Lina Palaiodimou, MD

Neilson LE, Rogers LR, Sundararajan S. Evaluation and Treatment of a Patient with Recurrent Stroke in the Setting of Active Malignancy. Stroke. 2018

This article by Neilson et al. reports a case of a 75-year-old female patient presenting with multiple ischemic lesions with temporal dispersion and localization in multiple arterial territories. The patient was newly diagnosed with lung cancer, more specifically mucinous adenocarcinoma, found randomly in MRI of cervical spine, which was performed as part of differential diagnosis of transient left arm weakness and numbness. Smoking was reported as a predisposing factor for lung cancer, as well as ischemic stroke.

An evaluation of the patient was then started, in order to clarify the etiology of multiple ischemic strokes. Lipoproteins measurement, ECG, carotid duplex ultrasound, lower extremity deep venous thrombosis scan and transthoracic echocardiogram were performed. It is of interest that holter heart rhythm monitoring was not performed, despite that atrial fibrillation could explain multiple strokes in different arterial territories. In fact, holter monitoring is considered necessary before characterizing an ischemic stroke as cryptogenic. D-dimers elevation (5859 ng/mL) was documented during laboratory testing and was thought to reflect the prothrombotic state of the patient, most probable due to the active malignancy. However, D-dimers elevation is also associated with cardioembolic source of an ischemic stroke, thus necessitating thorough examination of the heart, including holter monitoring and transesophageal echocardiogram. A transesophageal echocardiogram would additionally have shown the presence of valvular vegetations indicating non-bacterial thrombotic endocarditis. The test could also have been combined with bubble study, searching for right to left shunt, pointing to paradoxical venous thromboembolic event. It is not stated whether a CT pulmonary angiogram was performed, as part of increased D-dimers investigation, in search of possible asymptomatic pulmonary embolism. Such a finding would have guided to deep venous thrombosis rather than a non-bacterial thrombotic endocarditis of the left cavities of the heart. Nevertheless, as stated by the authors, treatment would have been the same both for non-bacterial thrombotic endocarditis and for intravenous thrombosis.

Consequently, the patient started enoxaparin 1.5 mg/kg daily, in addition to treatment of the primary cause (chemotherapy and radiation). This dosage of low-molecular weight heparin (LMWH) is questionable. In most studies about anticoagulation in cancer-related stroke (such as the OASIS-CANCER trial, which is used as a reference in the article by Neilsen et al.), LMWH is used in full anticoagulant doses, e.g., enoxaparin 1mg/kg twice daily. Measurement of anti-Xa factor could have guided a more targeted and individualized LMWH dosage and is recommended. Despite reduced LMWH dosage, the patient did not experience recurrent strokes since starting enoxaparin.

Having presented their case, Neilsen et al. discuss cancer-related stroke and pathogenetic mechanisms. Hypercoagulability, non-bacterial thrombotic endocarditis, radiation vasculopathy, tumor embolism, paradoxical embolism, chemotherapy and local tumor compression are all mechanisms that can cause ischemic stroke in cancer patients. The authors also comment on treatment of cancer-associated coagulopathy and stroke. Indeed, safety and efficacy of thrombolysis in patients with systemic malignancy and acute ischemic stroke is not well established, but active cancer is not included as an absolute contraindication for intravenous thrombolysis in the 2018 AHA/ASA Stroke Early Management Guidelines. In terms of prevention, LMWH is considered the standard of care, but larger randomized-controlled trials are needed to compare efficacy and safety issues of different treatment options for patients with active cancer and ischemic stroke. Non-vitamin K antagonist oral anticoagulants (NOACs) may appear as an attractive therapeutic option for secondary prevention of cancer-associated ischemic stroke.