Developmental Malformations
Vein of Galen malformations
Sep. 22, 2024
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Atrial myxoma, the most common intracardiac tumor in adults, may cause cardiac dysfunction embolic stroke and systemic manifestations that mimic infective, immunologic, and malignant diseases. Several cutaneous syndromes associated may facilitate timely recognition. Its protean clinical manifestations make the clinical diagnosis difficult. Approximately 60% of all tumors are found by echocardiogram. The definitive treatment is surgical excision. Potentially life-threatening, atrial myxomas require prompt diagnosis and urgent treatment.
• Atrial myxoma is the most common intracardiac tumor. Although benign, its central location often results in significant morbidity and mortality. | |
• Myxomas have a wide variety of cardiac, embolic, and systemic manifestations, including paraneoplastic syndromes, mediated by numerous humoral factors. | |
• No guidelines for acute ischemic stroke caused by atrial myxoma embolism treatment have been published. | |
• Intravenous thrombolysis within a 3-hour window was successful in patients with acute stroke caused by myxoma. | |
• Hemorrhagic complications after thrombolysis may be due to recent, undiagnosed infarcts or aneurysms. | |
• Intra-arterial recanalization is effective in patients with large artery occlusion due to myxoma embolization. |
Left atrial myxoma was first described in the 19th century (76) and was diagnosed by angiocardiography in 1952 (79). The first surgical excision occurred three years later (32).
The first nonembolic dermatologic manifestation of atrial myxoma was described in 1973 as the nevus, atrial myxoma, myxoid neurofibromata, and ephelides or endocrine hyperactivity (NAME syndrome). Later, it was described as the lentigines, atrial myxoma, and blue nevi (LAMB syndrome); Carney complex (atrial myxoma associated with multiple neoplasia lentigines) was also reported (52). Sneddon syndrome, which commonly presents with a livedo-type rash and diffuse cerebrovascular disease, has also been associated with atrial myxoma (150).
The following are the three ways in which atrial myxomas manifest:
• embolization | |
• cardiac and obstructive symptoms | |
• syndromes, including paraneoplastic |
Due to its protean manifestations, diagnosis of atrial myxoma may take a long time to recognize, up to 126 months in one series (125). Patients may present with fatigue, shortness of breath, fever of unknown origin, and various embolic symptoms (25).
Embolization. Embolic tumor fragments or thrombi may occur in 30% to 40% of patients with atrial myxomas. Embolization can occur to any organ leading to failure, depending on the myxoma location (135; 127). In a single center study encompassing 93 patients with atrial myxoma, predictors of embolization were atrial fibrillation, myxoma diameter larger than 4.6 cm, enlarged left atrium, and irregular tumor surface (69). Additionally, in a systematic review and metanalysis including 12 studies that enrolled 1814 patients, New York Heart Association (NYHA) heart failure class I and II, hypertension, atypical tumor location, narrow base of tumor, and increased fibrinogen were significant risk factors of embolism (93).
Cerebrovascular disease. Approximately 45% of patients with atrial myxoma experience neurologic deficits (79). Myxomas cause 0.4% of strokes, either ischemic or hemorrhagic. Most strokes occur by the age of 50 (125).
Transient ischemic attack is the most common initial neurologic manifestation of atrial myxoma (04). Global transient amnesia may also be triggered by atrial myxoma (155).
Strokes are often recurrent. Brain infarcts can also accrue asymptomatically resulting in multi-infarct dementia (74; 61). Alternatively, they may present with rapid multi-organ failure and death due to embolic showers or even a single massive embolic, potentially fatal stroke (20; 16). Monocular blindness may be caused by ocular embolism (166). Paraplegia may result from embolism to the anterior spinal cord artery or abdominal aorta (58; 174).
Aneurysms result from the mural invasion of the myxomatous emboli, which typically lodge in the distal branches of middle cerebral arteries. The aneurysms may be multiple and bilateral (22; 129; 33; 103). Approximately 90% of aneurysms are fusiform; the remaining are saccular (142).
Cardiovascular disease. Left atrial myxoma may embolize into the coronary, causing myocardial infarction (119). Right atrial myxoma embolization results in pulmonary embolism, right heart failure, and ascites (121; 67; 96).
Pulmonary embolism is usually caused by right atrial myxoma and may be the initial presentation of myxoma (94; 31). Even left atrial myxoma can present as pulmonary embolism. Because there was no shunt, the most likely cause was a hypercoagulable state promoted by myxoma (133).
Cutaneous embolization cause acral erythematous papules, petechiae, digital cyanosis, splinter hemorrhages, livedo reticularis, and Raynaud phenomenon (110; 52). Constitutional symptoms associated with a purpuric rash of unknown origin should prompt evaluation for atrial myxoma (95).
Gastrointestinal manifestations depend on the embolism location. Abdominal pain aggravated by eating or drinking and associated with lactic acidosis suggest small bowel ischemia (63). Small bowel obstruction may also occur (181). Right atrial myxoma may cause Budd-Chiari syndrome (73).
Limb ischemia may occur due to systemic embolization and requires immediate revascularization (188).
Cardiac and obstructive symptoms. The cardiac symptoms correlate with the tumor location, size, and mobility (50). Very rarely, myxoma is found in both atria.
Cardiac structural complications include mitral valve regurgitation (75), mitral valve obstruction with congestive heart failure (125), left ventricular failure (38; 96), and hypertrophic cardiomyopathy (71). A steal phenomenon in the large anterior descending artery was also described (159).
Cardiac arrhythmias like atrial fibrillation or paroxysmal supraventricular tachycardia may be triggered by atrial myxoma (21; 152).
Endocarditis is suggested by cardiac vegetations with positive cultures for histoplasma and Streptococcus sanguinis (45; 87; 137). Hypercoagulability in patients with myxomas was associated with elevated IL-6 and IL-8 (14; 15).
Compression by a giant myxoma may lead to dysphagia, Horner syndrome (anhidrosis, partial ptosis, and miosis), dyspnea, and cough-syncope syndrome (51; 105; 40).
Sudden death may occur due to obstruction of the intracardiac blood flow (78). Simultaneous embolization of the heart and brain circulation may lead to fatal cardiac arrest and stroke (66).
Auscultatory findings are associated with mitral valve dysfunction caused by larger lesions (50). A murmur suggesting mitral stenosis is heard in 54% (125). The classic "tumor plop," an extra heart sound heard 80 to 150 milliseconds after the second heart sound, occurs in approximately one third of the patients (135; 50).
Syndromes
NAME syndrome. The acronym NAME stood initially for nevi, atrial myxoma, myxoid neurofibromata, and ephelides (07). Later, ephelides was replaced by endocrine overactivity due to increased insulin-like growth factors level (185). Transmission is usually autosomal dominant, but X-linked dominant transmission may also occur (82).
LAMB syndrome. LAMB syndrome is characterized by mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi (136).
Carney complex is an autosomal dominant multiple neoplasia associated with myxomas, mottled cutaneous pigmentation, endocrine dysfunction, and nonmyxomatous extracardiac tumors (eg, breast fibroadenomas in women and testis Sertoli-cell tumors in men) (163; 184). The Carney complex, both familial and sporadic, is associated with mutation of the PRKAR1A gene (162; 17; 160). Cutaneous embolism may result in livedoid macules (110). Cushing syndrome and acromegaly are also associated with Carney complex (176).
Paraneoplastic syndromes. Paraneoplastic syndromes associated with myxomas may occur due to increased levels of humoral mediators. Several categories of paraneoplastic syndromes were described: constitutional symptoms, vasculitis/vasculopathy, hematological, constitutional, and other, uncommon manifestations (158). These manifestations resolve after tumor resection.
Constitutional symptoms like fever, fatigue, myalgia, arthralgia, and weight loss occur in up to 90% of atrial myxoma cases (85; 125). These symptoms mimic rheumatological disease and may be masked by nonsteroidal anti-inflammatories (18).
Vasculitis or vasculopathy syndromes include Raynaud phenomenon (101), livedo reticularis (89), malar erythematous violaceous eruption with peripheral cyanosis, splinter hemorrhages, serpiginous, annular, violaceous, and nonblanching lesions of fingertips (60), medium vessel vasculitis, erythema and petechiae of hands and feet, acral erythematous papular eruption (122), and biphasic changes in color of fingertips on cold exposure (23).
Hematologic manifestations include anemia, leukocytosis, increased acute phase reactants (85), thrombocytopenia (178), antiphospholipid antibodies (146), depletion of factor VII (42), systemic AL amyloidosis (106), and generalized AA amyloidosis (111).
Uncommon manifestations include iridocyclitis (Plewan et el 1996), worsening of coexistent systemic lupus (186), acute pancreatitis (183), acute renal failure (55), proteinuria (70), painful peripheral sensory neuropathy (147; 104), mimicking of polyarteritis nodosa (148), and mediastinal lymphadenopathy (168).
Intracerebral or subarachnoid hemorrhage may complicate the development of cerebral aneurysms. The aneurysms may regress and resolve after myxoma resection (33) but can also enlarge or even appear many years later (141; 179; 68).
Metastases to the vasculature walls may cause occlusion and infarction (35). They may penetrate through the vessel wall to form intra-axial metastases (11). Cerebral metastases may be diagnosed several years after resection of myxoma (30).
Recurrent embolization may occur despite anticoagulation (79).
Endocarditis due to infection of atrial myxoma may occur rarely (170).
The recurrence rate of myxoma is 1% to 3% in the sporadic cases, is often due to incomplete resection (100; 180). Recurrence may be up to 25% in the familial cases.
Vanished myxoma by systemic embolization was described (34).
Malignant transformation can rarely occur (145; 92).
A 56-year-old Caucasian woman with history of mild static encephalopathy developed acute right hemiparesis and dysarthria. She was afebrile, had a blood pressure of 123/71, and pulse of 79. General exam was remarkable for the lack of cervical bruits and a 2/6 diastolic rumble consistent with mitral stenosis. Peripheral pulses were intact. Neurologic exam showed dysarthria and mild right hemiparesis, worse in the arm than the leg. Routine laboratory evaluation, including complete blood count, chemistry panel, and coagulation studies, was significant for a microcytic anemia and elevated platelet count of 499,000/µL. EKG showed normal sinus rhythm, with chest x-ray showing minimal prominence of pulmonary vascular markings and mild cardiomegaly. Noncontrast head CT was normal. MRI of the brain showed gyral contrast enhancement on T1-weighted imaging in the left parieto-occipital region. Carotid artery ultrasound was normal. Transthoracic echocardiography showed a left atrial mass measuring 3.5 cm by 8.7 cm. The left atrial diameter was 4.6 cm (1.9 to 4.0 cm). The mass caused mitral valve obstruction. The attachment was not visualized. Mild pulmonary hypertension was also noted. She underwent open resection of the mass. A large gelatinous mass was found to be attached at the level of the superior portion of the septum, with a second point of attachment inferiorly at the level of the inferior vena cava. The mass was excised along with the underlying septum, creating an atrial septal defect, which was repaired. Transesophageal echocardiography was used to check mitral flow. Final pathology demonstrated an atrial myxoma. The patient did well postoperatively and was discharged with some improvement in her neurologic symptoms.
• Myxomas originate from mesenchymal cells. | |
• Most cases of atrial myxoma are sporadic. | |
• Familial cases have autosomal dominant transmission. | |
• Neuromodulators like IL-6 are elevated in patients with constitutional symptoms and usually decrease after resection. |
Most cases of atrial myxoma are sporadic. The familial cases are autosomal dominant with variability in the phenotype (135) and tend to present earlier than the sporadic ones. Most cardiac myxomas appear in the left atrium in the region of the fossa ovalis of the interatrial septum (135). Macroscopically, myxoma is a solid mass, pedunculated, shiny, and irregular (153); however, myxoma may also be cystic (120).
Myxomas originate from mesenchymal cells capable of endothelial differentiation surrounded by a myxoid extracellular matrix rich in proteoglycans (135; 144). Deriving from adult developmental remnants (116), myxoma consists of a highly mucinous myxoid stroma containing plasma cells, mast cells, and stromal stellate cells. Types I, III, and IV collagen are also found within the tumor. The surface is covered by myxoma cells and endothelium (84). Overexpression of matrix metalloproteinase contributes to degradation of the extracellular matrix, increasing the risk of embolism (117).
The constitutional symptoms are mediated by interleukin-6 (IL-6) (151) in up to 74% of cases (01). IL-6 is secreted by the immature mesenchyme cells of myxomas (167; 165).
Resection often leads to normalization of serum levels of IL-6 and resolution of the symptoms (102). Other modulators of the constitutional symptoms include IL-4, IL-12, p70, interferon gamma, and tumor necrosis factor alpha (90).
Tumor size is influenced by basic fibroblast growth factor (FGF), IL-6, monocyte chemotactic protein (MCP-1), thymidine phosphorylase TP-2, chemokine receptor 2 (CCR-2), and vascular endothelial growth factor (VEGF). IL-8 was associated with stroke and myocardial infarction and IL-6 with cerebral aneurysms (142; 158; 41).
Mutation of the tumor suppressor PRKAR1-alpha gene on chromosome 17q22-24 has been identified in the Carney complex (77; 184). A variant of the Carney complex, the trismus–pseudocamptodactyly syndrome with cardiac myxoma, has a missense mutation (Arg674Gln) in the perinatal myosin heavy-chain gene (MYH8) on chromosome 17p12–p13.1 (175). Screening for this mutation identifies family members at high risk of developing myxomas (10; 06). The most commonly involved regions in sporadic cases are 12p1 and 17p1. Dicentric chromosomes and telomeric associations are the most frequent genetic abnormalities (37).
Myxomas associated with Carney complex may reemerge after removal and cause heart dysfunction. The oncogene c-MYC, cancer-associated metabolic transcriptional factor HIF-1α, and the epithelial-mesenchyma transition protein vimentin could potentially detect malignancy in myxoma (118).
No association of myxoma with either human papillomavirus (HPV) or Epstein-Barr virus was found (27).
• Myxoma is the most common heart tumor in adults. | |
• Atrial myxoma may occur in all ages. | |
• Familial cases may occur as part of a syndrome. |
The incidence of atrial myxomas found at autopsy is 0.03% (21). Although it is the most common cardiac primary tumor in adults, myxomas represent only 10% of the primary intracardiac tumors in children (59). Overall, myxomas represent 50% of all primary cardiac tumors (153). Approximately 7% of myxomas are familial history or part of a syndrome (100). Atrial myxomas occur at all ages, with a peak between the ages of 30 and 60 years (128; 135). There is a predilection for women, with reported ratios ranging from 2:1 to 5.6:1 (128). Sporadic cases tend to be older than 40 years of age, have single myxomas in the typical location, and lack the other features of a syndrome.
• Screening plays an important role in early detection of atrial myxomas. | |
• Semiannual screening echocardiography is used to detect recurrence after resection. | |
• Recurrence after surgery is usually due to incomplete resection. |
Prevention of stroke related to atrial myxomas extends to screening for recurrences as well as early detection of affected family members. Approximately 7% of atrial myxomas have an autosomal dominant transmission. The chance to develop atrial myxoma in a first degree relative of a patient with myxoma is approximately 3.5%.
Recurrence occurring in 1% to 3% of cases is often due to incomplete resection of the primary tumor (100; 180). Familial tumors may recur in up to 25% of cases, discrete from the original site, and even at multiple sites (157). Semiannual echocardiography is recommended in all patients, especially in those with Carney complex (135; 10).
Given the various manifestations of atrial myxomas, the differential diagnosis is wide. Collagen disease or vasculitis is suggested by prominent and chronic constitutional symptoms.
Systemic vasculitis was thought to cause painless foot drop, peripheral vascular obstruction, decreased complement, and positive double stranded DNA testing in a patient with atrial myxoma (23).
Polyarteritis nodosa with muscle involvement was mimicked by myxoma in a case report. Discovery of arterial aneurysms raised the suspicion of myxoma, which was confirmed by biopsy (19).
Large vessel vasculitis may be diagnosed if myxoma is associated with decreased pulses (156; 44).
Granulomatosis with polyangiitis (former Wegener granulomatosis) is a small to medium size vasculitis of the respiratory tract and kidneys associated with granuloma. A few cases may involve the heart and may be mistaken for atrial myxoma (57).
Cardiologic conditions can be simulated by atrial myxoma, mitral stenosis, endocarditis, rheumatic disease, intracardiac thrombi, and other intracardiac tumors including cardiac lymphoma (132). Biopsy may be needed to differentiate myxoma from thrombus in the left atrial appendage (143).
Mimics of myxoma should always be considered. Approximately 67% of masses diagnosed as myxoma by echocardiogram are confirmed by biopsy. Other lesions mimicking myxoma are thrombus, metastasis, leukemia, papillary fibroelastoma, hemangioma, or granuloma (49; 88).
The following are key tests and procedures for diagnosis of atrial myxoma and its complications:
• Blood tests: CBC, ESR, CRP, antinuclear antibodies, rheumatoid factor, and blood cultures |
Because of its multisystem involvement, the diagnostic workup is guided by the suspicion of atrial myxoma and its complications.
Laboratory. The routine studies are helpful, but not diagnostic. Anemia is present in 40% and elevated erythrocyte sedimentation in 55% of patients (161). Elevated C-reactive protein, thrombocytosis or thrombocytopenia, serum globulins, antinuclear antibodies, and rheumatoid factor may suggest an infectious or autoimmune condition (135; 59). Blood cultures are needed to exclude infection (134). Streptococci and staphylococci are the most frequent organisms found in blood culture (53; 173; 65). However, histoplasma capsulatum has also been reported (08).
MRI of the brain. The deep white matter lesions seen on MRI mimic multiple sclerosis or metastatic lesions (112; 131; 182). Gadolinium brain MRI may detect fusiform aneurysms (113). The resolution of MR angiography is approximately 3 mm and is inferior to that of digital subtraction angiography (02).
ECG. ECG changes include left atrial enlargement, nonspecific T-wave and ST-segment abnormalities, and chronic as well as paroxysmal atrial fibrillation (21).
Chest x-ray. Chest x-ray may reveal left atrial enlargement, blood diversion to upper lobes, left ventricular enlargement, and calcification of the myxoma (161).
Transthoracic echocardiography is the diagnostic modality of first choice. 3-D echography helps determine the origin of the stalk and characterize the heterogeneity of the myxoma (187). Echography has a false-negative rate of 21% for detecting atrial masses, whereas transesophageal echocardiography (TEE) has a sensitivity of 100% for atrial myxoma (177). TEE better localizes the area of attachment, information needed for surgical planning (169).
Myxoma appears as a smooth globular surface, sometimes irregular and friable with a narrow stalk. Echolucent areas represent hemorrhage or necrosis (50). Echolucency helps distinguish myxomas from thrombi or vegetations. Larger size of myxoma correlates with constitutional, hemodynamic, and obstructive symptoms, whereas smaller size correlates with embolic phenomena (46; 50). Polypoid appearance also correlates with embolic phenomena (54).
Cardiac MRI with gadolinium can delineate the tumor size, attachment, and mobility, and help elucidate some histological characteristics (99; 03). An atypical appearance is that of a hypervascular mass (05). However, cardiac MRI is less sensitive than TEE (140).
Noncontrast chest CT helps detection of atrial myxomas (154) and preoperative evaluation (43). Cardiac contrast-enhanced CT may differentiate atrial myxoma from other intracardiac lesions like thrombi, fibroelastomas, or metastatic tumors and is helpful for preoperative assessment (24; 56).
FDG-PET/CT showing mildly hypermetabolic hypodense area in the atrium is useful for detecting myxomas in patients with systemic symptoms (48) or pulmonary embolism (91).
Coronary angiography should be performed in most, if not all, patients with atrial myxoma; a tumor blush suggests coronary artery supply (139). CT coronary angiography also helps to distinguish myxomas from thrombi (149). Coexistent coronary artery disease may require both coronary artery bypass grafting and myxoma resection (39).
• There is no medical therapy for myxoma. | |
• Anticoagulation may not be protective. | |
• Surgical resection is the definitive treatment. | |
• After resection, screening for recurrence with echocardiogram is needed. | |
• Intravenous tPA may be effective against embolic stroke. | |
• Large vessel occlusion may benefit from endovascular neurointervention. |
No medical therapy exists for atrial myxomas. Anticoagulation may not be protective and may be hazardous in the event of aneurysm formation. Early surgical resection is the definitive treatment as it prevents recurrent embolization (124; 64). Cardiac arrhythmia, occurring in 26% of patients, is the most common postoperative complication. Persistent bradycardia requires pacemaker placement in less than 2% of cases (125). Postoperative mortality ranges between 2.2% to 3.5% (86; 125).
Total robotic resection is relatively safe and causes minimal cosmetic complications (47; 114). Multiple aneurysms may be approached with a combination of endovascular and open surgical treatment (123). Minimally- invasive procedures make possible removal of increasingly large lesions (29).
Transthoracic echocardiography is used after resection to screen for recurrence (128). Most recurrences occur within the first two years, but there may be a delay up to 12 years (50). Addition of cryoablation to resection for right atrial myxoma helps preserve the cardiac conduction system (97). Percutaneous ablation with retrieval is another option (81).
Treatment of acute ischemic stroke caused by atrial myxoma is guided by a few case reports. In most instances, ischemic stroke is the first manifestation of atrial myxoma. Intravenous recombinant tissue plasminogen activator (IV rt-PA), the only FDA-approved medication for acute stroke treatment, was used with variable success (62; 108; 115; 164; 36). Significant improvement after endovascular thrombectomy was seen even in absence of intravenous tPA (172). However, the outcome is better outcome with earlier recanalization (98).
Because of the short therapeutic window, hemorrhagic transformation and subarachnoid hemorrhages are the most feared complications (26; 28). Bleeding may be associated with occult tumor emboli, microaneurysms, or asymptomatic ischemic infarcts with onset beyond the therapeutic window. Despite hemorrhagic conversion, some patients may still improve after thrombolysis.
Large vessel occlusions (LVO) may occasionally be opened with intravenous thrombolysis (72). However, most large vessel occlusions fail to open with intravenous therapy alone (80). Several case reports showed benefit from endovascular thrombectomy (09; 171; 13). Additionally, cerebral angiography helps exclude pseudoaneurysm formation and allows injection of intra-arterial thrombolytic (12).
The treatment of atrial myxoma during pregnancy is dictated by both the maternal and fetal status. Tumor excision during pregnancy, when causing mitral valve obstruction and cerebral emboli, has been reported (130; 83). If asymptomatic, however, it may be resected postpartum (109; 83).
Few specific reports exist regarding anesthesia for myxoma excision. However, hypotension and hypoxemia is reported intraoperatively. It is recommended that caution is taken with agents that may lower systemic vascular resistance or cause venous dilatation. Care should also be taken in positioning the patient, as this may affect the dynamics of tumor obstruction (138; 107).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Adrian Marchidann MD
Dr. Marchidann of Kings County Hospital has no relevant financial relationships to disclose.
See ProfileSteven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.
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