Stroke & Vascular Disorders
Basal ganglia hemorrhage
Aug. 27, 2021
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Atrial myxoma is the most common intracardiac tumor in adults. Cardiac function may suffer, and embolization may cause stroke. Additionally, myxoma may mimic infective, immunologic, and malignant diseases. Several cutaneous syndromes have been described that 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.
• Atrial myxoma is the most common intracardiac tumor. Although benign by histopathologic criteria, its central location may result in a fatal outcome if not treated in a timely manner.
• 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.
• The risk of hemorrhagic transformation after thrombolysis may be increased by 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 (70). The first antemortem diagnosis, by angiocardiography, was in 1952 (72), and the first surgical excision documented 3 years later (29).
The first nonembolic dermatologic manifestation of atrial myxomas was described in 1973. The nevus, atrial myxoma, myxoid neurofibromata, and ephelides or endocrine hyperactivity (NAME syndrome); lentigines, atrial myxoma, and blue nevi (LAMB syndrome); and Carney complex (atrial myxoma associated with multiple neoplasia lentigines) were first reported in 1980, 1984, and 1985, respectively (48). Sneddon syndrome, which commonly presents with a livedo-type rash and diffuse cerebrovascular disease, has also been associated with atrial myxoma (137).
The following are the 3 ways in which atrial myxomas manifest:
• cardiac and obstructive symptoms
• syndromes, including paraneoplastic
Due to its protean manifestations, diagnosis may take a long time to recognize, up to 126 months in 1 series (114).
Embolization. Tumor fragments or thrombi may embolize in 30% to 40% of patients with atrial myxomas. Approximately 45% of patients with atrial myxoma experience neurologic deficits (72). Myxomas cause 0.4% of strokes, either ischemic or hemorrhagic. Most strokes occur by the age of 50 (114).
Transient ischemic attack is the most common initial neurologic manifestation of atrial myxoma (04). Strokes often recur. Brain infarcts can also accrue asymptomatically (68), resulting in multi-infarct dementia (56). Alternatively, they may present with a single massive embolic potentially fatal stroke (15) or with rapid multi-organ failure and death due to embolic showers (19).
Aneurysms are formed by mural invasion of the myxomatous emboli. They may be multiple and are located typically in the distal branches of middle cerebral arteries (21; 30). Approximately 90% of aneurysms are fusiform; the remaining ones are saccular (130).
Isolated retinal or choroidal and ophthalmic artery infarctions may lead to monocular blindness (152). Paraplegia may result from embolism either to the anterior spinal cord artery (53) or abdominal aorta (160). Embolization to bone skin, coronary, renal, and visceral arteries also occurs (123; 116). The cutaneous manifestations of embolism include acral erythematous papules, petechiae, digital cyanosis, splinter hemorrhages, livedo reticularis, and Raynaud phenomenon (99; 48). If abdominal pain aggravated by eating or drinking is associated with lactic acidosis, small bowel ischemia should be suspected (58). Small bowel obstruction may also occur (166).
Embolization predictors are diameter larger than 4.6 cm, enlarged left atrium, and irregular tumor surface (63).
Cardiac and obstructive symptoms. The cardiac symptoms correlate with the location, size of the tumor, and its mobility (46). Very rarely, atrial myxoma may be found in both atria (Schwartz and Braun 1972).
Mitral valve regurgitation (69), mitral valve obstruction with congestive heart failure (114), left ventricular failure (35), hypertrophic cardiomyopathy (65) and myocardial infarction (108) have been described in patients with atrial myxoma. A steal phenomenon in the large anterior descending artery was also described (145).
Right atrial myxoma embolization results in pulmonary embolism, right heart failure, and ascites (110; 61). Another rare complication of right atrial myxoma is the Budd-Chiari syndrome (67).
Auscultatory findings associated with mitral valve disease occur more commonly in larger myxomas and may be associated with cardiac and systemic symptoms (46). A murmur suggesting mitral stenosis is heard in 54% (114). 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 (123; 46).
Endocarditis is suggested by cardiac vegetations with positive cultures for histoplasma and Streptococcus sanguinis (41; 80; 125). Hypercoagulability in patients with myxomas may be due to elevated IL-6 and IL-8 (13; 14).
Cardiac arrhythmia triggered by atrial myxoma manifests as either atrial fibrillation or paroxysmal supraventricular tachycardia (20; 139).
Compressive symptoms by giant myxomas include dysphagia, Horner syndrome (anhidrosis, partial ptosis, and miosis), and dyspnea (47; 94).
Syndromes. Several syndromes include atrial myxomas. The acronym NAME stood initially for nevi, atrial myxoma, myxoid neurofibromata, and ephelides (06). Later, ephelides was replaced by endocrine overactivity caused by the increased insulin-like growth factors level (170). Transmission is usually autosomal dominant, but X-linked dominant transmission may also occur (75). The LAMB syndrome is characterized by mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi (124).
The Carney complex, an autosomal dominant multiple neoplasia, is characterized by myxomas, mottled cutaneous pigmentation, endocrine dysfunction, and nonmyxomatous extracardiac tumors (eg, breast fibroadenomas in women and testis Sertoli-cell tumors in men) (149; 169). The Carney complex, both familial and sporadic, is associated with mutation of the PRKAR1A gene (148; 16; 146). Cutaneous embolism may result in livedoid macules (99). Cushing syndrome and acromegaly are also associated with Carney complex (162).
Paraneoplastic syndromes. Many paraneoplastic syndromes are associated with increased levels of several humoral mediators. The clinical manifestations and laboratory abnormalities resolve after tumor resection. The paraneoplastic syndromes are classified in several categories: vasculitis/vasculopathy, hematological, constitutional, and other, uncommon manifestations (144).
The vascular manifestations include Raynaud phenomenon (90), livedo reticularis (82), malar erythematous violaceous eruption with peripheral cyanosis, splinter hemorrhages, serpiginous, annular, violaceous, and nonblanching lesions of fingertips (55), medium vessel vasculitis, erythema and petechiae of hands and feet, acral erythematous papular eruption (111), and biphasic changes in color of fingertips on cold exposure (22).
The hematologic manifestations include anemia, leukocytosis, increased acute phase reactants (78), antiphospholipid antibodies (134), depletion of factor VII (38), systemic AL amyloidosis (95), and generalized AA amyloidosis (100).
Some form of constitutional symptom-like fever, weight loss (78), fatigue, myalgia, or arthralgia occurs in up to 90% of cases of atrial myxoma (114). Nonsteroidal anti-inflammatory agents may mask the systemic symptoms related to atrial myxomas (17).
Other case reports of uncommon manifestations include iridocyclitis (Plewan et el 1996), worsening of coexistent systemic lupus (171), acute pancreatitis (168), acute renal failure (51), proteinuria (64), painful peripheral sensory neuropathy (135; 93), mimicking of polyarteritis nodosa (136), and mediastinal lymphadenopathy that resolved after myxoma resection was reported (154).
Delayed intracerebral or subarachnoid hemorrhage is a complication of cerebral aneurysms. These are usually multiple, bilateral, and fusiform, and form on the distal arteries (118; 92). They may regress and resolve after myxoma resection (30) but can also enlarge or even appear many years later (129; 164; 62).
Metastases to the vessel walls may cause delayed vessel occlusion and infarction (32). They may penetrate through the vessel wall to form intra-axial metastases (10). Cerebral metastases may be diagnosed several years after resection of myxoma (28).
Recurrent embolization may occur despite anticoagulation (72). Rarely, the atrial myxoma may become infected, presenting as endocarditis (156).
The recurrence rate of myxoma is 1% to 3% in the sporadic cases, is often due to incomplete resection (89; 165), and may be up to 25% in the familial cases.
Vanishing myxoma was described (31) as was malignant transformation (133; 85).
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 increased at 4.6 cm (1.9 to 4.0 cm). The mass caused mitral valve obstruction. The mass' attachment was not able to be 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.
Most cases of atrial myxoma are sporadic. The familial cases are autosomal dominant with variability in the phenotype (123) 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 (123). Macroscopically, myxoma is a solid mass, pedunculated, shiny, and irregular (140); however, myxoma may be cystic (109).
Myxomas originate from mesenchymal cells capable of endothelial differentiation surrounded by a myxoid extracellular matrix rich in proteoglycans (123; 132). Deriving from adult developmental remnants (105), 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 (77). Overexpression of matrix metalloproteinase contributes to degradation of the extracellular matrix, increasing the risk of embolism (106).
The constitutional symptoms are mediated by interleukin-6 (IL-6) (138) in up to 74% of cases (01). IL-6 is secreted by the immature mesenchyme cells of myxomas (153; 151).
Tumor resection often leads to normalization of serum levels of IL-6 and resolution of the symptoms (91). Other modulators of the constitutional symptoms include IL-4, IL-12, p70, interferon gamma, and tumor necrosis factor alpha (83).
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 (144) and IL-6 with cerebral aneurysms (130; 37).
Mutation of the tumor suppressor PRKAR1-alpha gene on chromosome 17q22-24 has been identified in the Carney complex (71; 169). A variant form 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 (161). Genetic screening for this mutation may be helpful in identifying family members at high risk of developing myxomas (09; 05). The most commonly involved regions in sporadic cases are 12p1 and 17p1. Dicentric chromosomes and telomeric associations are the most frequent genetic abnormalities (34).
After surgical removal of myxomas associated with Carney complex, they may reemerge and cause dysfunctional heart. The oncogene c-MYC, cancer-associated metabolic transcriptional factor HIF-1α, and the epithelial-mesenchimal transition protein vimentin could potentially detect malignancy in myxoma (107).
No association of myxoma with either human papillomavirus (HPV) or Epstein-Barr virus was found (25).
The incidence of atrial myxomas found at autopsy is 0.03% (20). It is the most common primary tumor of the heart in adults but comprises only 10% of the primary intracardiac tumors in children (54). Overall, myxomas represent 50% of all primary cardiac tumors (140). Approximately 7% of patients have a family history or myxoma as part of a syndrome (89). Atrial myxomas can occur in all ages, but most often between the ages of 30 and 60 years (117; 123). There is a predilection for women, with reported ratios ranging from 2:1 to 5.6:1 (117). 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 of family members
• Screening for recurrence after resection
• Semiannual echocardiography
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 occurs in 1% to 3% of cases and is often due to incomplete resection of the primary tumor (89; 165). Familial tumors may recur in up to 25% of cases, discrete from the original site, and may be in multiple sites (143). Semiannual echocardiography is recommended in all patients, in particular in those with Carney complex (123; 09).
Given the varied manifestations of atrial myxomas, the differential diagnosis is wide. Atrial myxomas can mimic mitral stenosis, endocarditis, rheumatic disease, intracardiac thrombi, and other intracardiac tumors including cardiac lymphoma (121).
When associated with prominent constitutional symptoms, myxomas may mimic collagen vascular disease. Myxomas may mimic a thrombus in the atrial appendage; only biopsy can confirm the diagnosis (131).
The aneurysms in the cerebral circulation and elsewhere may suggest polyarteritis nodosa (18). In patients with decreased pulses, myxoma may mimic large vessel vasculitis (142; 40). Conversely, a left atrial metastasis may present as a myxoma (45).
Approximately 67% of masses diagnosed as myxoma by echocardiogram are confirmed by biopsy. Other lesions mimicking myxoma are papillary fibroelastoma, thrombus, hemangioma, granuloma, or leukemia (81).
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
• Chest x-ray
• ECG and cardiac monitoring
• Transthoracic and transesophageal echocardiogram
• CT chest with contrast
• Cardiac CT with contrast
• MRI brain with and without contrast and MR angiography of head
• Cardiac MR with contrast
• Coronary angiography
Routine laboratory studies may be helpful, but not diagnostic. Anemia was found in 40% of patients and an elevated erythrocyte sedimentation rate was found in 55% of patients (147). Elevated C-reactive protein, thrombocytosis or thrombocytopenia, serum globulins, antinuclear antibodies, and rheumatoid factor may suggest an infectious or autoimmune condition (123; 54). Blood cultures are needed to exclude infection (122). Streptococci and staphylococci are the most frequent organisms found in blood culture (49; 159; 60). However, histoplasma capsulatum has also been reported (07).
MRI of the brain may show multiple deep white matter lesions mimicking multiple sclerosis or multiple metastatic lesions (101; 120; 167). Brain MRI may detect contrast enhancing fusiform aneurysms with homogeneous or ring enhancement (102). MR angiography of the cerebral circulation may miss aneurysms smaller than 3 mm and is inferior to digital subtraction angiography (02).
ECG changes include left atrial enlargement, nonspecific T-wave and ST-segment abnormalities, and chronic and paroxysmal atrial fibrillation (20). Chest x-ray may show left atrial enlargement, blood diversion to upper lobes, left ventricular enlargement, and calcification of the myxoma (147).
Transthoracic echocardiography has a false-negative rate of 21% for detecting atrial masses, whereas transesophageal echocardiography (TEE) has a sensitivity of 100% for atrial myxoma (163). TEE better localizes the area of attachment, information needed for surgical planning (155).
Myxoma appears as a smooth globular surface, sometimes irregular and friable with a narrow stalk, often with echolucent areas representing hemorrhage or necrosis (46). Echo lucency helps distinguish myxomas from thrombi or vegetations. Larger size correlates with constitutional, hemodynamic, and obstructive symptoms, whereas smaller size correlates with embolic phenomena (42; 46). Polypoid appearance also correlates with embolic phenomena (50).
Cardiac MRI with gadolinium can delineate the tumor size, attachment, and mobility, and help elucidate some histological characteristics (88; 03). However, cardiac MRI may miss small myxomas seen on TEE (128).
Noncontrast chest CT are useful for detection of atrial myxomas (141) and preoperative evaluation (39). Cardiac contrast-enhanced CT may help differentiate atrial myxoma from other intracardiac lesions like thrombi, fibroelastomas, or metastatic tumors and is helpful for preoperative assessment (23; 52).
FDG-PET/CT showing mildly hypermetabolic hypodense area in the atrium is useful for detecting myxomas in patients with systemic symptoms (44) or pulmonary embolism (84).
Coronary angiography should be performed in most, if not all, patients with atrial myxoma; a tumor blush suggests coronary artery supply (127). The presence of co-existent coronary artery disease may necessitate coronary artery bypass grafting as well as myxoma resection (36).
• There is no medical therapy for myxoma.
• Anticoagulation may not be protective.
• Surgical resection is the definitive treatment; screening for recurrence with echocardiogram at regular intervals is needed.
• Intravenous thrombolysis with tPA may be effective against embolic stroke.
• Large vessel occlusion may need endovascular neurointervention.
No medical therapy exists for atrial myxomas. Anticoagulation may not be protective and may be hazardous in the event of aneurysm formation. Definitive treatment is early surgical resection to avoid recurrent embolization. In general, surgical management of myxoma gives good results (113; 59). Postoperative mortality ranges between 2.2% to 3.5% (79; 114). The most common postoperative complication is arrhythmia, occurring in 26% of patients. Persistent bradycardia required pacemaker placement in less than 2% of patients (114).
Total robotic resection is relatively safe and may give excellent cosmetic results (43; 103). Patients with multiple aneurysms may benefit from a combination of endovascular and open surgical treatment (112). Minimally-invasive procedures make possible removal of increasingly large lesions (27).
Surgery should be followed by transthoracic echocardiography for evidence of recurrence (117). Most recurrences occur within the first 2 years, but the delay may be up to 12 years (46). Addition of cryoablation to resection for right atrial myxoma helps preserve the cardiac conduction system (86). Percutaneous ablation and retrieval is another option (74).
There are no guidelines for acute treatment of the ischemic stroke caused by atrial myxoma embolism; only a few case reports can be cited. 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, has been used with variable success (Díaz et al 2018). Because of the short therapeutic window and better outcome with earlier recanalization (87), the priority is to administer rt-PA via the intravenous route. Hemorrhagic transformation and subarachnoid hemorrhages are the most feared complications (24; 26). The cause of bleeding may be occult tumor emboli, microaneurysms, or recent asymptomatic ischemic infarcts treated beyond the therapeutic window. Yet, despite the hemorrhagic conversion, the patients may still improve. Other patients were treated successfully with intravenous rt-PA (57; 97; 104; 150). Large vessel occlusions (LVO) may occasionally be opened with intravenous tPA by the time endovascular thrombectomy is attempted (66). However, intravenous therapy alone may fail to open most large vessel occlusions (73). In these cases, endovascular thrombectomy proved effective (08; van den Wingaard et al 2014). Additionally, cerebral angiography can also exclude pseudoaneurysm formation and allow safe injection of intra-arterial thrombolytic (11). Significant improvement after endovascular thrombectomy was seen even in absence of intravenous tPA (158). In patients with large vessel occlusions, intra-arterial intervention was associated with better functional outcome compared to the conventional treatment, including intravenous tPA (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 (119; 76). If asymptomatic, however, it may be resected postpartum (98; 76).
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 (126; 96).
Adrian Marchidann MD
Dr. Marchidann of Kings County Hospital owns stock in Lilly, Merck, Pfizer, Abbot, Aeterna Zentaris, and Illumina.See Profile
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
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