Child Neurology: Arterial ischemic stroke in a 12-year-old patient with cardiac myxomas

Differential diagnosis and workup

Common differential diagnosis of the risk factors and etiology of PAIS may be broadly classified into arteriopathies, cardiac disorders, inherited or acquired thrombophilia, sickle cell disease, malignancy, inborn errors of metabolism, and rheumatologic diseases including systemic vasculitides.² There are frequently multiple risk factors present in a single patient. In patients who present with symptoms and signs of stroke with evidence of extensive obstructive lesions of large vessels, a working differential of arterial thrombophilias, large vessel vasculitis, malignancy, and cardioembolic etiologies is reasonable. In this clinical context, it is not unreasonable to evaluate for the benefit of systemic steroid therapy. However, before initiating systemic therapy, it is important to note that several published cases have reported atrial myxomas being initially misdiagnosed as vasculitis, including Takayasu arteritis, polyarteritis nodosa, and giant cell arteritis.³ One of these case reports also mentions that a prolonged course of high-dose corticosteroids may predispose myxomas and the surrounding cardiac tissue to endocarditis. Because of such implications of a presumptive treatment, it was proposed that patients with suspected diagnosis of vasculitis should undergo an echocardiography to rule out myxoma before initiating treatment.³ In addition to echocardiography and telemetry monitoring, the PAIS workup at our institution is outlined in the table.

Epidemiology and pathophysiology

The incidence of cardiac tumors causing PAIS is unknown, but the pathophysiology of these tumors leading to cerebral embolization has been studied. Most primary cardiac tumors are benign, with myxomas being the most common type.⁴ The majority of cardiac myxomas are sporadic; however, a familial pattern has been described in Carney complex, which is an autosomal-dominant syndrome with cardiac myxomas, extracardiac myxomas, cutaneous pigmentation, endocrine abnormalities, and other tumors, and accounts for about 5%–10% of cardiac myxomas.^4,5 The histologic origin of these tumors is uncertain; however, they are thought to develop from multipotent mesenchymal stem cells. Macroscopically, myxomatous tissue is gelatinous and may have a polypoid or papillary appearance.⁴ Due to their fragile nature along with higher potential for erosion and embolization, papillary myxomas are more likely to lead to embolism than polypoid tumor.^4,5 Systemic embolization from cardiac myxoma is seen in up to 50% of cases. This may involve cerebral vasculature in up to half of these cases, with extracerebral involvement that includes retinal, lower extremity, renal, coronary, and occasionally abdominal aortic vessels in the remainder.⁵ Embolization may result from tissue fragmentation, tumor detachment, or spread of overlying thrombi/vegetations from the tumor surface. In addition to embolization limited to arterial lumen, metastatic extracardiac lesions have been reported in various tissues including brain parenchyma and vessel wall.⁵ The incidence of these metastasis is unknown.

Treatment and prognosis

Treatment of cardiac myxoma and its neurologic sequela, including AIS, fusiform aneurysms, cavernous malformations, and myxomatous metastasis, begins with resection of the primary mass (American Heart Association, class 1C guideline).⁶ Recurrence rates of myxomas in patients with Carney complex (as opposed to sporadic myxomas) is up to 25%, with a recommendation of lifetime annual echocardiography for the patient and familial screening.⁷ The most common neurologic sequel of cardiac myxoma is AIS, of which the management in pediatric patients is largely extrapolated from adult studies. Whereas formal guidelines do not recommend the routine use of IV recombinant tissue plasminogen activator outside of research protocols in pediatric patients, thrombectomy has been reported to be successful in PAIS secondary to occlusive embolism from cardiac myxoma and may be considered based on institutional experience and the individual clinical picture.⁸ For secondary prevention of PAIS due to a cardioembolic source, anticoagulation with low-molecular-weight heparin or warfarin is recommended if the risk of recurrence remains high.⁶ Otherwise, in the absence of sickle cell disease, secondary prevention of PAIS with antiplatelet therapy may be considered, though the optimal length of treatment is unknown.⁶

In patients with cardiac myxomas, intracerebral myxomatous aneurysms may be found on initial workup or as a delayed manifestation reported up to 25 years after tumor resection.⁹ Digital subtraction angiography is preferred for diagnosis given limitations of MRA and CT angiogram in detection of myxomatous aneurysms.¹⁰ Whereas endovascular coiling, surgical management, and embolization have all been reported, treatments are limited given fusiform morphology and peripheral cerebral vascular predilection.¹⁰ It is generally accepted to maintain antiplatelet therapy, though recurrent AIS is often reported in the presence of antiplatelet agents started at initial presentation. In patients who develop parenchymal metastasis, a combination of surgical resection, radiation, and chemotherapy leading to complete remission has been reported, and theoretically could be considered in aneurysm prevention or treatment as well.⁹

Prognosis of PAIS from all causes remains suboptimal. Studies show that more than 50%–80% of children will experience long-term neurologic deficits,² and up to 14% will experience recurrent stroke.⁶ Echocardiography is an important diagnostic test with treatment and prognostic implications in patients with AIS who present with signs and symptoms suggestive of large vessel vasculitis. In the absence of tissue diagnosis, patients may be misdiagnosed with diseases like systemic vasculitis, collagen vascular disease, infective endocarditis, or rheumatic heart disease.^4,5 In the subpopulation of PAIS due to cardiac myxoma with or without aneurysm formation, optimal management or prognosis remains unknown. Unique patient characteristics may pose further management challenges. In such cases, a multidisciplinary approach with transparent discussions with the patient and his or her parents is necessary to determine the treatment course.