohno et al., 2012). The variable response is probably dependent on at least two factors: the composition of the embolus (thrombotic material or myxoma) (da Silva et al., 2012) and the presence or absence of myxomatous aneurysm (Chong et al., 2005). Therefore, determining the dominant tissue type within the cerebral embolus from an atrial myxoma, an approach advocated by some for typical embolic stroke (Cho et al., 2005), and sufficient vascular imaging to exclude aneurysm formation are probably necessary when deciding on thrombolysis in patients with embolic stroke from atrial myxoma. Treatment of aneurysms associated with atrial myxoma is also uncertain. Treatment options are similar to those for nononcogenic aneurysms: endovascular coiling and surgical clipping.

Other cardiac tumors Fibroelastomas may cause embolic neurologic deficits and therefore the surgical approach should be as aggressive as that used in treating atrial myxoma. It is suggested that care be taken to avoid embolization in patients with this tumor. A conservative approach with simple excision of the tumor is recommended in most patients (McFadden and Lacy, 1987). When the heart valve is involved, resection plus valve repair or complete valve replacement may be necessary. For treatment of other cardiac tumors the therapy should be addressed to the type of tumor. Some malignant tumors may not be resectable due to extensive tumor involvement. A metastatic workup should be performed prior to surgical resection. Chemotherapy and radiotherapy may be used in these settings. Cardiac transplantation has been attempted in this setting with only limited success due to tumor recurrence (Cusimano, 2008). Blackmon et al. have reported promising preliminary results with autotransplantation (cardiac explantation, ex vivo tumor resection, reconstruction, and reimplantation) for malignant or complex

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS primary left heart tumors (Blackmon et al., 2008). A general review of the approach to cardiac tumors is provided by Molina et al. (1990).

REFERENCES Abe M, Kohama A, Takeda T et al. (2011). Effective intravenous thrombolytic therapy in a patient with cerebral infarction associated with left atrial myxoma. Intern Med 50: 2401–2405. Acampa M, Tassi R, Guideri F et al. (2011). Safety of intravenous thrombolysis in ischemic stroke caused by left atrial myxoma. Curr Drug Saf 6: 343–345. Acebo E, Val-Bernal JF, Gomez-Roman JJ et al. (2003). Clinicopathologic study and DNA analysis of 37 cardiac myxomas: a 28-year experience. Chest 123: 1379–1385. Albers GW, Avalos SM, Weinrich M (1987). Left ventricular tumor masquerading as multiple sclerosis. Arch Neurol 44: 779–780. Alessi A, Gomes De Carvalho R, Bertolin Precoma D et al. (2001). Fibroelastoma of the mitral valve as a cause of transient ischemic stroke. Arq Bras Cardiol 77: 77–84. Altundag MB, Ertas G, Ucer AR et al. (2005). Brain metastasis of cardiac myxoma: case report and review of the literature. J Neurooncol 75: 181–184. Alvarez-Sabin J, Lozano M, Sastre-Garriga J et al. (2001). Transient ischaemic attack: a common initial manifestation of cardiac myxomas. Eur Neurol 45: 165–170. Anderson JD, Lubow M (1973). Atrial myxoma as a source of retinal embolization. Am J Ophthalmol 76: 769–772. Bekavac I, Hanna JP, Wallace RC et al. (1997). Intra-arterial thrombolysis of embolic proximal middle cerebral artery occlusion from presumed atrial myxoma. Neurology 49: 618–620. Blackmon SH, Patel AR, Bruckner BA et al. (2008). Cardiac autotransplantation for malignant or complex primary leftheart tumors. Tex Heart Inst J 35: 296–300. Bonnefoi B, Mesana T, Camilleri JF et al. (1990). Neurological disorders disclosing auricular myxoma: 3 cases. Rev Neurol (Paris) 146: 508–510. Branch CL Jr, Laster DW, Kelly DL Jr (1985). Left atrial myxoma with cerebral emboli. Neurosurgery 16: 675–680. Browne WT, Wijdicks EF, Parisi JE et al. (1993). Fulminant brain necrosis from atrial myxoma showers. Stroke 24: 1090–1092. Bulkley BH, Hutchins GM (1979). Atrial myxomas: a fifty year review. Am Heart J 97: 639–643. Burke AP, Virmani R (1993). Cardiac myxoma a clinicopathologic study. Am J Clin Pathol 100: 671–680. Burke AP, Rosado-De-Christenson M, Templeton PA et al. (1994). Cardiac fibroma: clinicopathologic correlates and surgical treatment. J Thorac Cardiovasc Surg 108: 862–870. Burton C, Johnston J (1970). Multiple cerebral aneurysms and cardiac myxoma. N Engl J Med 282: 35–36. Butany J, Nair V, Naseemuddin A et al. (2005). Cardiac tumours: diagnosis and management. Lancet Oncol 6: 219–228. Campbell JK (1974). Early diagnosis of an atrial myxoma with central retinal artery occlusion. Ann Ophthalmol 6: 1207–1208, 1210–1211.

219

Casey M, Mah C, Merliss AD et al. (1998). Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 98: 2560–2566. Chalmers N, Campbell IW (1987). Left atrial metastasis presenting as recurrent embolic strokes. Br Heart J 58: 170–172. Cho K-H, Jong K, Sun K et al. (2005). Significance of susceptibility vessel sign on T2*-weighted gradient echo imaging for identification of stroke subtypes. Stroke 36: 2379–2384. Chong JY, Vraniak P, Etienne M et al. (2005). Intravenous thrombolytic treatment of acute ischemic stroke associated with left atrial myxoma: a case report. J Stroke Cerebrovasc Dis 14: 39–41. Clay R, Shorter R (1957). Intramural fibromas of the heart. J Pathol Bacteriol 74: 163–169. Cogan DG, Wray SH (1975). Vascular occlusions in the eye from cardiac myxomas. Am J Ophthalmol 80: 396–403. Croxson RS, Jewitt D, Bentall HH et al. (1972). Long-term follow-up of atrial myxoma. Br Heart J 34: 1018–1023. Currey HL, Mathews JA, Robinson J (1967). Right atrial myxoma mimicking a rheumatic disorder. Br Med J 1: 547–548. Cusimano RJ (2008). Surgical management of cardiac tumors. Semin Diagn Pathol 25: 76–81. da Silva IR, Ferreira de Freitas GR (2012). Is it safe to proceed with thrombolytic therapy for acute ischemic stroke in a patient with cardiac myxoma? Case report and review of the literature. Eur Neurol 68: 185–186. Damasio H, Seabra-Gomes R, Da Silva JP et al. (1975). Multiple cerebral aneurysms and cardiac myxoma. Arch Neurol 32: 269–270. Dein JR, Frist WH, Stinson EB et al. (1987). Primary cardiac neoplasms early and late results of surgical treatment in 42 patients. J Thorac Cardiovasc Surg 93: 502–511. Deshpande RP, Casselman F, Bakir I et al. (2007). Endoscopic cardiac tumor resection. Ann Thorac Surg 83: 2142–2146. Desousa AL, Muller J, Campbell R et al. (1978). Atrial myxoma: a review of the neurological complications metastases and recurrences. J Neurol Neurosurg Psychiatry 41: 1119–1124. Endo A, Ohtahara A, Kinugawa T et al. (1997). Characteristics of 161 patients with cardiac tumors diagnosed during 1993 and 1994 in Japan. Am J Cardiol 79: 1708–1711. Feldman AR, Keeling JH 3rd (1989). Cutaneous manifestation of atrial myxoma. J Am Acad Dermatol 21: 1080–1084. Fernandes F, Soufen HN, Ianni BM et al. (2001). Primary neoplasms of the heart clinical and histological presentation of 50 cases. Arq Bras Cardiol 76: 231–237. Flipse TR, Tazelaar HD, Holmes DR Jr (1990). Diagnosis of malignant cardiac disease by endomyocardial biopsy. Mayo Clin Proc 65: 1415–1422. Frank RA, Shalen PR, Harvey DG et al. (1979). Atrial myxoma with intellectual decline and cerebral growths on CT scan. Ann Neurol 5: 396–400. Fueredi GA, Knechtges TE, Czarnecki DJ (1989). Coronary angiography in atrial myxoma: findings in nine cases. AJR Am J Roentgenol 152: 737–738. Furuya K, Sasaki T, Yoshimoto Y et al. (1995). Histologically verified cerebral aneurysm formation secondary to

220

D. ROELTGEN AND C.S. KIDWELL

embolism from cardiac myxoma. Case report. J Neurosurg 83: 170–173. Gassanov N, Nia AM, Dahlem KM et al. (2011). Local thrombolysis for successful treatment of acute stroke in an adolescent with cardiac myxoma. Scientific World 11: 891–893. Gindea AJ, Steele P, Rumancik WM et al. (1987). Biventricular cavity obliteration by metastatic malignant melanoma: role of magnetic resonance imaging in the diagnosis. Am Heart J 114: 1249–1253. Glancy DL, Roberts WC (1968). The heart in malignant melanoma. A study of 70 autopsy cases. Am J Cardiol 21: 555–571. Gold AP (1989). Tuberous sclerosis. In: LP Roland (Ed.), Merrit’s Textbook Of Neurology. Lea and Febiger, Philadelphia, pp. 586–593. Gomez MR (1989). Strokes in tuberous sclerosis: are rhabdomyomas a cause? Brain Dev 11: 14–19. Goodwin JF (1968). The spectrum of cardiac tumors. Am J Cardiol 21: 307–314. Gorton ME, Soltanzadeh H (1989). Mitral valve fibroelastoma. Ann Thorac Surg 47: 605–607. Grande AM, Ragni T, Vigano M (1993). Primary cardiac tumors. A clinical experience of 12 years. Tex Heart Inst J 20: 223–230. Grandmougin D, Fayad G, Moukassa D et al. (2000). Cardiac valve papillary fibroelastomas: clinical histological and immunohistochemical studies and a physiopathogenic hypothesis. J Heart Valve Dis 9: 832–841. Greenwood WF (1968). Profile of atrial myxoma. Am J Cardiol 21: 367–375. Guenther F, Siepe M, Schlensak C et al. (2011). Recurrence of a familial giant multiocular cardiac myxoma in a patient with Carney’s complex. Circulation 123: 929–932. Gupta A, Gulati GS, Hote MP et al. (2010). Cavitating atrial myxoma mimicking hydatid cyst on echocardiography: utility of cardiac magnetic resonance imaging and computed tomography for diagnosis and preoperative evaluation. J Thorac Imaging 25: W85–W88. Hanfling SM (1960). Metastatic cancer to the heart review of the literature and report of 127 cases. Circulation 22: 474–483. Harding CO, Pagon RA (1990). Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Am J Med Genet 37: 443–446. Harvey WP (1968). Clinical aspects of cardiac tumors. Am J Cardiol 21: 328–343. Heath D (1968). Pathology of cardiac tumors. Am J Cardiol 21: 315–327. Herbst M, Wattjes MP, Urbach H et al. (2005). Cerebral embolism from left atrial myxoma leading to cerebral and retinal aneurysms: a case report. AJNR Am J Neuroradiol 26: 666–669. Hirose G, Kosoegawa H, Takado M et al. (1979). Spinal cord ischemia and left atrial myxoma. Arch Neurol 36: 439. Ho YL, Wu CC, Chen WJ et al. (1995). Flow pattern of four pulmonary veins in a case with prolapsing left atrial myxoma. A case report. Angiology 46: 1053–1057.

Horvath A, Bossis I, Giatzakis C et al. (2008). Large deletions of the Prkar1a gene in Carney complex. Clin Cancer Res 14: 388–395. Huston KA, Combs JJ Jr, Lie JT et al. (1978). Left atrial myxoma simulating peripheral vasculitis. Mayo Clin Proc 53: 752–756. Hutton JT (1981). Atrial myxoma as a cause of progressive dementia. Arch Neurol 38: 533. James U, Stanfield MH (1955). A case of fibroma of the left ventricle in a child of 4 years. Arch Dis Child 30: 187–192. Jampol LM, Wong AS, Albert DM (1973). Atrial myxoma and central retinal artery occlusion. Am J Ophthalmol 75: 242–249. Jean WC, Walski-Easton SM, Nussbaum ES (2001). Multiple intracranial aneurysms as delayed complications of an atrial myxoma: case report. Neurosurgery 49: 200–202, discussion 202–203. Joynt RJ, Zimmerman G, Khalifeh R (1965). Cerebral emboli from cardiac tumors. Arch Neurol 12: 84–91. Kandt RS, Gebarski SS, Goetting MG (1985). Tuberous sclerosis with cardiogenic cerebral embolism: magnetic resonance imaging. Neurology 35: 1223–1225. Kasarskis EJ, O’Connor W, Earle G (1988). Embolic stroke from cardiac papillary fibroelastomas. Stroke 19: 1171–1173. Kimbrell OC Jr, Kaasa LJ (1973). Primary intraluminal aortic myxoma with involvement of several vertebrae. JAMA 226: 459–460. Knepper LE, Biller J, Adams HP Jr et al. (1988). Neurologic manifestations of atrial myxoma. A 12-year experience and review. Stroke 19: 1435–1440. Kohno N, Kawakami Y, Hamada CT et al. (2012). Cerebral embolism associated with left atrial myxoma that was treated with thrombolytic therapy. Case Rep Neurol 4: 38–42. Kutalek SP, Panidis IP, Kotler MN et al. (1985). Metastatic tumors of the heart detected by two-dimensional echocardiography. Am Heart J 109: 343–349. Larsson S, Lepore V, Kennergren C (1989). Atrial myxomas: results of 25 years’ experience and review of the literature. Surgery 105: 695–698. Lee VH, Connolly HM, Brown RD Jr (2007). Central nervous system manifestations of cardiac myxoma. Arch Neurol 64: 1115–1120. Lefkovitz NW, Roessmann U, Kori SH (1986). Major cerebral infarction from tumor embolus. Stroke 17: 555–557. Leonhardt ET, Kullenberg KP (1977). Bilateral atrial myxomas with multiple arterial aneurysms – a syndrome mimicking polyarteritis nodosa. Am J Med 62: 792–794. Levine J, Swanson PD (1969). Nonatherosclerotic causes of stroke. Ann Intern Med 70: 807–816. Limper AH, Prakash UB, Kokmen E et al. (1988). Cardiopulmonary metastatic lesions of osteosarcoma and associated cerebral infarction. Mayo Clin Proc 63: 592–595. Liou CW, Chang CS, Chen HJ et al. (1990). Delayed intracranial aneurysm of left atrial myxoma – a case report. Changgeng Yi Xue Za Zhi 13: 231–236. Mahar LJ, Lie JT, Groover RV et al. (1979). Primary cardiac myxosarcoma in a child. Mayo Clin Proc 54: 261–266.

NEUROLOGIC COMPLICATIONS OF CARDIAC TUMORS Maisch B (1990). Immunology of cardiac tumors. Thorac Cardiovasc Surg 38 (Suppl 2): 157–163. Malijevic V, Zdravka P, Ilic I et al. (2011). Cardiac papillary fibroelastoma: source of cerebral embolism treated with intravenous thrombolysis. J Stroke Cerebrovasc Dis 20: 485–487. Mandel MM, Strimel WH Jr (1970). Ventricular myxoma associated with cerebral embolism. JAMA 214: 2154–2156. Markel ML, Waller BF, Armstrong WF (1987). Cardiac myxoma. A review. Medicine (Baltimore) 66: 114–125. Marvasti MA, Obeid AI, Potts JL et al. (1984). Approach in the management of atrial myxoma with long-term follow-up. Ann Thorac Surg 38: 53–58. Mattle HP, Maurer D, Sturzenegger M et al. (1995). Cardiac myxomas: a long term study. J Neurol 242: 689–694. Mcfadden PM, Lacy JR (1987). Intracardiac papillary fibroelastoma: an occult cause of embolic neurologic deficit. Ann Thorac Surg 43: 667–669. Mendoza CE, Rosado MF, Bernal L (2001). The role of interleukin-6 in cases of cardiac myxoma clinical features immunologic abnormalities and a possible role in recurrence. Tex Heart Inst J 28: 3–7. Michael AS, Mikhael MA, Christ M (1989). Myxoma of the heart presenting with recurrent episodes of hemorrhagic cerebral infarction: MR findings. J Comput Assist Tomogr 13: 123–125. Molina JE, Edwards JE, Ward HB (1990). Primary cardiac tumors: experience at the University of Minnesota. Thorac Cardiovasc Surg 38 (Suppl 2): 183–191. Molinari GF, Smith L, Goldstein MN et al. (1973). Pathogenesis of cerebral mycotic aneurysms. Neurology 23: 325–332. Moskowitz MA, Rosenbaum AE, Tyler HR (1974). Angiographically monitored resolution of cerebral mycotic aneurysms. Neurology 24: 1103–1108. Mugge A, Daniel WG, Haverich A et al. (1991). Diagnosis of noninfective cardiac mass lesions by two-dimensional echocardiography comparison of the transthoracic and transesophageal approaches. Circulation 83: 70–78. Nagy CD, Levy M, Mulhearn TJ et al. (2009). Safe and effective intravenous thrombolysis for acute ischemic stroke caused by left atrial myxoma. J Stroke Cerebrovasc Dis 18: 398–402. New PF (1970). Myxomatous emboli in brain. N Engl J Med 282: 396. Ngaage DL, Mullany CJ, Daly RC et al. (2005). Surgical treatment of cardiac papillary fibroelastoma: a single center experience with eighty-eight patients. Ann Thorac Surg 80: 1712–1718. Oguz KK, Firat MM, Cila A (2001). Fusiform aneurysms detected 5 years after removal of an atrial myxoma. Neuroradiology 43: 990–992. Olmsted WW, Mcgee TP (1977). The pathogenesis of peripheral aneurysms of the central nervous system: a subject review from the AFIP. Radiology 123: 661–666. Ong C-T, Chang R-Y (2011). Intravenous thrombolysis of occlusion in the middle cerebral and retinal arteries from presumed ventricular myxoma. Stroke Res Treat 2010, Article

221

Id 735057, 3 pages, 2011. http://dx.doi.org/104061/2011/ 735057. Pinede L, Duhaut P, Loire R (2001). Clinical presentation of left atrial cardiac myxoma a series of 112 consecutive cases. Medicine (Baltimore) 80: 159–172. Price DL, Harris JL, New PF et al. (1970). Cardiac myxoma a clinicopathologic and angiographic study. Arch Neurol 23: 558–567. Prichard RW (1951). Tumors of the heart; review of the subject and report of 150 cases. AMA Arch Pathol 51: 98–128. Rankin LI, DeSousa AL (1978). Metastatic atrial myxoma presenting as intracranial mass. Chest 74: 451–452. Read RC, White HJ, Murphy ML et al. (1974). The malignant potentiality of left atrial myxoma. J Thorac Cardiovasc Surg 68: 857–868. Reynen K (1995). Cardiac myxomas. N Engl J Med 333: 1610–1617. Roberts WC (1997). Primary and secondary neoplasms of the heart. Am J Cardiol 80: 671–682. Rodriguez FJ, Brown RD, Mohr JP et al. (2006). Embolic atrial myxoma with neoplastic aneurysm formation and haemorrhage: a diagnostic challenge. Neuropathol Appl Neurobiol 32: 213–216. Roeltgen DP, Weimer GR, Patterson LF (1981). Delayed neurologic complications of left atrial myxoma. Neurology 31: 8–13. Roh MS, Huh GY, Jeong JS et al. (2001). Left atrial myxosarcoma with systemic metastasis: a case report. J Korean Med Sci 16: 111–114. Rubens F, Goldstein W, Hickey N et al. (1989). Hoarseness secondary to left atrial myxoma. Chest 95: 1139–1140. Sabolek M, Bachus-Banaschak K, Bachus R et al. (2005). Multiple cerebral aneurysms as delayed complication of left cardiac myxoma: a case report and review. Acta Neurol Scand 111: 345–350. Sandok BA, Von Estorff I, Giuliani ER (1980). CNS embolism due to atrial myxoma: clinical features and diagnosis. Arch Neurol 37: 485–488. Seigle JM, Caputy AJ, Manz HJ et al. (1987). Multiple oncotic intracranial aneurysms and cardiac metastasis from choriocarcinoma: case report and review of the literature. Neurosurgery 20: 39–42. Semple PL, Denny L, Coughlan M et al. (2004). The role of neurosurgery in the treatment of cerebral metastases from choriocarcinoma: a report of two cases. Int J Gynecol Cancer 14: 157–161. Sheppard MN, Mohiaddin R (2010). Tumors of the heart future. Cardiol 6: 181–193. Shimono T, Makino S, Kanamori Y et al. (1995). Left atrial myxomas using gross anatomic tumor types to determine clinical features and coronary angiographic findings. Chest 107: 674–679. Silverman J, Olwin JS, Graettinger JS (1962). Cardiac myxomas with systemic embolization review of the literature and report of a case. Circulation 26: 99–103. Stehbens W (1972). Pathology of the Cerebral Blood Vessels. CV Mosby, St Louis.

222

D. ROELTGEN AND C.S. KIDWELL

Steinke WE, Perry LW, Gold HR et al. (1972). Left atrial myxoma in a child. Pediatrics 49: 580–589. Steinmetz EF, Calanchini PR, Aguilar MJ (1973). Left atrial myxoma as a neurological problem: a case report and review. Stroke 4: 451–458. Stoane L, Allen JH Jr, Collins HA (1966). Radiologic observations in cerebral embolization from left heart myxomas. Radiology 87: 262–266. Stratakis CA, Kirschner LS, Carney JA (2001). Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 86: 4041–4046. Sun JP, Asher CR, Yang XS et al. (2001). Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective and prospective study in 162 patients. Circulation 103: 2687–2693. Swartz MF, Lutz CJ, Chandan VS et al. (2006). Atrial myxomas: pathologic types tumor location and presenting symptoms. J Card Surg 21: 435–440. Telman G, Mesica O, Kouperberg E et al. (2010). Microemboli monitoring by trans-cranial Doppler in patient with acute cardioemboliogenic stroke due to atrial myxoma. Neurol Int 2: e5.

Tonz M, Laske A, Carrel T et al. (1992). Convulsions hemiparesis and central retinal artery occlusion due to left atrial myxoma in child. Eur J Pediatr 151: 652–654. Tschirkov A, Michev B, Topalov V et al. (1990). Incidences and surgical aspects of cardiac myxomas in Bulgaria. Thorac Cardiovasc Surg 38 (Suppl 2): 196–200. Walker MT, Kilani RK, Toye LR et al. (2003). Central and peripheral fusiform aneurysms six years after left atrial myxoma resection. J Neurol Neurosurg Psychiatry 74: 281–282. Wolman L, Bradshaw P (1967). Spinal cord embolism. J Neurol Neurosurg Psychiatry 30: 446–454. Yarnell PR, Spann JF Jr, Dougherty J et al. (1971). Episodic central nervous system ischemia of undetermined cause: relation to occult left atrial myxoma. Stroke 2: 35–40. Yuehua L, Jing G, Kai F et al. (2003). Left atrial myxoma presenting with erythematous macules and loss of memory. Clin Exp Dermatol 28: 383–386. Yufe R, Karpati G, Carpenter S (1976). Cardiac myxoma: a diagnostic challenge for the neurologist. Neurology 26: 1060–1065. Zisbrod Z, Rose DM, Jacobowitz IJ et al. (1987). Results of open heart surgery in patients with recent cardiogenic embolic stroke and central nervous system dysfunction. Circulation 76: V109–V112.