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Show ORIGINAL CONTRIBUTION Multiple Brain Infarcts and Balint Syndrome in Aortic Arch Angiosarcoma Iris Ben- Bassat Mizrachi, MD, Jonathan D. Trobe, MD, Michael G. Deeb, MD, Stephen R. Ramsburgh, MD, David M. Williams, MD, and Stephen S. Gebarski, MD Abstract: A 50- year- old woman presented with subacute cognitive decline, impaired eye movements, and simultanagnosia, components of the Balint syndrome. She had relatively low blood pressure in the left arm and left finger clubbing. Brain imaging identified multiple acute infarcts. Transesophageal echocardiography showed no cardiac abnormalities but demonstrated a thickened aortic wall and an intraluminal aortic arch mass. The surgical specimen revealed angiosarcoma. Of the few reported angiosarcomas involving the aorta, most have been located in the abdominal segment. This is only the second reported case of aortic arch sarcoma presenting with stroke. (/ Neuro- Ophthalmol 2006; 26: 107- 112) Aortic arch disease is a rare cause of stroke. When stroke does occur, it usually results from calcific atherosclerosis ( 1,2), or much less commonly, from Takayasu aortitis ( 3,4). We report a patient who had multiple brain infarcts that manifested as the Balint syndrome. In the course of cardiac imaging, a lesion of the aortic arch was demonstrated. The surgical specimen revealed extensive angiosarcoma involving the aortic arch and origins of the great vessels. We believe this to be only the second case in which aortic arch sarcoma has presented with stroke. CASE REPORT A 50- year- old- woman presented with progressive visual problems and cognitive deterioration over a period of Department of Ophthalmology ( IB- BM, JDT), W. K. Kellogg Eye Center, and Departments of Neurology ( JDT), Surgery ( MGD), Pathology ( SRR), and Radiology ( DMW, SSG), University of Michigan, Arm Arbor, Michigan. Address correspondence to Iris Ben- Bassat Mizrachi, MD, Gold-schleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel 52621; E- mail: irismizrachi@ yahoo. com Supported in part by a fellowship from the American Physician Fellowship for Medicine in Israel. three months. She reported difficulty finding and identifying objects. Her son reported that she had displayed increasing confusion, inertia, and untidiness. There had been a 40- lb weight loss over a three- month period. Six months earlier, she had successfully driven a public bus and negotiated the purchase of a house. She had polycystic kidney disease and was a heavy cigarette smoker. Blood pressure was 162/ 81 in the right arm, 78/ 63 in the left arm; radial and ulnar pulses in the left arm were thready Clubbing of the fingers of the left hand was marked ( Fig. 1). She knew the year but not the day of the week and could not name the city or the hospital. She could not follow three- step commands and was flawed in object naming. Visual acuities were 20/ 20 in both eyes, pupil size and reactivity were normal, and ophthalmoscopy was normal. There was a complete right homonymous hemianopia to confrontation. Saccades to command and pursuit eye movements were markedly reduced in amplitude in all directions, but spontaneous saccades were full. She could not interpret magazine action photographs. She consistently misreached toward the left when instructed to touch external objects but did not misreach in touching her own body parts. Motor examination was otherwise normal. Sensory and reflex examinations were normal. MRI ( Fig. 2) demonstrated an extensive area of high signal in the left parieto- occipital region on T2 and FLAIR sequences. Restricted diffusion was present in that region. There were smaller areas of restricted diffusion in the left cerebellar hemisphere, the thalamus bilaterally, and the periventricular white matter bilaterally. There was a small area in the right parieto- occipital region with high signal on T2 and FLAIR sequences but without restricted diffusion, suggesting an older infarct. A high- signal lesion above the left centrum semiovale on a pre- contrast Tl sequence was initially interpreted as consistent with a hemorrhagic infarct. Brain magnetic resonance arteriography ( MRA) showed no significant large artery disease. Standard serum chemistries were normal, and a workup for hypercoagulability and inflammatory processes was negative except for an erythrocyte sedimentation rate of 105 mm/ h and a C- reactive protein level of 5.4 mg/ dl J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 107 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Mizrachi et al FIG. 1. A. Normal right hand. B. Clubbing of the fingers of the left hand. ( normal, 0.0- 0.6 mg/ dl). Lumbar puncture revealed a normal opening pressure and glucose level ( 57 mg/ dl). The protein level was mildly elevated at 51 mg/ dl ( normal, 15- 45 mg/ dl); cytology and flow cytometry were normal. Because multiple acute brain lesions were demonstrated on imaging, a cardiac source of emboli was sought in a transesophageal echocardiogram ( TEE). The heart images were normal, but there was a large multilobulated soft tissue mass occupying approximately 50% of the aortic arch lumen with a smaller mobile component in the proximal descending thoracic aorta ( Fig. 3). CT and computed tomographic angiography ( CTA) ( Fig. 4) of the neck, thorax, and abdomen demonstrated enhancement of a thickened aortic arch wall extending to the origin of the left subclavian artery. In the superolateral portion of the aortic arch, there was a focal irregularity suggestive of an intraluminal mass extending into the innominate and common carotid arteries and causing FIG. 2. Brain MRI. A. Axial T2 images show lesions in both cerebral hemispheres. The left fronto- parietal lesion shows sulcal flattening, suggestive of recent infarct ( large arrow). The right parieto- occipital lesion shows focal loss of brain substance suggestive of an older infarct ( small arrow). B. Axial diffusion-weighted imaging at the same level shows restricted diffusion in the left cerebral lesion consistent with recent infarct ( large arrow). The right hemispheric lesion shows no restricted diffusion ( small arrow). C. Axial pre-contrast T1 image above the centrum semiovale shows a high- signal lesion in the left frontal lobe consistent with subacute hemorrhage ( arrow). D. Axial post- contrast T1 image at the same level shows nodular enhancement ( small arrow) posterior to the hemorrhage ( large arrow), suggesting metastasis. 108 © 2006 Lippincott Williams & Wilkins Aortic Arch Angiosarcoma J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 FIG. 3. Transesophageal echocardiogram demonstrates a mass in the wall and lumen of the aortic arch ( arrow). complete occlusion of the left subclavian artery. The other large vessels in the chest and abdomen appeared normal. The kidney and liver showed multiple cysts consistent with the history of polycystic kidney disease, and there was a wedge area of low attenuation in the spleen suggestive of an infarct. Arch and neck MRA demonstrated similar findings but did not show the mass as well as did CT and CTA. These radiographic and clinical findings raised the suspicion of Takayasu aortitis or severe atherosclerosis. Given the protracted clinical course, constitutional symptoms, weight loss, and elevated acute phase reactants, the diagnosis of aortitis was favored. The patient was treated with prednisone 60 mg/ d and heparin 24,000 units/ d. On the tenth hospital day, she became more confused and less responsive. Although brain imaging failed to disclose new findings, she was taken for surgical replacement of the aortic arch, including the proximal descending aorta, innominate artery, and carotid arteries with a Hemashield graft ( Boston Scientific, Wayne, NJ), together with ligation and oversewing of the left subclavian artery. At surgery, the aortic arch was indurated thickened and adherent to the surrounding soft tissues. Gross pathology ( Fig. 5A) demonstrated a firm, thickened aortic wall with severe atherosclerosis and occlusion of the proximal subclavian and partial occlusion of the innominate and left common carotid arteries by necrotic tumor and thrombus. Histopathology of the aortic arch and large vessels demonstrated intraluminal tumor with obvious invasion of the vessel wall and extensive necrosis. The neoplastic cells were pleomorphic, spindled and epithelioid with hyperchromatic nuclei and abundant eosinophilic cytoplasm. Occasional mitotic figures were seen. In some areas of the tumor, the cells were arranged in rudimentary vascular channels ( Fig. 5, B and C). Immunohistochemical staining was positive for CD31 antibody, an endothelial marker ( Fig. 5D). The pathologic diagnosis was high- grade angiosarcoma with thrombus and atheroma. Because of the patient's general ill health, adjuvant oncologic treatment was deferred. A follow- up CT scan three weeks later disclosed a new pancreatic lesion believed to be a metastasis. The patient died four months after presentation. An autopsy was not performed. DISCUSSION Our patient presented with stepwise neurologic and cognitive deterioration over a period of three months. Neurologic examination consisted of volitional gaze paresis, FIG. 4. Aortic imaging. A. Coronal reformatted magnetic resonance angiography of the aortic arch and neck vessels shows irregular stenosis at the origin of the left common carotid artery ( large arrow) and ill- defined signal inhomogeneity of the superior aspect of the aortic arch ( small arrows). The left subclavian artery is not seen. B. Computed tomographic angiography ( CTA) axial source image shows irregular luminal narrowing of the left common carotid artery origin ( arrows) and, less so, of the innominate artery origin. C. CTA axial source image at a level below that of ( B) shows a bulky irregular intraluminal soft tissue mass that spreads along the aortic arch superiorly, invading the aortic wall and nearby tissues ( arrows). 109 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Mizrachi et al aortic wall FIG. 5. Pathology of surgical specimen. A. Gross pathology shows narrow and thickened aortic arch superiorly with occlusion of the left subclavian artery ( large arrow), partial occlusion of the left common carotid artery ( small arrow), and a patent innominate artery ( asterisk). B. Histopathology demonstrates intraluminal tumor with invasion of the vessel wall ( arrow) ( hematoxylin and eosin stain, x10). C. Pleomorphic spindled ( white arrowhead) and epithelioid ( black arrowhead) cells containing abundant eosinophilic cytoplasm and occasional mitotic figures ( white arrow). In some areas of the tumor, the cells are arranged in rudimentary vascular channels ( black arrow) ( hematoxylin and eosin stain, x40). D. Immunohistochemical stain for CD 31, an endothelial marker, is positive ( brown staining). misreaching only under visual guidance, and simultanag-nosia, features of Balint syndrome. Brain imaging showed a large new left parieto- occipital infarct and smaller new infarcts in the left cerebellar hemisphere, thalamic nuclei, and periventricular white matter. The multiplicity of fresh brain infarcts led to a search for a cardiac source of emboli, but the heart was normal. Instead, TEE and chest imaging surprisingly disclosed an aortic arch lesion, a finding we should have suspected because of the relatively low blood pressure recorded in the left arm and the dramatic left finger clubbing. At the time of surgical revascularization, the lesion proved to be an angiosarcoma with atherosclerotic occlusion of the great vessels. Angiosarcomas are rare malignant tumors that recapitulate many of the functional and morphologic features of normal endothelium ( 5). They vary from highly differentiated tumors that resemble hemangiomas to those with severe anaplasia. Most angiosarcomas have a predilection for skin, muscle, and bone, but they may occur at any location in the body and rarely arise from major blood vessels. Of the 21 reported cases of aortic angiosarcoma ( 6), most have involved the abdominal aorta, with only five involving the aortic arch, as in our patient. A comprehensive review of the 180 reported cases of malignant tumors of the aorta ( 7) revealed that angiosarcoma makes up a small fraction ( Table 1). Among these 180 cases, 50 were mural tumors originating in the ad-ventitia and media and 130 were luminal tumors originating in the intima. Among those of intimal origin, 28 cases were differentiated sarcomas, including myxofibrosarcoma, leiomyosarcoma, angiosarcoma, myxoid chondrosarcoma, hemangioendothelioma, and undifferentiated pleomorphic 110 © 2006 Lippincott Williams & Wilkins Aortic Arch Angiosarcoma J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 TABLE 1. Primary malignant tumors of the Tumor type Mural tumors ( media/ adventitial origin) Luminal tumors ( intimal origin) Differentiated Myxofibrosarcoma Leiomyosarcoma Angiosarcoma Myxoid chondrosarcoma Hemangioendothelioma Undifferentiated pleomorphic sarcoma Undifferentiated Uncertain morphology * From Reference 7. sarcoma; 81 were undifferentiated intimal sarcomas; and 21 cases were of uncertain histologic morphology and location. In this comprehensive review ( 7), the authors questioned the pathologic diagnosis of some of the reported cases of intimal origin and redefined them as undifferentiated angiosarcoma. Because primary aortic arch tumors comprise a wide range of histologic entities ( 7,8), histopathology and adjunctive immunohistochemistry are critical in diagnosis, particularly in poorly differentiated forms in which endothelial differentiation is difficult to identify ( 5,9,10). Angiosarcoma usually expresses endothelial antigens, including von WiUebrand Factor, CD31, and CD34. Although von WiUebrand Factor, which was not tested in our case, is the most specific vascular marker, its sensitivity is very low and it often produces weak staining. Staining for CD31, which was positive in our case, combines relatively high specificity and sensitivity, being positive in approximately 90% of angiosarcomas ( 7,11- 13). The clinical presentation of angiosarcoma of large vessels includes weight loss, fever, elevated acute- phase reac-tants ( 14), and manifestations of tumor or platelet emboli to the abdominal viscera, bone, skin ( 14), or brain ( 15). Stroke as the presentation of aortic arch sarcoma has been reported only once before ( 16). That patient had expressive aphasia and right hemiparesis caused by left middle cerebral artery infarct ( and reduced left arm blood pressure, as our patient had). That case emphasized the aortic arch imaging features but did not provide details of the pathology or brain imaging. An additional single case report described a middle cerebral artery stroke from a carotid artery angiosarcoma ( 17). Our case underscores the importance of high-definition imaging of the thorax in the diagnosis of aortic arch disease. In the past, most large vessel sarcomas were diagnosed after embolectomy or on autopsy. In a compre-aorta* No. of reported cases ( n = 180) 50 130 28 16 2 2 1 2 5 81 21 hensive review of cases reported until 1998 ( 8), more than half of the 87 aortic tumors were discovered at autopsy. In a 1990 review of pulmonary artery sarcomas ( 18), 56 ( 60%) of 93 patients were diagnosed at autopsy. On the other hand, a 1997 review ( 19) found that 38 ( 90%) of 42 cases of pulmonary artery sarcoma were diagnosed at antemortem examination. The authors attributed the antemortem diagnosis to the use of MRI, which demonstrated three differentiating features: 1) enhancement of the vessel wall and mass, a finding not seen in thrombus ( 20,21); 2) a vessel distended by a soft tissue mass or extravascular spread, findings characteristic of a tumor; 3) lack of abrupt luminal narrowing, a finding characteristic of embolus. MRA can show the arterial narrowing and irregularity, but CT, CTA, and MRI can demonstrate the irregular lumen, the intraluminal mass, and the invasion of the vessel wall and surrounding tissues. Conventional angiography is not favored in evaluation of angiosarcoma because of the risk of embolic spread of tumor ( 16). There are no meaningful guidelines as to treatment of angiosarcoma because the condition is so rare. Surgical resection of the rumor- bearing aortic region with graft interposition is the standard therapy, although endarterectomy without resection might be equaUy effective in intimal sarcomas, in which the malignant ceUs are limited to the luminal surface ( 6). Adjuvant chemotherapy ( doxorubicin and ifosfa-mide) has been used palliatively for embolic, metastatic, or non- resectable tumors. In a report of 21 patients with the aortic angiosarcoma ( 6,8), the mean survival rate was 13 months. REFERENCES 1. Amareco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N EnglJMed 1994; 331: 1474- 9. / / ; J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Mizrachi et al 2. Anonymous. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke: The French study of an aortic plaques in stroke group. N EnglJ Med 1996; 334: 1216- 21. 3. Ringleb PA, Strittmatter EI, Loewer M, et al. 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