Case Presentation: A 61-year-old female awoke one morning to thirty minutes of right sided weakness and slurred speech prompting hospital admission for stroke. Treatment with metronidazole and ciprofloxacin for colitis diagnosed two days ago was continued in hospital. Diffusion weighted imaging (DWI) of the brain MRI revealed infarctions in multiple vascular territories involving bilateral cerebral and cerebellar hemispheres. A trans-thoracic echocardiogram (TTE) failed to show a valvular vegetation but trans-esophageal echocardiogram (TEE) revealed a 0.4 x 0.2 cm mass on the P2 segment of the mitral valve. Rheumatologic and hyper-coagulability studies tested negative. Antibiotics were stopped and blood cultures were sent on three different days across her eleven day hospital course. After an intentional delay to increase culture yield, intravenous(IV) vancomycin and ceftriaxone were started on day eight for possible culture negative endocarditis when all three cultures detected no growth. Anticoagulation was not started over concerns of hemorrhagic conversion of the infarcts. On the tenth day, she developed per vaginal spotting. CA-125 was elevated at 47 units/mL and trans-vaginal sonography disclosed a 7mm endometrial thickness. She was discharged on hospital day eleven to complete IV antibiotics at home. One week later, she returned to the hospital with expressive aphasia, mild dysarthria and generalized weakness. Over the next six weeks despite receiving anti-coagulation , she developed three more episodes of stroke presenting as global aphasia, dysmetria, persisting weakness and dysarthria, caused by occlusions in the left middle cerebral artery M2 segment and right anterior cerebral artery A2 segment leading to bilateral frontal, parietal , temporal , occipital lobe infarctions noted on multiple follow-up DWI brain. Repeat TEE showed an increase in the mitral valve mass to 0.8 x 0.4 cm. A liquid biopsy using microbial cell-free DNA sequencing was negative for infectious etiologies of endocarditis. The multi-territorial nature of the recurrent strokes in the presence of ongoing antibiotic treatment shifted the diagnosis of infective endocarditis (IE) towards non-bacterial thrombotic endocarditis (NBTE). Malignancy-induced NBTE was a compelling possibility and an endometrial biopsy revealed serous endometrial adenocarcinoma.

Discussion: NBTE has a post-mortem frequency of 0.9-1.6%, and among cancer patients, an ante-mortem frequency of 19%. Differentiating NBTE from culture negative bacterial endocarditis can be challenging, especially in the setting of recent antibiotic use. Microbial cell-free DNA sequencing can rule out IE as the test has a sensitivity of 90-95%. Following an unrevealing TTE with a TEE may aid in visualizing small masses situated on undamaged cardiac valves pathognomonic for NBTE. Analyzing the contrasting stroke pattern of NBTE and IE on DWI – multi-territorial infractions of varying sizes vs. small single arterial territorial involvement respectively – can also aid in the differential diagnosis.

Conclusions: We experienced a case of recurrent embolic strokes whose workup led to the diagnosis of an endometrial serous adenocarcinoma. An unrelenting clinical picture of embolic strokes of uncertain etiology despite antibiotic treatment for IE warrants a diagnostic workup for malignancy-induced NBTE.