Thrombosis of cerebral veins or dural sinuses is a rare event in any patient population, including those with cancer. Cerebral venous thrombosis accounted was diagnosed in only 0.3% of neurological consultations in cancer patients over a four year period at Memorial Sloan-Kettering Cancer Center [23].

The most common cause of cerebral venous thrombosis in cancer patients is a coagulopathy associated with hematologic tumors. Invasion or compression of dural sinuses or cortical veins by tumor occurs most commonly in solid tumors that are metastatic to the dura, skull, or rarely, the leptomeninges [23, 24].

The most common vein affected by metastasis is the superior sagittal sinus. Headache is the most frequent presenting symptom of venous thrombosis. This may be accompanied by focal neurological deficits, encephalopathy, or seizures when there is adjacent venous infarction. Occasionally patients present with an isolated intracranial hypertension syndrome, with headache that may be accompanied by visual disturbances associated with papilledema or abducens palsy. When due to neoplastic vessel compression or invasion, neurologic symptoms from venous thrombosis often develop subacutely, in contrast to the thrombosis associated with coagulopathy, in which symptom onset is typically acute [23].

Brain CT or MRI scanning with contrast may reveal a lack of contrast within the sagittal sinus because of the thrombosis, a finding known as the “empty delta sign” but this is uncommon. Overall MRI is superior to CT in detecting venous thrombosis. The sensitivity increases with the concomitant use of MRA and MRV. MRI can also demonstrate parenchymal abnormalities of venous infarction or hemorrhage, and identify adjacent tumor.

When venous occlusion is due to tumor compression or infiltration, the clinical course is generally progressive and antineoplastic therapy to treat the tumor may be indicated. Therapeutic options include tumor resection, radiation, or systemic therapy. The use of anticoagulation or thrombolysis has not been studied in this setting.

Neoplastic infiltration of arterial vessels has been reported to cause both hemorrhagic and ischemic strokes. Cerebral tumor embolization can result in aneurysm or pseudoaneurysm formation and subsequent aneurysm rupture produces intracerebral and/or subarachnoid hemorrhage. A recent literature review of neoplastic cerebral aneurysms identified 96 published cases. Cardiac myxoma was the most common underlying tumor (60%), choriocarcinoma was next most common (26%) and other malignant tumors accounted for 13.5%. Hemorrhage was universal in choriocarcinoma, less common in other malignant tumors (84.6%) and uncommon in myxoma (19.6%) [25]. Figure 10.3a–c shows multiple brain hemorrhages in a patient with ruptured neoplastic pseudoaneurysms associated with metastatic choriocarcinoma. The diagnosis of neoplastic aneurysm can be made by cerebral arteriography. Neoplastic aneurysms are typically small in size and are often located in distal cerebral arterial branches, in contrast to saccular aneurysms which arise in proximal cerebral arteries. Those from cardiac myxoma are usually multiple, whereas those from malignant tumors are usually single. The prognosis is poor in tumors other than cardiac myxoma. A second, less common, mechanism of aneurysm formation is secondary invasion of nearby vessels by parenchymal brain metastases [26].

Ischemic stroke has also been associated with infiltration of arteries by tumor in the leptomeninges [27, 28]. Patients experiencing ischemia secondary to leptomeningeal metastasis present with abrupt, focal neurological deficits alone or in addition to the typical clinical features of leptomeningeal tumor. Angiography may reveal focal arteriolar narrowing at the base of the brain, over the cerebral convexities, or both. Figure 10.4 demonstrates the angiographic findings in a patient with diffuse leptomeningeal dissemination of glioblastoma. Biopsy showed that leptomeningeal tumor caused vascular narrowing by vessel encasement, vascular wall invasion, and thrombosis [28].

Myeloproliferative disorders are acquired clonal disorders characterized by the proliferation of bone marrow myeloid cells. Among these, polycythemia vera and essential thrombocythemia are the most common to be associated with systemic and neurologic thrombotic complications, including cerebral infarction, TIA and venous thrombosis. Risk factors for thrombosis include those associated with the underlying disease, including increased white blood cell counts, vascular cell activation, endothelial dysfunction, and plasmatic risk factors, such as increased plasma viscosity, reduced levels of protein S, increased thrombin generation and standard stroke risk factors such as increased age, previous thrombotic events, smoking, hypertension, diabetes, dyslipidemia and obesity for arterial events. Oral contraceptives and pregnancy/puerperium) may contribute to venous thrombosis. Primary prevention includes antiplatelet therapy for arterial thrombosis and anticoagulation for venous thrombosis [29]. Of interest, cerebral thromboembolic complications frequently occur during the two years preceding the diagnosis of a myeloproliferative disorder [30]. Cytoreductive treatment of blood hyperviscosity by phlebotomy or chemotherapy substantially reduces thrombotic events and improves survival.

Hyperleukocytosis (>100,000 WBC/mm³) is a rare presentation of acute lymphoblastic leukemia (ALL) . It can also occur in patients with acute and chronic myelogenous leukemias. It typically occurs during blast crisis and results in leukostasis, the plugging of blood vessels by blasts, most commonly in the lung and brain. Coalescence of cells forms leukemic nodules and can be complicated by brain hemorrhage, typically located in the white matter. Clinical signs include focal neurologic deficits and encephalopathy. Brain MRI findings in hyperleukocytosis are rarely reported; one well-characterized case demonstrated multiple hemorrhages and nonhemorrhagic changes on T1- and T2-weighted images with delayed enhancement and restricted diffusion [31]. It is rapidly fatal if not treated. Emergency treatments include hydration, cytoreduction, prevention of tumor lysis, leukapheresis and brain radiation therapy [32, 33].

Intravascular lymphomatosis (IVL) is a rare variant of non-Hodgkin’s lymphoma characterized by a proliferation of lymphoma cells within small caliber blood vessels, with a predilection for the skin and CNS. Figure 10.5 is a brain biopsy depiction of IVL pathology. IVL patients with neurologic involvement most commonly present with subacute progressive multifocal cerebral infarcts and/or a rapidly progressive encephalopathy accompanied by fever. Other sites, such as lung, spleen, and bone marrow may also be involved. In a meta-analysis of the literature between 1962 and 2011, Fonkem et al. [34] identified 740 published cases. The median age was 64 years. The majority (88%) were of B cell origin.

Brain MRI typically demonstrates multiple lesions, most commonly in the cerebral hemispheres. Early diffusion changes that follow the typical time course noted in ischemic events can be observed. Noninvasive and catheter angiography may demonstrate a vasculitis-like appearance [35]. Because the diagnosis is difficult to establish from clinical symptoms, there is often a delay in diagnosis or lack of diagnosis during life. Historically, the majority of cases have been diagnosed postmortem. The most effective therapy is not known, but reports indicate that chemotherapy and rituximab or radiotherapy can stabilize the clinical course.

Abnormalities of the coagulation system are very common in the cancer patient, and there is a high propensity for thrombosis of venous or arterial vessels, especially in widely disseminated solid tumors and in glioblastoma. Venous thromboembolism (VTE) and disseminated intravascular coagulation complicate the course in a significant percentage of patients, depending on the histology. Increases of coagulation factors V, VIII, IX, and XI are often documented in malignancy. Markers of coagulation activation are frequently elevated, including prothrombin fragment 1.2, thrombin antithrombin complex, fibrin degradation products, and D-dimers. Also consistent with a consumptive coagulopathy is the frequent finding of increased fibrinogen and platelet turnover.

Schwarzbach et al. [40] documented the presence of hypercoagulation as a cause of stroke in cancer patients, especially those with significantly elevated D-dimer levels, as compared with controls, and in the absence of conventional stroke risk factors. A hypercoagulable state can result in intravascular thrombosis as well as sterile platelet-fibrin deposition on cardiac valves termed nonbacterial thrombotic endocarditis (NBTE). In comparing the sensitivity of transthoracic and transesophageal echocardiograms, a retrospective review of 654 consecutive cancer patients in whom infectious or noninfectious endocarditis was suspected confirmed the diagnosis of endocarditis in 45 patients (75%). TEE was significantly more sensitive in detecting endocarditis: in 21 of 22 cases, TEE examinations were diagnostic and 16 (42%) of 38 patients with initially nondiagnostic TTE studies had the diagnosis confirmed by TEE study. Vegetations were larger in patients with culture positive endocarditis than in patients without culture positive infection [41].

In a study to determine the frequency of cardioembolic findings in 51 consecutive patients with cancer referred for TEE evaluation of cerebrovascular events, 18% had NBTE and 47 and 55% had definite and definite or probable cardiac sources of embolism, respectively [42]. Singhal et al. [43] compared the MRI findings in patients with infectious endocarditis and NBTE. Patients with NBTE uniformly had multiple, widely distributed, small (<10 mm) and large (>30 mm) infarctions (Fig. 10.7a–c), whereas patients with infectious endocarditis had a variety of stroke patterns including a single lesion, territorial infarction, and disseminated punctate lesions, and numerous small, medium or large lesions in multiple territories.

Cerebral venous thrombosis can occur from direct tumor invasion or compression of the dural sinuses (reviewed above), but more commonly occurs from a hypercoagulable state induced by a neoplasm or chemotherapy. A systemic coagulopathy is the most common cause of cerebral venous thrombosis in patients with hematologic malignancies, especially ALL or lymphoma after treatment with l-asparaginase [23]. Steroids may contribute to the development of thrombosis.

The clinical presentation is similar to patients without cancer who develop sinus thrombosis, and includes headache, vomiting, papilledema, and seizures. Focal neurological signs or encephalopathy may also occur if there is associated cerebral infarction or hemorrhage. Imaging characteristics are reviewed above, but in the instance of coagulation-related venous thrombosis, no skull or dural tumor is identified [44]. Spontaneous resolution or recanalization of nonmetastatic sinus thrombosis can occur, especially early in the course of cancer and its treatment. When the thrombus is symptomatic and persistent, treatment should be considered. Two randomized clinical trials have studied the benefits and risks of anticoagulation in patients without cancer who develop sinus thrombosis. A small trial of intravenous unfractionated heparin found a benefit; a larger trial of low molecular weight heparin found only a nonsignificant trend to benefit [45, 46]. The safety of anticoagulation in ALL patients has been reported in small numbers of patients [47, 48]. Small series also document the benefit of endovascular thrombectomy and thrombolysis [49, 50]. The safety and efficacy of these latter treatments in the cancer population has not been established.

Cerebral arterial occlusions constitute a major source of morbidity in cancer patients. The most common cause for thrombotic arterial occlusions in cancer-associated thrombophilia is NBTE (see above) Vegetations are most commonly located on the aortic and mitral valves. NBTE is significantly more common in cancer patients than in patients without malignancy; it occurs most commonly in adenocarcinoma patients, especially pancreatic cancer [51, 52]. Mucin-producing adenocarcinomas, of which many are pancreatic, are strongly associated with NBTE [53]. Rarely, NBTE is the presenting sign of cancer.

The mechanism of cerebral TIA or infarction in NBTE is small vessel thrombosis as a result of intravascular thrombosis or embolization of a sterile vegetation to brain vessels [54]. Systemic thromboembolism, both venous and arterial, may be a clue to NBTE in a cancer patient with cerebral ischemia. However, one-third of patients have only neurologic symptomatology [52]. The diagnosis may be difficult to suspect on clinical grounds alone, because NBTE can result in signs of encephalopathy caused by multiple small vascular thrombosis. In other patients, sudden focal neurological symptoms of TIA or stroke suggest embolization. The majority of patients with NBTE have only mildly abnormal coagulation parameters. The diagnosis of NBTE is most often rendered in vivo by echocardiographic detection of valvular vegetations. Transesophageal echocardiography is more sensitive than transthoracic. Both neuroimaging and autopsy studies show that cerebral infarcts may be multiple and sometimes have a hemorrhagic component. Cerebral angiography typically discloses multiple vessel branch occlusions, commonly in the middle cerebral artery territory [52].

Appropriate treatment of NBTE includes treatment directed to the underlying cause for the coagulation disorder, such as the neoplasm or sepsis if this coexists. There are no prospective studies of anticoagulation in NBTE; however, individual case reports and retrospective cases series suggest that anticoagulation with heparin appears to reduce ischemic symptomatology in some patients [52]. The potential benefits of anticoagulation should be weighed cautiously against the potential risks of hemorrhage in the cancer patient with NBTE-associated stroke.

Mucin-producing adenocarcinomas are associated with arterial ischemic stroke both in association with, and independently of, NBTE. A 1989 study examined patients with mucinous adenocarcinoma and systemic and cerebral ischemia [55]. Widely disseminated metastases were present in all cases. Varying sizes of cerebral infarctions were found, including disseminated microinfarcts in all patients and large or small/moderate sized infarcts in most. Ischemia affected widespread areas of the CNS, including the cerebral hemispheres, cerebellum, brainstem, basal ganglia, spinal cord, and dorsal spinal roots. Petechial and small hemorrhages were also relatively common. In each of the cases in this series, intravascular mucin was noted within central nervous system capillaries and small arteries on pathological examination.

The mechanism of hypercoagulability in mucin-secreting adenocarcinoma is still not fully understood. Mucin itself may be prothrombotic, the mucin-producing tumor cells may be prothrombotic, or both [56]. There may also be fat emboli in association with mucin [57]. At present, the diagnosis of mucin-positivity is only reliably made pathologically, typically at autopsy. Treatment of the underlying malignancy is the only known method to reduce further cerebrovascular events. Cautious anticoagulation has been suggested in the setting of ischemic stroke and mucin-positive neoplasm, but this therapy is unproven. Figure 10.8 shows multifocal bilateral ischemia visualized on MRI in two patients with breast cancer in whom intravascular mucin was identified pathologically.

Normal physiologic hemostasis involves a balance between thrombus formation and thrombolysis [58]. Disseminated intravascular coagulation (DIC) is characterized by widespread activation of coagulation, with resulting production of fibrin clot formation and thrombotic occlusion of small and medium size vessels. Formation of thrombi leads to consumption of endogenous coagulation factors, platelets, and anticoagulant factors such as Protein S, Protein C, and antithrombin, increasing a risk for bleeding [59]. Acute DIC is most commonly observed in acute promyelocytic leukemia (APML) because of a unique constellation of factors associated with the leukocytes [60]. Other risk factors for acute DIC are pancreatic and other mucin-producing solid tumors, age >60 years, male gender, breast cancer, tumor necrosis, and advanced stage disease [61]. Patients may present with symptoms and signs of excessive hypercoaguability, uncontrolled hemorrhage, or both simultaneously. In aPML, brain hemorrhage is often fatal. Acute, or uncompensated, DIC occurs most frequently with hematogenous malignancies such as the acute leukemias, and is less frequent with solid tumors. Acute DIC typically presents with clinically significant bleeding with concomitant thrombosis. Bleeding from venipuncture sites and surgical wounds may be seen, as well as diffuse mucosal, skin, or retroperitoneal hemorrhage. Central nervous system hemorrhage is a significant and potentially fatal complication, especially in acute promyelocytic leukemia (APML) Laboratory findings in acute DIC include thrombocytopenia, prolonged PT and aPTT, low fibrinogen, elevated D dimer and microangiopathic changes on the peripheral blood smear.

Chronic DIC develops when blood is continuously or intermittently exposed to smaller amounts of procoagulant substances. The coagulation factors and platelets are consumers, but production is able to compensate. Thrombosis generally predominates over bleeding. Chronic DIC more often manifests as thrombosis, rather than bleeding, although either or both hematologic dyscrasias are possible. Chronic DIC has been reported in the clinical settings of NBTE and mucin-positive adenocarcinoma-associated thrombosis. Patients in chronic DIC typically present with deep venous thrombosis and pulmonary thromboembolism, although some may also develop arterial ischemia. Coagulation tests may be normal or show mild thrombocytopenia, mild prolongation of PT and aPTT, and normal or slightly elevated fibrinogen. D dimer is often elevated.

No prospective clinical trials address the optimal treatment for chronic or acute DIC associated with symptomatic cerebral thrombosis or hemorrhage. Treatment of the cancer is fundamental to successful long-term therapy. Anticoagulants, by interrupting the coagulation cascade, are of theoretical benefit. Unfractionated and low molecular weight heparins have appeared beneficial in small, uncontrolled cohorts but have not been definitively evaluated in controlled clinical trials [62]. Direct thrombin inhibitors are promising but unvalidated in controlled trials [59].