Cerebrovascular Complications of Cancer

Abstract

A wide variety of cerebrovascular disorders can complicate the clinical course of cancer patients and, in rare instances, can be the presenting sign of cancer. Central nervous system (CNS) hemorrhage and ischemic events are typically symptomatic. Hemorrhage can occur into the parenchymal, subdural, epidural, or subarachnoid compartments and usually presents with symptoms typical for those sites. Cerebral infarction may cause focal signs, presenting as a transient ischemic attack (TIA) or infarction, or may cause encephalopathy when there are multiple and progressive small infarctions. The most common mechanisms of cerebrovascular disease in cancer patients are related to the presence of CNS tumor, either primary or metastatic, and coagulopathy. The coagulopathy in many instances is a direct effect of the neoplasm; in other cases it develops from cancer treatment. Cancer treatment can also result in blood vessel injury. Radiation therapy directed to the neck or brain can result in vessel stenosis, thrombosis and other vascular pathologies. Chemotherapy and molecularly-targeted agents can lead to vascular injury or thrombosis resulting in hemorrhage or infarction. Infection is a less common cause of stroke. It is important to identify cerebrovascular disease as the cause of neurologic symptoms in the cancer patient in order to determine appropriate evaluation and treatment. This is usually possible by a careful review of the cancer histology and sites of disease, types of antineoplastic therapy administered, and associated comorbidities. Laboratory studies of coagulation function and CNS imaging techniques are useful in identifying the precise etiology of the cerebrovascular disorder. Prompt diagnosis leads to appropriate therapy that, in certain patients, can improve the quality of life and survival as well as prevent additional vascular episodes.

Introduction

In a large retrospective autopsy study of 3426 systemic cancer patients, stroke was identified in 14.6% of patients, second only to metastasis as the most common CNS pathology. Hemorrhages and ischemic lesions were present in equal numbers. Overall, more than half the patients had significant clinical symptomatology associated with the cerebrovascular disorder, more often in hemorrhages than infarctions [1]. More recent clinical prospective and retrospective studies describe the CNS vascular complications of new antineoplastic treatments and also provide additional information on the risk of stroke in cancer patients, the most sensitive methods for determining the etiology, and the results for stroke and stroke prevention.

The largest prospective study of stroke in cancer patients is a Swedish cohort of 820,491 cancer patients followed for first hospitalization for hemorrhagic or ischemic stroke, as compared to patients without cancer. The overall risk of hemorrhagic and ischemic stroke during the first six months after cancer diagnosis was 2.2 and 1.6, respectively. The risk decreased rapidly, but remained elevated even ten years after cancer diagnosis [2].

A recent clinical retrospective study of intracranial hemorrhages in cancer patients identified 208 intracerebral and 46 subarachnoid hemorrhages. The majority of patients (68%) had systemic solid tumors, and equal numbers were hematopoietic and primary brain tumors. Intratumoral hemorrhage and coagulopathy accounted for the majority of hemorrhages. Hypertension was a rare cause. The prognosis was similar to intracranial hemorrhage in the general population [3]. In a clinical retrospective review of ischemic strokes in 96 cancer patients, the cancers were most commonly lung, brain, and prostate. The most common cause was embolism, due partially to hypercoagulability. Atherosclerosis was the cause in less than 25% [4]. In children with cancer, the prevalence of stroke is approximately 1%, with an equal distribution of hemorrhagic and ischemic strokes [5]. The most common underlying cancers are leukemia and primary brain tumors.

Stroke can also rarely be the presenting sign of cancer. In a retrospective review of 5106 patients admitted for ischemic stroke, Taccone et al. [6] identified less than 1% to have a previously undiagnosed malignancy. The principal mechanisms of stroke in the cancer patients were nonbacterial thrombotic endocarditis (NBTE), diffuse intravascular coagulation, and atherosclerosis. The most frequent neoplasms were lung and breast cancer.

The prognosis of cancer-related CNS hemorrhage varies widely, depending upon the etiology. No detailed retrospective or prospective studies of prognosis are available. The prognosis of patients with ischemic stroke varies depending on the activity of cancer. In a retrospective review of ischemic stroke patients (4918) admitted to a university hospital, 300 were identified to have cancer that was inactive in 227 patients and active in 73 patients. Stroke patients with active cancer were significantly younger than those without active cancer, had more severe strokes, more frequently had cryptogenic strokes, and more often had infarcts in multiple vascular territories of the brain. In-hospital mortality was significantly higher in patients with active cancer (21.9% vs. 5.2%) [7].

In determining the etiology of stroke in the cancer patient, various factors must be considered. Traditional cerebrovascular risk factors seen in the general population such as age, hypertension, coronary artery disease, hypercholesterolemia, tobacco use, diabetes, and family history of stroke should be assessed, but cancer patients more often have stroke as a cancer-related event, in which the malignancy directly or indirectly contributes to the cerebrovascular insult. Thus, additional consideration must be given to the causes of stroke that are unique to the cancer patient. A detailed investigation and precise diagnosis of cerebrovascular disorders in cancer patients are critical because early recognition of stroke may allow the cancer patient access to surgical or medical interventions to improve the clinical outcome. In addition, secondary stroke prevention therapies are guided by the etiology of the cerebrovascular event. Lastly, the diagnostic evaluation in young or cryptogenic stroke patients may lead to the first recognition of an underlying malignancy.

This chapter will explore the etiologies of stroke within the oncologic population and discuss their diagnosis and management.

Stroke Due to Central Nervous System Tumor

Intratumoral Parenchymal Hemorrhage

Hemorrhage into brain tumors, both metastatic and primary, is reported to account for 1–10% of all intracranial hemorrhages [8,9,10]. The variation in reported frequency is due, in part, to the method of diagnosis; some hemorrhages are clinically silent and identified only on imaging or at autopsy. Metastatic tumors are more often associated with hemorrhage than are primary tumors, including hemorrhage as the initial manifestation of CNS tumor.

The most common metastatic brain tumors associated with bleeding are melanoma, lung, renal cell, breast, thyroid, hepatocellular cancer and choriocarcinoma [3, 10, 11]. Hemorrhage associated with metastatic tumors can occur in any location in the cerebral hemispheres, brain stem, or cerebellum and may be single or multiple. In some instances, notably malignant melanoma and other angioinvasive tumors, the diagnosis of brain metastasis is established only at hematoma resection demonstrating microscopic malignant cells.

The most common primary CNS tumors associated with intratumoral hemorrhage are glial tumors, especially glioblastoma, and germ cell tumors. Figure 10.1a, b shows the macroscopic and microscopic features of a fatal intratumoral hemorrhage into a GBM. Oligodendrogliomas are particularly prone to hemorrhage because of the delicate retiform capillaries associated with them [12]. Hemorrhage into meningioma is relatively uncommon and occurs most often in patients who are less than 30 or more than 70 years of age, located in the convexity or ventricle, and of fibrous histology [13]. Intratumoral hemorrhages are also reported infrequently in association with a wide variety of other primary brain tumors, including medulloblastoma, choroid plexus papilloma, schwannoma, ependymoma, pineal region tumors, and lymphoma.

Fig. 10.1

a Brain coronal section demonstrating a glioblastoma with necrosis and intratumoral hemorrhage, centered within the right anterior frontal white matter. There is prominent mass effect. b Microscopic image in this patient at autopsy reveals fibrillary and giant cells, with intervening areas of hemorrhage (H&E ×200)

The most common clinical symptoms in patients with intratumoral hemorrhage are headache, nausea, vomiting, obtundation, seizures, and focal neurologic deficits, similar to hemorrhages of other etiology. The symptoms may be acute or subacute. Bleeding may be spontaneous or associated with predisposing factors such as head trauma, hypertension, coagulopathy, shunting procedures, surgery, and anticoagulation [3]. Various pathophysiologic processes unique to the tumor also contribute to intratumoral hemorrhage, including overexpression of vascular endothelial growth factor and matrix metalloproteinases, endothelial proliferation, rapid tumor growth, vessel necrosis, and compression or invasion of adjacent parenchymal vessel walls by tumor [14, 15].

Imaging findings on brain CT or MR scan that suggest neoplastic hemorrhage include early edema, an indentation appearing on the hematoma surface that enhances with administration of contrast, delayed hemorrhage evolution and early perihemorrhage enhancement [16, 17].

Treatment is directed to the underlying tumor and may include surgical resection followed by radiation therapy and medical therapies appropriate to the histology. Patient outcome after intratumoral hemorrhage is related to the specific histological malignancy of the tumor and extent of the systemic cancer. There appears to be a higher risk of recurrent hemorrhage if the tumor is incompletely excised or if metastases recur.

Hemorrhage into pituitary adenomas (pituitary apoplexy) is a unique and rare disorder, often accompanied by infarction of the pituitary gland. It can be life-threatening because of corticotropin and thyroid hormone deficiency. The most common presenting symptom is headache, followed by visual field abnormalities and cranial nerve palsies. MRI is superior to CT in establishing the diagnosis. MRI typically shows an intra-and suprasellar expanding mass with T1 and T2 signal intensities consistent with the evolution of blood products. Enhancement is usually faint. Thickening of the sphenoid sinus mucosa is highly indicative of pituitary apoplexy [18].

A recent retrospective review from the Mayo Clinic identified 87 cases of pituitary apoplexy, mostly male, with a mean age of 51 years. Only 25% had a known pituitary adenoma. The most common associated factor was hypertension (39%). Long-term outcome was good, although most patients required long-term hormonal placement [19]. There are no controlled studies to prove a benefit of surgical decompression; observation, with replacement of hormones as clinically indicated, is appropriate in many patients.

Neoplastic Subdural Hemorrhage

Subdural hematomas and hygromas are common etiologies for cerebrovascular disease in cancer patients, comprising 12.6% of all strokes and 25.8% of hemorrhagic lesions identified at autopsy within this population [1]. Overall, subdural hemorrhages related to dural metastasis are less common than those related to coagulopathy or trauma in cancer patients [20]. Neoplastic subdural hemorrhages occur more commonly in patients with solid, rather than hematological tumors, and in particular with tumors metastatic from prostate, lung, or breast cancer primaries [20, 21].

Neoplastic infiltration of the dura results from hematogenous spread of tumor into the dural vessels or from direct extension of skull metastasis. Proposed mechanisms for the occurrence of subdural hematoma with dural metastasis include hemorrhage directly into the dural tumor, hemorrhage secondary to dilatation and rupture of the inner dural capillaries/venules/veins due to outer vessel layer obstruction by tumor, and in rare cases, dural tumor production of a hemorrhagic effusion.

Acute and subacute subdural hemorrhages are more common than are chronic. Graus et al. [1] reported that one-quarter of their 53 autopsied subdural hematoma patients with cancer were symptomatic. Clinical manifestations in the oncologic population differ little from the general population. The most common clinical symptoms are altered mental status, headache, and lethargy. Focal neurological deficits and seizures may also be present.

Acute or chronic subdural hematomas and skull metastases are generally easily visualized with both CT and MRI. Contrast studies are helpful in revealing skull or dural enhancement. Histologic examination of the dura with biopsy or cytologic studies of the subdural fluid may be necessary to confirm the tumoral origin of the subdural hematoma. Figure 10.2a–c shows the imaging and subdural fluid cytology findings in a patient with dural metastasis from lung cancer [22].

Fig. 10.2

a Brain magnetic resonance image taken on admission shows bilateral masses in the brain. b Brain magnetic resonance image taken on deterioration of symptoms shows bilateral crescent-shaped isointensity lesions and a shrunken brain mass. c Adenocarcinoma cells detected in hematoma fluid (All Used with permission of Elsevier from Hata et al. [22])

Treatment of dural metastasis-associated hemorrhage is palliative and includes drainage of subdural fluid and radiation therapy.

Neoplastic Infiltration of Cerebral Vessels

Venous Infiltration

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.

Arterial Infiltration

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].

Fig. 10.3

Intracerebral hemorrhages due to metastatic choriocarcinoma with pseudoaneurysm formation. a Computed tomography on day 20 shows right frontal (large arrow) and right parietal hemorrhages with extension to the lateral ventricle (small arrows). b Magnetic resonance imaging on day 25 shows a new left posterior frontal hemorrhage (large black arrow) and left parieto-occipito-temporal subdural hematoma (large white arrow) and old right frontal and parietal hemorrhages (small arrows). c Computed tomography on day 29 shows increase in the left frontal hemorrhage and new occipital hemorrhages (large arrows) and old right temporal and parietal hemorrhages (small arrows) (All Used with permission of John Wiley and Sons from Kalafut et al. [131])

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].

Fig. 10.4

Digital subtraction angiography of vertebral artery injection performed in the anteroposterior projection shows multiple zones of irregularity and narrowing involving the basilar artery, bilateral posterior cerebral arteries, bilateral superior cerebellar arteries and bilateral anterior inferior cerebellar arteries (Used with permission from Herman et al. [28])

Hematologic Malignancies

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.

Fig. 10.5

Brain biopsy in a patient with confusion and multiple enhancing parenchymal lesions on brain MRI reveals intravascular lymphoma (H&E ×400)

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.

Tumor Embolus

Ischemic stroke secondary to tumor embolism is rare. In the series by Graus et al. [1] only two patients had tumor emboli identified as the etiology of infarction. Most reported cases of tumor embolic stroke result from intracardiac tumors. The majority of the tumors arise from the left side of the heart. They are most often benign. In a large recent series of resected primary cardiac tumors, myxoma was the most common histology (72.6%). Fibromas and sarcomas were rare, 6.9 and 6.4% respectively. Ten percent of patients with intracardiac tumor experienced a stroke [36].

Cerebral TIA or infarction may also occur from tumor emboli arising from tumors metastatic to the heart. Cardiac metastasis usually occurs in the presence of widely metastatic disease. In an autopsy study of 95 patient with cardiac metastases, the underlying cancers, in descending order, were of lung, lymphoma, breast, leukemia, gastric, melanoma, liver and colon origin [37, 38]. Figure 10.6a–d shows the head CT, echocardiography and brain pathology of cerebral embolism from a cardiac metastatic tumor.

Fig. 10.6

Imaging and histologic findings in a patient with multifocal stroke from tumor emboli. a Head computed tomography demonstrating a left frontal lobe hypodensity consistent with middle cerebral artery territory infarction. b Transthoracic echocardiogram with apical 3-chamber view showing 2 large mobile echodensities attached to the septum and inferolateral wall of the left ventricle (V). c Frontal lobe arteriole occluded by moderately differentiated squamous cell carcinoma. Recent infarction is present surrounding the embolus, with disintegration, vacuolization, and pyknosis of neurons (hematoxylin-eosin, original magnification ×20). d Tumor embolus of squamous cell carcinoma occluding a cerebellar vessel. Small areas of infarction surround the embolus, with proliferation of capillaries and macrophages (hematoxylin-eosin, original magnification ×40) (All Used with permission of American Medical Association from Navi et al. [38]. All rights reserved)

As in other embolic strokes, neurological symptoms are typically sudden and infarction may be preceded by TIA. History and physical examination findings of cardiac dysfunction such as limb edema, dyspnea, arrhythmias, peripheral vascular emboli, and precordial murmurs are helpful in identifying a cardiac tumor. Echocardiography is a reliable means of diagnosing cardiac tumors and may suggest the histology. Transesophageal echocardiogram is superior to transthoracic echocardiography in evaluating atrial tumors. False negative echocardiograms have been reported in cardiac neoplasm patients; cardiac MRI and CT can be useful in this situation. Tissue diagnosis involves obtaining a pathological specimen through endomyocardial biopsy or surgical resection of the tumor.

Primary or metastatic lung cancers can also produce TIA or cerebral infarction from a tumor embolus that accesses the pulmonary venous system and then passes through the left heart chambers to the cerebral vasculature. Cerebral infarction that is identified in the peri-operative period after lung cancer biopsy or resection should suggest embolization of a tumor fragment [39]. Patients with tumor embolic ischemia should be followed with surveillance brain imaging to observe for tumor growth.

Stroke Due to Remote Effects of Tumor: Hyper- and Hypocoagulopathies

Hypercoagulability and Thrombosis

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.

Fig. 10.7

a Initial DWI in a patient with infective endocarditis shows disseminated punctate ischemic lesions (pattern 3). Note the incidental ventricular hyperintensity (arrow), suggestive of ventriculitis. b Follow-up DWI after 1 week shows additional punctate lesions but no change in the stroke pattern. c Initial DWI in a patient with nonbacterial thrombotic endocarditis shows multiple small and large lesions (pattern 4) (All Used with permission from Singhal et al. [43])

Venous Occlusions

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.

Arterial Occlusions

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-Positive Adenocarcinoma-Associated Hypercoaguability

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.

Fig. 10.8

MRI, focal T2 hyperintensities involving all lobes in Case 1, most prominently left occipital lobe in Case 2 (All Used with permission of Springer Science from Bernardo et al. [56])

Combined Hypercoaguability/Bleeding Diathesis

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].

Bleeding Diathesis/Hemorrhage

Primary Fibrinolysis

Primary fibrinolysis is characterized by systemic activation of plasmin or direct fibrinogen degradation. Intracranial hemorrhage may result from primary fibrinolysis in association with acute DIC early in the course of APML. Primary fibrinolysis, without DIC, has been observed in some leukemias and solid tumors, especially prostate cancer. Cerebrovascular complications are rare in this setting. Treatment consists of administering cryoprecipitate or fresh frozen plasma. Epsilon-aminocaproic acid or tranexamic acid may also be given [63].

Thrombocytopenia

Thrombocytopenia is not uncommon in the cancer population and poses a risk for intracranial hemorrhage Thrombocytopenia-associated cerebral hemorrhage in oncology patients can be secondary to extensive marrow infiltration by tumor, peripheral destruction of platelets due to tumor-associated hypersplenism, under-production of platelets due to radiation- or chemotherapy-induced toxicity, DIC, autoimmune dysfunction, and/or microangiopathic hemolytic anemia. Cancer-associated hemolytic anemia is a Coombs-negative hemolytic anemia. A review of published cases published in 2012 reported 154 cases associated with solid cancer and 14 cases with lymphoma. The majority of the cancers were metastatic. The prognosis is poor. Treatment includes antitumor treatment and plasma exchange or fresh frozen plasma; the latter was rarely effective, except in prostate cancer patients [64].

Immune-mediated peripheral platelet destruction is rarely seen with solid tumors, but has been reported with lymphoproliferative disorders such as Hodgkin’s disease, chronic lymphocytic leukemia, and low-grade lymphoma [65]. Diagnosis is difficult but may be supported by the acute onset of thrombocytopenia, large platelet size, elevated megakaryocyte count, and increased platelet-associated immunoglobulin. Treatment may include corticosteroids, immunoglobulin infusions, plasmapheresis, antineoplastic therapy directed at the specific underlying malignancy, vincristine, danazol, and immunoabsorption with staphylococcal protein A.

Thrombotic thrombocytopenic purpura (TTP) is a syndrome of target organ dysfunction due to marked platelet aggregation in the microcirculation that can be induced both by cancer and by chemotherapeutic treatment [66]. Thrombotic thrombocytopenic purpura is characterized by severe thrombocytopenia, a microangiopathic hemolytic anemia, and renal failure (hemolytic-uremic syndrome) Intracerebral hemorrhage and cerebral infarction are potentially disastrous events that may complicate the course of patients with TTP. Platelet aggregates in TTP most commonly occlude the arterioles and capillaries in the brain, heart, kidneys, and adrenal glands. Clinically, purpuric rash, fever, and neurological and renal symptoms are common. Laboratory studies demonstrate severe hemolytic anemia, thrombocytopenia, and schistocytosis. Thrombotic thrombocytopenic purpura can be differentiated from DIC by the absence of a coagulopathy. In cancer patients, TTP is most commonly seen with gastric adenocarcinoma, followed by breast, colon, and small cell lung carcinoma. Treatment options include corticosteroids, plasma exchange, immunoabsorption with staphylococcal protein A, platelet inhibitor drugs, vincristine, and splenectomy. Platelet transfusions are reserved for situations of documented bleeding. Mortality in TTP without treatment is 90–100%. With appropriate treatment, mortality decreases to 10%.

Sequelae of Cancer Treatment

In addition to cancer and its associated coagulopathies as a cause of stroke, ischemic or hemorrhagic strokes can result from certain diagnostic procedures, radiation therapy, surgical therapy, endovascular treatments, or chemotherapy.

Cancer Therapy: Radiation

Radiation-Induced Vasculopathy

A variety of delayed vasculopathies can complicate therapeutic radiation to the brain or neck. Pathologic studies demonstrate that radiotherapy produces a sequence of vascular changes characterized by initial damage to endothelial cells, followed by thickening of the intimal layer, cellular degeneration, and hyaline transformation. Stenosis and occlusion of medium and large vessels leading to ischemic infarction is the most common sequela, but lacunar infarction, primary intracerebral hemorrhage, moyamoya changes resulting in ischemia or hemorrhage, and the formation of cerebral aneurysms and pseudoaneurysms also occur [67, 68].

Several large scale studies, particularly those from the Childrens Cancer Study Group (CCSG) describe the risk of stroke in pediatric cancer survivors (alive > five years), especially those with brain tumors and those with leukemia who received cranial radiation therapy. The rate of first occurrence of late-occurring stroke was determined in leukemia (n = 4828) and brain tumor survivors (n = 1871) as compared with a group of a random sample of cancer survivor siblings (n = 3846). The rate for leukemia survivors was 57.9 per 100,000 person-years and the relative risk for stroke, as compared with the sibling comparison group, was 6.4. In brain tumor survivors, the rate was 267.6 per 100,000 person-years and the relative risk was 29. Mean cranial radiation therapy dose >30 Gy was associated with an increased risk in both leukemia and brain tumor survivors in a dose-dependent fashion, with the highest risk after doses of >50 Gy [69].

The CCSG also recently identified that among childhood cancer survivors with stroke, there is a risk of recurrent stroke, especially those receiving >50 Gy cranial radiation therapy. The risk persists for decades after the first stroke: the ten-year cumulative incidence of late recurrent stroke was 21% overall and 33% for those treated with high dose cranial radiation therapy. Hypertension also independently predicted recurrent stroke in this population [70].

Single institution studies also confirm and characterize the risk of stroke in survivors of pediatric brain tumors and that location of tumor influences the risk. Multivariate and logistic regression analysis in one study showed that children treated with cranial radiation therapy and those with optic pathway gliomas had the highest risk of nonperioperative stroke [71]. Treatment of tumors close to the circle of Willis, especially optic pathway gliomas and the prepontine cistern, were associated with the highest risk in another study [72]. Location of tumor is also important in adult patients. Aizer and coworkers [73] recently identified that radiation therapy administered to primary brain tumors near the circle of Willis was associated with an increased risk of death secondary to cerebrovascular disease as compared to radiation to distant sites. Adults irradiated for pituitary adenomas (especially males) are also at risk for delayed stroke and TIA [74].

A recent literature review between 1978 and 2013 identified 46 patients with 69 intracranial aneurysms within the irradiated field. The mean age at radiation exposure was 34 years and the mean lag time between radiation and diagnosis was 12 years (range, 4 months to 50 years). Aneurysms were saccular in 83%, fusiform in 9, and 9% were considered pseudo-aneurysms. Just over half of the aneurysms presented with hemorrhage [75]. Aneurysms can develop after radiosurgical treatment as well as external beam radiation [76]. There is a high rate of rupture in radiation-induced aneurysms and they are associated with significant morbidity and mortality. Treatment includes surgery or endovascular treatment [77].

Another vascular abnormality that can develop after cranial radiation therapy is a cavernous malformation, reported predominantly in pediatric patients radiated for leukemia, primary brain tumor, and within the setting of hematopoietic stem cell transplantation. They are more common after whole brain than reduced-field radiation [78] and typically develop several years after radiation [79, 80]. Most cavernous malformations are detected incidentally, as seen in Fig. 10.9. In symptomatic patients, the most common presenting symptom is seizure. Roughly one third have hemorrhage and may require surgery [81]. The clinical behavior can be more aggressive when chemotherapy is administered, especially methotrexate [82]. Spinal cord cavernous malformations are also reported within the field of spine radiation therapy [83].

Fig. 10.9

Transverse T2-weighted spin-echo MR images (3000/100) obtained in 20-month-old girl with telangiectasia. Image obtained 4 years after completion of radiation therapy shows two telangiectatic foci (arrows) in the left frontal lobe and right parietal lobe (Used with permission of RSNA from Koike et al. [79])

Telangiectasias are smaller vascular malformations that can be observed on MRI after brain radiation therapy administered in childhood. Among 90 children who were followed for at least six months after brain radiation, telangiectasias were observed in at least one area in 18 (20%) patients. The frequency was similar following low dose and high dose radiation. The number of lesions increased on followup of ten years [84].

A literature review of moyamoya syndrome diagnosed after brain radiation therapy from 1967 to 2002 identified 54 patients. Patients with neurofibromatosis 1 and those who received radiation to the parasellar region at a young age (<5 years) were found to be the most susceptible. The incidence increases with time, with half of cases occurring within four years of radiation and 95% occurring within 12 years [85].

Radiotherapy can produce or accelerate atherosclerosis and it is a causative factor in transient or permanent cerebral ischemia in some patients radiated for head and neck cancer. Because of the radiation treatment portals, extensive areas of the common carotid artery and its branches in the neck are radiated. In a report of stroke in patients younger than 60 years of age who received therapeutic neck radiation for head and neck tumors, Dorresteijn and coworkers reported a 12% 15-year cumulative risk of stroke [86]. In a well-characterized retrospective study, Dorth and coworkers [87] found that 14% of head and neck cancer patients treated with neck radiotherapy had evidence of carotid stenosis at four years as compared to 4.2% in the general population.

The degree to which conventional stroke risk factors, such as hypertension, dyslipidemia, smoking history, and diabetes in head and neck patients also contribute to carotid stenosis is debated. Among 50 patients radiated for head and neck cancer, and comparing carotid artery stenosis and plaque formation between the radiated and non-radiated side, Gujral and coworkers [88] determined that traditional vascular risk factors do not play a significant role in radiation-induced carotid atherosclerosis. A summary of published studies in which the rate of extracranial carotid stenosis was compared between neck cancer patients who received radiation and those who did not (controls) includes 1070 patients. The incidence of severe extracranial carotid stenosis is significantly higher among those who received radiation. Like others, the authors recommend that irradiated patients be closely monitored with periodic carotid ultrasound [89].

Survivors of childhood Hodgkin’s disease are also at risk for stroke if they receive mantle radiation exposure. In these patients cerebral ischemia may be related to carotid artery disease or to cardiac valve disease with embolism [90].

Stroke-like migraine attacks after radiation (SMART syndrome) is a rare syndrome occurring within years of brain radiation and is characterized by the occurrence of cerebral symptoms and signs associated with migraine headaches and cortical enhancement on brain MRI. The mechanism is not known, but is speculated to be a delayed manifestation of vascular injury. It typically has a good prognosis, but a recent report indicates that not all patients recover [91].

For symptomatic or high grade post-radiation carotid stenosis revascularization procedures may be indicated. The superiority of endarterectomy versus stenting is controversial. Sano et al. [92] reported that, by comparison, carotid endartectomy is safer. However, Cam et al. [93] reported that stenting is safe and durable. A recent multi-institutional comparison of carotid artery stenting for radiation therapy-associated carotid artery stenosis (43 patients) with non-irradiated patients found no difference in morbidity, revascularization, and restenosis [94].

In head and neck cancer patients, arterial injury due to surgery and radiation therapy may also present as arterial rupture (carotid blow-out ). Post-radiation rupture of the carotid artery typically occurs within 2–16 weeks after radical neck surgery and radiation therapy. Rupture may be associated with other local treatment-related complications, such as infection, sloughing of the skin flaps and orocutaneous fistulas. Carotid blowout is a life threatening complication that requires surgical intervention. Brinjikji and Cloft [95] reviewed 2003–2011 data from the Nationwide Inpatient Sample and among 1218 patients who underwent endovascular treatment for carotid blowout; 89% underwent embolization procedures and 11% underwent carotid stenting. Hemiplegia rates were higher in stented patients than embolization (3.8% vs. 1.4%). The mortality rate was similar.

Cancer Therapy: Effects of Surgery

Direct Effects of Surgery

A rare complication of biopsy or removal of a primary or metastatic lung cancer is a peri-or postoperative cerebral infarction due to the release of tumor emboli [96]. It is important to monitor such patients with tumor embolic infarction for the subsequent development of a mass lesion associated with tumor growth [97]. Stroke is also a potential complication of advanced head and neck cancer resection because of the necessity to remove tumor in close proximity to the cervical carotid artery. However, the incidence of this complication has significantly declined in recent years. A recent retrospective study of 14,387 patients undergoing neck dissection found that the 30-day incidence of ischemic stroke was 0.7%, similar to matched patients undergoing thoracic surgery and colectomy. Factors independently associated with a higher risk of stroke within 30 days following neck dissection were standard stroke risk factors: age above 75 years, diabetes, hypertension, or prior stroke [98].

Resection of brain tumors is also associated with adverse effects on blood vessels.

The largest study of surgically-related cerebral infarction and hemorrhage in patients undergoing resection of malignant brain tumors is obtained from the Nationwide Inpatient Sample. Among 16,530 such patients undergoing tumor resection, the most common surgical complication was cerebral infarction, with an estimated incidence of 16.3/1000 cases. The second most common complication was brain hemorrhage or hematoma, with an incidence of 10.3/1000 cases. Because of the nature of data collection by ICD9 codes, it is not possible to determine if the diagnosis of infarction or hemorrhage/hematoma was based on incidental postoperative imaging findings or associated with neurological deficits. However, infarctions and hemorrhage/hematoma were associated with an increase of in-hospital mortality by 9-fold and 3-fold, respectively, suggesting that many of them were symptomatic [99].

Immediate post-operative diffusion-weighted MRI sequences often reveal changes of cerebral ischemia in patients undergoing removal of brain tumors. In recent years, the clinical significance of these imaging changes, particularly after glioma surgery, has been recognized. Rather than simply cortical or subcortical structural damage of eloquent brain tissue from surgery, Gempt et al. [100] demonstrated that peri- or postoperative ischemic lesions play a crucial role in the development of surgery-related motor deficits.

A matched case-control study assessing new postoperative deficits as compared to no deficits in patients undergoing resection of WHO grade 2–4 gliomas identified that postoperative neurological deficits were associated with peritumoral infarction and that volumes of DWI abnormalities were larger in those with deficits than those without. Peri-tumoral infarctions were more common and were larger in patients with acquired deficits after glioma surgery compared to glioma patients without deficits when assessed by early postoperative DWI [101]. Longitudinal followup of the post-operative ischemic lesions shows that the diffusion-weighted abnormality typically resolves and is replaced by contrast enhancement, ultimately demonstrating encephalomalacia at long-term follow up [102]. The early enhancement can be confused with tumor progression and correlation with the immediate postoperative DWI changes can assist in the differential. Figure 10.10a–d shows the evolution of diffusion-weighted MRI abnormalities following resection of a low-grade glioma.

Fig. 10.10

Neuroimages obtained in a 27-year-old man with a left frontal Grade II fibrillary astrocytoma. a Axial T1-weighted MR image (left) and diffusion-weighted trace image (right) revealing a left frontal nonenhancing mass with no evidence of reduced diffusion. b Unenhanced and contrast-enhanced T1-weighted images (upper) obtained immediately postoperatively. Diffusion-weighted trace image and an ADC map (lower) demonstrating a new area of reduced diffusion (arrows) in the anterior surgical bed. c Two MR images obtained at the 1-month follow-up examination depicting the emergence of new contrast enhancement (arrow) corresponding to the area of reduced diffusion seen on the diffusion weighted image obtained immediately postoperatively. d An MR image obtained at the 3-month follow-up examination (All Used with permission from Smith et al. [102])

Diffusion-weighted changes associated with new postoperative deficits have also been reported after resection of brain metastasis. Ischemic lesions were more common in patients who had been treated with brain radiation as compared with those without. Presence of such lesions was significantly associated with transient or permanent neurological deficits [103].

Immediate post-operative areas of brain ischemia can also be identified outside the area of a resected brain tumor and the mechanism for this is not known. Tumor biopsy or resection can also be complicated by hemorrhage. Hemorrhage may also be remote from the site of surgery, most commonly cerebellar hemorrhage following supratentorial tumor surgery. Potential mechanisms include arterial hypertension, coagulation disorders, overdrainage of cerebrospinal fluid, disturbances of venous drainage associated with head position, and unrelated vascular lesions [104].

Other rare vascular complications of surgery for brain tumors include cerebral venous thrombosis, cerebral vasospasm especially following resection of base of skull tumors, and PRES following resection of posterior fossa tumors in children [105, 106].

Endovascular Treatment : Associated Stroke

Selective intra-arterial infusion of blood–brain barrier disruption and antineoplastic agents is a treatment approach for selected cerebral malignancies that can be complicated by ischemic stroke [107]. Catheter-administered embolization to occlude the vascular supply to meningiomas is very effective in obliterating blood supply but carries a small risk of cerebral infarction and hemorrhage [108, 109].

Cancer Therapy: Chemotherapy and Other Antineoplastics

Hypercoagulability and Thrombocytopenia

Antineoplastic chemotherapy, including single or multiagent chemotherapy, hormonal therapy, and hematopoietic growth factors can produce a hypercoagulable state in cancer patients and contribute to cerebral arterial and venous thrombosis [110]. Physiologic investigations in patients treated with chemotherapeutic agents have documented activation of the coagulation pathway, suppression of natural anticoagulants, suppression of natural fibrinolysis, and injury to vascular endothelium. Thrombocytopenia, TTP, DIC, and microangiopathic hemolytic anemia have all been linked to chemotherapeutic agents. Postulated mechanisms for antineoplastic drug-related thrombophilia include release of procoagulants and cytokines from injured tumor cells, direct drug toxicity to vascular endothelium, direct induction of monocyte or malignant cell tissue factor, and decrease in physiological anticoagulants.

Among individual chemotherapeutic agents associated with stroke, l-asparaginase is one of the most well-known. l-asparaginase is an enzymatic inhibitor of protein synthesis that is used in combination with other chemotherapeutic agents in the treatment of acute lymphoblastic leukemia and some other lymphoid malignancies [111, 112]. The reduction in protein synthesis produced by l-asparaginase not only inhibits growth of leukemic neoplasms, but also decreases liver production of multiple plasma proteins involved in hemostasis. Strokes associated with l-asparaginase induction therapy may present as dural sinus thrombosis, cortical or capsular infarction, or intracerebral hemorrhage. Venous thrombosis is most common.

The incidence of stroke in patients treated with l-asparaginase induction therapy has ranged in different series from 0.9 to 2.9%. Stroke tends to occur shortly after induction treatment. The clinical presentation varies depending on the location and type of stroke. The precise mechanism for l-asparaginase-associated thrombosis stroke is unclear, although l-asparaginase has been shown to diminish antithrombin III, protein C, protein S, factor XI, factor IX, and fibrinogen, and to increase PT/PTT and platelet aggregability. Coagulation factors return to normal within 7–10 days after therapy. Therapies for l-asparaginase-associated strokes, depending on the clinical situation, vary widely and may include fresh frozen plasma, heparin, cryoprecipitate, platelet transfusion, aspirin, and surgery for hematoma drainage.

Stroke has also been associated with a variety of other chemotherapeutic agents. 5-fluorouracil therapy, alone and in combination with cisplatin, methotrexate, and cyclophosphamide, has been associated with acquired protein C deficiency and stroke. Acute stroke and acquired protein C deficiency has also been reported following cisplatin therapy without 5-fluorouracil. Stroke has been associated with paclitaxel, shortly after administration and in breast cancer survivors after adjuvant chemotherapy and radiation [113].

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been associated with venous and arterial thrombosis, possibly by enhancing aggregation and binding of neutrophils to vascular endothelium. A meta-analysis of 52 reported series found an incidence of venous and arterial thrombosis of 4.2% with GM-CSF and 1.2% with G-CSF.

Bevacizumab, a monoclonal antibody that binds to and inhibits the biologic activity of vascular endothelial growth factor (VEGF) , is approved for treatment of metastatic colon carcinoma, nonsmall cell lung carcinoma, and recurrent glioblastoma. The most significant toxicities of this agent are systemic thrombosis or hemorrhage, including deep venous thrombosis, myocardial infarction, and hemoptysis. Imatinib mesylate administration for leukemia is rarely associated with subdural hemorrhage [114].

The posterior reversible encephalopathy syndrome (PRES) is increasingly recognized as a neurological complication of cytotoxic chemotherapies and targeted agents used to treat cancer, including brain tumors. It is also a known complication of uncontrolled hypertension, preeclampsia, sepsis, and adverse effect of immunosuppressive drugs used in organ and stem cell transplant. The mechanism of PRES is controversial; it is primarily thought to be a result of endothelial injury leading to impaired autoregulation and vasoconstriction. Characteristic neurological signs commonly include headache, generalized seizures, encephalopathy, sometimes progressing to coma or alteredvision (typically cortical blindness or hemianopia). The onset may be acute or subacute.

The basic PRES pattern resembles the brain watershed zones, with the cortex and subcortical and deep white matter involved to varying degrees. Figure 10.11a, b shows extensive bilateral cerebral hemisphere signal intensity abnormality and abnormal cerebral angiography in a patient with PRES [115].

Fig. 10.11

FLAIR MRI in a patient with PRES associated with bevacizumab treatment shows the typical subcortical white matter hyperintensities throughout both cerebral hemispheres (a), more prominent posteriorly (b)

The largest review of PRES in cancer patients includes 31 patients from Memorial Sloan-Kettering Cancer Center. A retrospective review of the clinical signs of PRES in cancer patients identified that most patients had active cancer at the time of diagnosis. The disorder occurred more commonly in women. Symptoms included confusion, headache, and visual disturbance. More than half of the patients experienced a seizure at onset. 13% had a severely depressed level of consciousness. The majority of patients experienced resolution of neurologic symptoms at the median of 7.5 days [116].

Treatment for PRES includes aggressive supportive care, and antiepileptic drugs and aggressive antihypertensive therapy when seizures or hypertension are present. Rechallenge with the suspected antineoplastic drug is safe in some patients and can be considered if indicated.

Cardiomyopathy

Cardiomyopathy is a well-known complication of anthracycline chemotherapy, occurring in up to 20% or more of patients. Other chemotherapeutic agents less commonly associated with cardiotoxicity include cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, and mitomycin. Cardiac arterial or muscle damage can also occur from chest radiation, especially in the treatment of breast cancer [117, 118]. Severe cardiomyopathy with reduced flow in the cardiac chambers permits thrombus formation and cardioembolic stroke. In patients presenting with cerebral cardioembolism, long-term anticoagulation may be recommended for secondary prevention.

Infection and Stroke

Patients with immunosuppression due to cancer, especially leukemia and lymphoma patients, or to the effects of antineoplastic therapy are at increased risk for infection-related stroke. Mechanisms include sepsis-induced DIC, bacterial endocarditis, and angioinvasive microorganisms. Intravascular fungal hyphae can be associated with thrombus formation, contributing to parenchymal ischemia. In the autopsy series by Graus et al. [1], the majority of patients with septic infarction were symptomatic with seizures, focal neurological deficits, and encephalopathy.

The most common fungal infection in cancer patients is Aspergillus, typically arising from the lungs or paranasal sinuses. Cerebral aspergillosis typically presents with large multifocal lesions showing isointense to low signal intensity on T2-weighted images, often with areas of high signal on T1-weighted images due to hemorrhage and reduced diffusion. Irregular parenchymal contrast enhancement can be present in association with infarction [119, 120]. Figure 10.12a–e demonstrates ischemic changes on brain MRI in a patient with Aspergillosis in whom intravascular hyphae contributing to thrombosis were identified. Mucormycosis is characterized by frontal lobe lesions with markedly reduced diffusion [121]. Paranasal sinusitis due to Mucor species can be complicated by mycotic aneurysms in the adjacent internal carotid artery. Treatment of fungal infection is often unsuccessful and the prognosis of CNS fungal infection is poor.

Fig. 10.12

a 43-year-old woman (patient 2), aspergillosis manifestation: basal ganglia. a, b Unenhanced (a) T1-weighted image without pathological signal changes and (b) ce T1-weighted image with faint contrast uptake near caudate nuclei on the left-hand side as an expression of subacute ischemic lesion (arrow). c T2-weighted image: lesion with high signal intensity (arrow). d DWI: very high signal intensity on reflecting infarction (arrow). e Histopathology: extended parenchymal infiltration by the branched hyphal forms of aspergillus with penetration (arrows) of vascular wall and resulting thrombosis (All Used with permission of John Wiley and Sons from Gabelmann et al. [120])

Anticoagulation-Induced Hemorrhage

Systemic venous thromboembolism (VTE) is common patients with a primary brain tumor as well as patients with systemic cancer. The potential risk of intracranial hemorrhage in patients with a primary or metastatic brain tumor who are treated with anticoagulation for VTE must be assessed with the benefit. In a review of the outcome of anticoagulation for VTE in brain tumor patients, Jo et al. [122] found that therapeutic anticoagulation, particularly low molecular weight heparin, followed by secondary prophylaxis is generally safe. In glioma patients treated with bevacizumab who are anticoagulated for VTE, there is a slight increase in the rate and severity of intracranial hemorrhage, as compared to bevacizumab-treated patients not receiving anticoagulation [123], but this small risk may compare favorably to the potential lack of benefit and risk of complications from inferior vena cava filters when deciding on individual patient management.

Bone Marrow Transplant

A retrospective study of the neurologic complications of 425 patients who underwent bone marrow transplant (BMT) (310 allogeneic, 115 autologous) for leukemia identified 11% with CNS complications, most commonly hemorrhage, metabolic encephalopathy and CNS infections. Eleven of 16 hemorrhages were subdural hematomas (69%), which were more frequent in autologous (8%) than in allogeneic (0.6%) BMT and in patients with acute myelogenous leukemia (AML) , as opposed to other leukemias. Eight of 11 subdural hematomas occurred in AML patients receiving autologous BMT. Platelet refractoriness correlated with an increased risk of subdural hematoma [124]. Subdural hematomas can often be managed conservatively [125, 126]. Intraparenchymal hemorrhage has also been identified at autopsy following BMT and is associated with a high mortality rate [127].

PRES is most common during the early post-transplant period of hematopoietic cell transplant (HCT) but the risk continues because of the use of cyclosporine, tacrolimus, or other immune suppressants. This is followed by a risk of Aspergillosis with vascular invasion during the next several months. A thrombotic microangiopathy, which may affect the CNS, occurs in up to 6% of patients following BMT [128, 129]. Contributing factors include the administration of cyclosporine, graft-versus-host disease, irradiation, intensive conditioning chemotherapy, and infection. Rare cases of NBTE-associated stroke have also been reported following bone marrow transplantation.

Miscellaneous

Granulomatous angiitis is a rare condition that can be associated with Hodgkin lymphoma. Therapy directed to the lymphoma typically treats the angiitis [130].

Conclusion

A diverse array of pathophysiologic processes predispose to stroke in patients with cancer. A systematic evaluation will often disclose the type, location, and proximate cause of stroke, allowing classification among the specific etiologies of cerebral infarction and hemorrhage reviewed in this chapter. Accurate diagnosis will guide acute intervention and secondary prevention treatment. All physicians who encounter patients with cancer should be cognizant of the risk of cerebrovascular disease within the oncology population, and include stroke in the differential diagnosis of any alteration in central nervous system function.