Worsening Focal Neurologic Status in an Older Man
What's The "Take-Home"?
Pearls From Clinical Cases
A 72-year-old man with a history of diabetes, hypertension, and heavy smoking presented to the emergency department with left leg pain and altered mental status of about 1 week’s duration.
INITIAL IMAGING RESULTS
A CT scan of the head showed no evidence of acute hemorrhage; however, a chronic lacunar infarct and a small segmental infarct of indeterminate age were noted. Venous Doppler studies revealed a left leg deep vein thrombosis (DVT). Anticoagulation was started.
HOSPITAL COURSE
Throughout his hospital stay, the patient had a low-grade fever and an elevated white blood cell count. His neurologic status worsened during his stay, and he reported focal weakness, vision changes, and severe right-sided headaches. The results of a neurologic examination raised suspicion for stroke, and an MRI scan confirmed multi-territorial infarcts involving both sides of the cerebrum as well as the cerebellum, with some areas showing hemorrhagic transformation, highly suggestive of “septic emboli” (Figure).
A CT scan of the chest revealed emphysema, interstitial thickening, mediastinal lymph enlargement, and a 4-cm opacity in the right lower lobe. Laboratory findings included mild anemia (hemoglobin, 9 g/dL), thrombocytopenia (99,000/µL), low serum sodium (129 mmol/L), normal prothrombin time (PT) and partial thromboplastin time (PTT), low fibrinogen (192 mg/dL), and multiple sets of blood cultures that did not show the growth of a pathogen.
Figure – MRI scans of the patient described in this case demonstrate multiple infarcts
with peripheral edema.
Which of the following is the most likely diagnosis in this patient?
A. Embolic stroke from DVT with a left to right shunt.
B. Septic emboli, likely from lung infection.
C. Rupture of an atheromatous plaque from the carotid arteries or the aorta, given the history of heavy smoking, diabetes, and hypertension.
D. Non-bacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis.
(Answer and discussion on next page)
Correct Answer: D
NON-BACTERIAL THROMBOTIC ENDOCARDITIS: AN OVERVIEW
Armand Trousseau first reported an association between cancer and thromboembolism, and the syndrome still bears his name. Since then, coagulation in cancer has been an area of active research. Almost half of cancer patients have evidence of thromboembolism on autopsy. Thromboembolic events also mark the antemortem clinical course of a significant proportion of cancer patients.
Coagulation homeostasis is significantly altered in the presence of malignancy by a number of proposed, but not fully understood, mechanisms. A spectrum of clinical manifestations ranging from exsanguinating bleeding to diffuse clots is observed with cancer-related chronic disseminated intravascular coagulation (DIC). NBTE is one such manifestation of DIC in malignancy.
The incidence of NBTE is largely quoted from postmortem studies: over a 10-year period, 51 of 65 patients with NBTE (an overall incidence of 1.6% in adult autopsies) had a malignant neoplasm.1 In another series, NBTE was more often associated with malignancy than with non-malignant neoplasms, adenocarcinoma than with non-adenocarcinoma, and the pancreas than with other sites.2
CLINICAL FEATURES
Patients with NBTE present with symptoms resulting from systemic emboli. Although sudden neurologic deficits are the most common presentation, coronary, renal, and mesenteric (splenic infarcts) circulations can also be involved. Valvular vegetations vary greatly in size, though the majority of them are small, and they are composed of degenerating platelets interwoven with strands of fibrin. They are not accompanied by a marked inflammatory reaction and do not form valvular abscesses, thus leaving the valvular surface undamaged. Left-sided valves are affected, and the vegetations have a tendency to detach and embolize much more readily than the vegetations of infective endocarditis. Diligent cardiac auscultation to detect murmurs is not as helpful as it is in infective endocarditis because of the reported frequent absence of cardiac murmurs.
DIAGNOSIS
A high index of suspicion is necessary to consider this diagnosis. A study that classified strokes related to endocarditis (both bacterial and non-bacterial) into four patterns on MRI concluded that patients with NBTE uniformly have multiple, widely distributed, small and large strokes.3 This pattern should raise suspicion for NBTE in the appropriate clinical setting.
Although transesophageal echocardiography (TEE) is more sensitive than a transthoracic approach for detection of NBTE, even TEE identified valvular vegetations in only a small proportion (18%) of cancer patients with stroke.4 Basic coagulation studies (PT, PTT, and fibrinogen level) should be obtained. These may reflect evidence of DIC and should further alert the clinician to the possibility of NBTE. In addition, appropriate tests to rule out infective endocarditis, anti-phospholipid syndrome, and rupture of atheromatous plaques should of course be undertaken.
This patient’s negative bubble study, negative blood cultures, and benign echocardiogram as well as aortic and carotid vascular imaging render the alternate diagnoses highly unlikely. The pattern of strokes observed in the setting of a highly suspicious lung mass makes NBTE (choice D) the most likely diagnosis.
MANAGEMENT
Standard heparin should be used for therapeutic anticoagulation whenever there are no obvious contraindications. This can then be transitioned to a low molecular weight heparin (LMWH) on discharge. There is no strong evidence for or against the use of LMWH initially in NBTE. Vitamin K antagonist (warfarin) should not be used for anticoagulation in cancer patients. The CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial5 and a subsequent 2008 Cochrane Database Review6 show that LMWH is superior and reduces recurrent thromboembolic events in cancer patients, although without improving survival. Use of newer agents (rivaroxaban, apixaban, and dabigatran) has not been evaluated in this setting and should be avoided if possible for now.
Therapeutic options for the underlying cause should of course be considered. However, in patients with malignancy as an underlying cause, it is often difficult to administer the recommended multidisciplinary interventions (chemotherapy, radiation, extensive surgeries) because of the patient’s performance status and advanced stage of cancer. Nonetheless, appropriate consultations should be obtained, since a potentially curable or controllable malignancy deserves to be treated as aggressively as tolerated. El-Shami and associates7 and Asopa and colleagues8 reviewed this topic in further detail.
OUTCOME OF THIS CASE
A transbronchial biopsy revealed adenocarcinoma of the lung. Further imaging exposed metastatic disease in the liver. The patient’s neurologic status continued to deteriorate. His family decided on hospice care, and he died on the 27th day.
REFERENCES:
1. Deppisch LM, Fayemi AO. Non-bacterial thrombotic endocarditis: clinicopathologic correlations. Am Heart J. 1976;92:723-729.
2. Gonzalez Quintela A, Candela MJ, Vidal C, Roman J, Aramburo P. Non-bacterial thrombotic endocarditis in cancer patients. Acta Cardiol. 1991;46:1-9.
3. Singhal AB, Topcuoglu MA, Buonanno FS. Acute ischemic stroke patterns in infective and nonbacterial thrombotic endocarditis: a diffusion-weighted magnetic resonance imaging study. Stroke. 2002;33:1267-1273.
4. Dutta T, Karas MG, Segal AZ, Kizer JR. Yield of transesophageal echocardiography for nonbacterial thrombotic endocarditis and other cardiac sources of embolism in cancer patients with cerebral ischemia. Am J Cardiol. 2006;97:894-898.
5. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-153.
6. Akl EA, Barba M, Rohilla S, et al. Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006650. doi: 10.1002/14651858.CD006650.pub2.
7. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in
cancer patients: pathogenesis, diagnosis, and treatment. Oncologist. 2007;12:518-523.
8. Asopa S, Patel A, Khan OA, Sharma R, Ohri SK. Non-bacterial thrombotic endocarditis. Eur J Cardiothorac Surg. 2007;32:696-701.