A previously healthy 5-year-old boy developed a sudden onset of headaches, dizziness, and weakness while at school. He fell out of his chair twice and was unable to walk to his teacher. He was brought to the emergency department (ED), where his laboratory test results were unremarkable and a head computed tomography (CT) scan revealed only mild sinusitis. At discharge he was prescribed azithromycin. Later that day, he developed twitching on the left side of his face, a left-sided facial droop, left-sided weakness in the upper and lower extremities with inability to walk or grasp objects, dysarthria, and recurrent headache. He was admitted to the pediatric intensive care unit (PICU) for further testing.
Upon admission to the PICU, the patient’s test results were significant for anemia (9 mg/dL) and mild thrombocytosis (550 K/uL), erythrocyte sedimentation rate (ESR) of 66 mm/h, and C-reactive protein (CRP) of 3.8 mg/dL. Magnetic resonance angiography (MRA) of the brain revealed a completely occluded right common carotid artery, as well as narrowed innominate, left common carotid, and left subclavian arteries at their arch origins, and bilateral vertebral artery dilatation (Figure 1). He had diffuse wall thickening in the ascending aorta, innominate artery, and left subclavian artery, and focal stenosis at the celiac artery origin. Additionally, there were filling defects at the junction of the right M1 and M2 segments of the middle cerebral artery. Magnetic resonance imaging (MRI) of the brain revealed an acute, large nonhemorrhagic cortical and subcortical infarction in the distribution of the right middle cerebral artery. Renal ultrasound showed increased flow in the renal arteries but no visible stenosis.
Magnetic resonance angiography of the patient’s neck shows the occluded right common carotid artery. The innominate, left common carotid, and left subclavian arteries are narrowed at their arch origins. There are large vertebral arteries bilaterally, and diffuse wall thickening in the ascending aorta, innominate aorta, and left subclavian arteries.
Rheumatology was consulted and concluded that the patient’s presentation was most consistent with Takayasu’s arteritis. He was given solumedrol (2 mg/kg), infliximab (3 mg/kg), and methotrexate (10 mg/m2), and was started on aspirin and low-molecular weight heparin (which was later transitioned to warfarin). Follow-up imaging 6 months later revealed interval occlusion of the right internal carotid artery. Encephalomalacia was noted on MRI of the brain—an expected sequela of infarction. Laboratory results at this time were significant for continued elevation of his inflammatory markers. His methotrexate and infliximab doses were increased to 15 mg/m2 and 5 mg/kg, respectively. Since this increase in medication dose, his laboratory results have normalized, imaging has revealed improved stenoses, and his physical examination is now normal.
Takayasu’s arteritis (TA) was first reported in 1908 by Mikito Takayasu, a Japanese ophthalmologist who described an abnormality in the retinal vasculature in one of his patients.1 Since this time, it has been further characterized as a granulomatous vasculitis affecting the medium and large arteries, primarily the aorta, its major branches, and the pulmonary arteries.2 Women are affected more often than men, and the incidence in Asia and Mexico is higher than in other regions. The incidence of TA in adults, and likely in children as well, in North America is 2.6 per 1 million per year.3 TA most commonly presents in young women in their second and third decades of life.4 Clinical manifestations of this disease are diverse, ranging from vague complaints of fever and fatigue to more severe presentations such as stroke. Laboratory results are often unhelpful, and the diagnosis rests on imaging. The gold standard for imaging is conventional angiography. Corticosteroids are first-line therapy, with methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide being used both in refractory disease and as steroid-sparing agents.5,6 More recently, there have been promising results using biologic therapy such as tumor necrosis factor (TNF)-alpha inhibitors to treat TA,6 as demonstrated in this case.
The cause of TA is unknown. An infectious etiology has been proposed, with possible pathogenic roles for tuberculosis, Chlamydia pneumoniae, Staphylococcus aureus, Salmonella, fungi, and viruses including parvovirus, influenza, and varicella virus.4,7,8 Genetic susceptibility may also contribute. Specific genetic associations include HLA-B52, particularly in people of Japanese and Mexican ancestry, and HLA-DR4 in whites.9,10 Autoimmunity plays a major role in the pathogenesis of TA. TA has been observed in conjunction with inflammatory bowel disease, juvenile idiopathic arthritis, systemic lupus erythematosus, granulomatosus with polyangiitis (formerly termed Wegener’s granulomatosis), anterior uveitis, and sarcoidosis.11 Several specific autoimmune mechanisms have been elucidated. Cell-mediated autoimmunity targeting the vascular endothelium has been observed. Activation of dendritic cells in the endothelium triggers recruitment and activation of T lymphocytes and macrophages, leading to granuloma formation and elaboration of cytokines including IFN-gamma, TNF-alpha, and interleukin-6 (IL-6).4,7 Both TNF-alpha and IL-6 are increased in the serum of patients with TA, and levels (particularly of IL-6) correlate with disease activity.7 TNF-alpha plays a central role in granuloma formation,12 which is a hallmark of the disease. IL-6 stimulates expression of adhesion molecules, facilitating the infiltration of inflammatory cells into vascular tissue. IL-6 also induces differentiation of proinflammatory T-helper 17 cells, has a negative effect on the generation of T-regulatory cells, and has a major role in the acute phase response.13,14 B cells are also likely to participate in pathogenesis, as specific auto-antibodies have been detected in the serum and lymphoid tissue of patients with TA. These include antiendothelial cell antibodies, antiphospholipid antibodies, and anti-annexin V antibodies.15
As previously discussed, the primary pathologic lesion in TA is granulomatous inflammation triggered by an aberrant immune response in the blood vessel wall. The inflammatory response starts in the tunica adventitia, the outermost layer of the vessel wall, and spreads inward. In the tunica media (the middle layer), granulomas form and release mediators such as matrix metalloproteinases, which cause tissue destruction, and vascular endothelial growth factor and platelet-derived growth factor (PDGF), which induce proliferation. The amount of PDGF produced correlates with the degree of vessel occlusion, demonstrating the central role of these growth factors in pathogenesis. Aneurysms occur in about 25% of cases, resulting from disruption of the elastic lamina in the tunica media.4,7
Identification of TA can be challenging, often leading to diagnostic delays. The differential diagnosis for acute stroke with systemic inflammation, as in our case, is fairly limited. However, many patients with TA present primarily with vague systemic complaints. The most common symptom in children is hypertension, followed by abdominal pain and fever. Weight loss, fatigue, musculoskeletal pain, and headaches are also frequent presentations. To further complicate the matter, it has been estimated that approximately one-third of children have inactive disease at diagnosis, in which case their presentation is actually suggestive of disease sequelae as opposed to active vessel inflammation.3 Diagnostic criteria were proposed in 2005 by the European League Against Rheumatism, the Pediatric Rheumatology European Society, and the Pediatric Rheumatology International Trials Organization for childhood TA and validated in 2008 for patients younger than age 18 years.2 These criteria include a mandatory angiographic abnormality (conventional angiogram, CT, or MRA) of the aorta or its main branches and pulmonary arteries, as well as one of the following: decreased peripheral artery pulses and/or claudication of extremities, blood pressure differences >10 mm Hg in any limb, bruits over large arteries, hypertension (>95th percentile for height), and elevation of acute phase reactants.2 Of note, these criteria have not been prospectively validated in children but are useful guidelines.
Unfortunately, there are no specific laboratory tests for TA. Although ESR and CRP are considered the best available markers for vessel inflammation, they are neither sensitive nor specific measures of disease activity.3,16 For instance, in one study nearly one-half of patients had elevated inflammatory markers without radiographic evidence of active vessel inflammation, and almost one-quarter had normal inflammatory markers despite having active disease.16
Several disorders can present with vascular lesions and must be differentiated from TA. A detailed history, systemic signs of inflammation such as weight loss and fever, and elevated inflammatory markers (when present), can be crucial in distinguishing inflammatory from noninflammatory vasculopathies. Noninflammatory mimics of TA include coarctation of the aorta, Ehlers-Danlos syndrome, and Marfan syndrome. Coarctation of the aorta may present with hypertension and a murmur, but is typically distinguished from TA via echocardiographic findings. Ehlers-Danlos syndrome and Marfan syndrome can present with aneurysmal dilations. However, these diseases are usually accompanied by extravascular features such as joint hypermobility, soft and hyperextensible skin, Marfanoid body habitus, and dislocations of the lens of the eye. Other primary inflammatory vasculitides, such as Kawasaki disease, Behcet’s disease, and primary angiitis of the central nervous system (CNS), can mimic TA; clinical history, associated symptoms, and the pattern of vessel involvement can be helpful in distinguishing these diagnoses. Although these patients may have similar vague complaints of fatigue, abdominal pain, and fevers, Kawasaki disease and Behcet’s disease involve the small vessels, and primary angiitis of the CNS should be associated with specific radiographic or cerebrospinal fluid abnormalities. Additionally, systemic lupus erythematosus (SLE), sarcoidosis, and mixed connective tissue disease (MCTD) can present with vasculopathy. Similarly, clinical features and laboratory studies, particularly specific autoantibodies in SLE and MCTD, can usually differentiate these entities from TA. Sarcoidosis is associated with noncaseating granulomas, whereas the granulomas in TA are media-necrotizing. Furthermore, the vasculitis in SLE and MCTD is usually associated with vasculitis of the smaller vessels.
Infectious causes of aortitis are rare in children but include tuberculolosis, syphilis, Staphylococcus aureus, Salmonella, herpes simplex virus, and cytomegalovirus. Fibromuscular dysplasia, a noninflammatory condition causing defects of the walls of large vessels, can mimic medium or large vessel vasculitis. Patients with fibromuscular dysplasia are often hypertensive and aneurysms can be seen on imaging, but the lesions are typically more focal compared with the widespread vascular abnormalities often seen in TA. Again, signs and symptoms of systemic inflammation should be absent.17 Finally, ergotism and radiation fibrosis may trigger a vasculopathy that can mimic vasculitis; patients should be queried regarding these exposures.3,18,19
Given the location of the vascular lesions in TA, biopsy is not usually feasible. In children, the most frequently involved arteries include the renal arteries, the abdominal and thoracic aorta, the subclavian artery, and the carotid arteries.3,20 Therefore, imaging is essential to evaluate for vasculitis. Angiography is the gold standard but it is invasive, technically difficult in young children, and involves a significant dose of radiation, which is particularly undesirable in the pediatric population. Angiography provides information about the patency of the vessels as well as the presence of collateral circulation.3 However, angiography may not detect wall thickening, which can be a sign of early disease.6
CTA, MRA, high-resolution ultrasound, and 18F fluorodeoxyglucose–positron emission tomography (18F-FDG-PET) scans also have roles in both the diagnosis and follow-up imaging. In particular, these methods enable visualization of inflammation within the vessel wall, which may be helpful in determining disease activity.6 Contrast-enhanced MRA is a particularly attractive imaging modality in children given the lack of radiation. Furthermore, a correlation between the level of edema and enhancement of the vessel wall seen on MRA and the level of acute phase reactants has been shown in studies.3 High-resolution ultrasound is limited anatomically, but it is useful for the detection of abnormalities in the common carotid and proximal subclavian arteries.6 18F-FDG-PET, which measures the metabolism, uptake, and accumulation of deoxyglucose in inflamed endothelium, is also used in the diagnosis of TA. It is a useful and sensitive screening tool for vasculitis, but it is not very specific and cannot show structural damage or alterations in blood flow.3,6,16
Therapy for TA is aggressive immunosuppression, anticoagulation, and, if necessary, surgical intervention. Glucocorticoids are commonly used as first-line immunomodulatory therapy, and approximately 50% of patients respond. The initial prednisone dose is usually 2 mg/kg per day, with a taper after 1 to 2 months. Among prednisone nonresponders, a further 50% achieve remission with the use of methotrexate. Usual dosing for methotrexate is 10 to 15 mg/m2 given orally or subcutaneously once weekly.3 Those who are refractory to methotrexate and steroids, or who have severe disease at presentation, warrant more potent cytotoxic agents such as azathioprine, cyclophosphamide, and mycophenolate mofetil. About 20% of patients are resistant to these therapies.21 Biologic agents, such as TNF inhibitors (eg, adalimumab, etanercept, certolizumab, infliximab) and anti–IL-6 (tocilizumab) medications have been used more recently in this patient population, and the results are promising.3,5 One prospective open-label, multicenter trial and two retrospective single-center studies as well as several case reports support the use of TNF-alpha inhibitors in adults.22–24 There are only isolated case reports in children documenting efficacy of these medications.25 Blocking IL-6 may provide more targeted therapy, as it is thought to be downstream to TNF-alpha in the cytokine cascade.26 There have been no clinical trials evaluating the effectiveness of anti–IL-6 therapy in TA, but there are case reports (including one pediatric report) of tocilizumab being used successfully.27,28
Although the use of anticoagulants such as warfarin is controversial, antiplatelet medication, such as aspirin, has shown a clear protective effect from ischemic events. Markers of thrombosis, such as platelet factor 4, thrombin–antithrombin III, fibrinopeptide A, and d-dimer, are substantially higher in TA patients.29
Surgical intervention (revascularization) is occasionally warranted, based on location and extent of disease, and ideally should be attempted after the patient has attained clinical remission.6