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Cerebrovascular Disease

LISA R. ROGERS

Cerebrovascular disease is an important cause of neu-rologic morbidity and mortality in patients with can-cer, and its presence must be considered in any can-cer patient who experiences cerebral symptoms. It isthe second most common cause of pathologically de-finable central nervous system (CNS) disease found incancer patients at autopsy and is often symptomatic. Anautopsy study from the Memorial Sloan-Kettering Can-cer Center identified cerebrovascular disease in 500(14.6%) of 3426 cancer patients at autopsy (Graus etal., 1985). Of those patients in whom cerebrovasculardisease was identified, 51% had experienced clinicalsymptoms related to the disease.

Identifying cerebrovascular disease in the cancerpatient is important because identification and treat-ment of the disorder can sometimes ameliorate neu-rologic symptoms and prevent subsequent episodes.Even when a stroke occurs in the setting of advancedcancer, treatment can improve the patient’s quality oflife. If a stroke occurs when cancer is limited, failureto identify and treat the cerebrovascular disease un-derlying the stroke may doom an otherwise success-ful outcome of the cancer treatment. In a small per-centage of patients, stroke is the presenting sign ofcancer, and identification of cerebrovascular diseasein this subset may lead to the diagnosis of cancer.

Identifying cerebrovascular disease in the patientwith cancer presents a challenge to the clinician, asthe pathogenesis is often unique to this group of pa-tients. In cancer patients, the common risk factorsfor stroke, such as systemic and cerebral atheroscle-rosis, hypertension, and advanced age, are over-shadowed by the pathophysiologic effects of cancer

and its treatment. Coagulation disorders, toxicity ofantineoplastic treatment, and direct effects of cere-bral tumor are the most common causes of stroke inthis group. Neuroimaging studies are helpful in iden-tifying the type and location of stroke, but the mostimportant clues to its etiology in cancer patients arethe type and extent of systemic cancer, the presenceof CNS metastasis, and the type of antineoplastic ther-apy. This chapter reviews the cerebral hemorrhageand cerebral infarction syndromes that occur in can-cer patients, with emphasis on the clinical settings inwhich they occur and current methods of diagnosisand treatment.

CEREBRAL HEMORRHAGE

Pathophysiology and Clinical Presentation

Table 21–1 lists the etiologies of the most commoncerebral hemorrhage syndromes that occur in cancerpatients. Hemorrhage is usually caused by coagulationabnormalities, brain metastasis, or a combination ofthe two. Hemorrhage typically occurs in the brain pa-renchyma, but associated intraventricular or sub-arachnoid hemorrhage may also occur, depending onthe location of the primary hemorrhage. Primary sub-dural or subarachnoid hemorrhage is uncommon.Cerebral hemorrhage occurs more often in patientswith leukemia than in those with lymphoma or solidtumors and is more common in acute than in chronicleukemias and in myelogenous rather than lymphocytic

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leukemias. The symptoms of intraparenchymal hem-orrhage may be acute or gradual and include one ormore of the following: headache, vomiting, reducedlevel of consciousness, seizures, focal neurologic signs,and confusion. The symptoms of subdural hematomain cancer patients are typically confusion and lethargy,and these are usually acute. Rarely, there may be focalneurologic signs (e.g., hemiparesis, hemianopsia,monoparesis). Subdural hemorrhage is less often fatalthan parenchymal hemorrhage (Graus et al., 1996).Subarachnoid or intraventricular hemorrhage usuallyproduces rapid deterioration in the level of con-sciousness, resulting in coma.

Coagulopathy

In cancer patients, abnormal coagulation that pre-disposes to cerebral hemorrhage is typically due to

(1) acute disseminated intravascular coagulation(DIC), (2) the presence of liver metastasis, (3) sep-sis, and/or (4) thrombocytopenia induced by tumorinvasion of the bone marrow or effects on the bonemarrow of radiation or chemotherapy. Coagulationdisorders are the most frequent cause of cerebralhemorrhage in patients with leukemia, and hemor-rhages in these patients are usually symptomatic. Inpatients with acute promyelocytic leukemia, a subtypeof acute myelogenous leukemia, DIC is triggered byrelease of procoagulant material from the granules inthe progranulocytes. The coagulopathy worsens afterthe administration of chemotherapy. Cerebral hem-orrhage occurs early in the course of this type of leu-kemia and is often fatal. In contrast, laboratory evi-dence of DIC is detected in as many as one-third ofpatients early in the course of acute lymphoblasticleukemia, but is rarely associated with clinically sig-

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Table 21–1. Pathophysiology of Cerebral Hemorrhage in Patients with Cancer

Etiology Pathology Tumor Type and Setting

Coagulopathy

Disseminated intravascular Intraparenchymal hemorrhage Leukemia, especially early in the course ofcoagulation promyelocytic leukemia

Thrombocytopenia Intraparenchymal hemorrhage Leukemia, usually at relapse or the failureto induce remission

Subdural or subarachnoid hemorrhage Leukemia, often associated withdisseminated intravascular coagulationor sepsis

Tumor related

Hemorrhage into parenchymal Intraparenchymal hemorrhage Melanoma, germ cell tumors, lung cancerbrain metastases

Ruptured neoplastic aneurysm Intraparenchymal and subarachnoid Cardiac myxoma, choriocarcinoma, lunghemorrhage cancer

Leukostasis, leukemic nodules Intraparenchymal hemorrhage Leukemia with hyperleukocytosis

Dural metastases Subdural hemorrhage Carcinoma, leukemia, lymphoma

Treatment related

L-asparaginase Intraparenchymal hemorrhage Acute lymphocytic leukemia during inductiontherapy

Hemolytic uremic-like syndrome Intraparenchymal hemorrhage Adenocarcinoma treated with chemotherapy,especially mitomycin C

Miscellaneous

Idiopathic thrombocytopenic Intraparenchymal hemorrhage Lymphoma, multiple myeloma, or chronicpurpura, platelet dysfunction, myeloproliferative disordershyperviscosity, acquiredvon Willebrand’s disease

Hypertensive cerebrovascular disease Intraparenchymal hemorrhage Solid tumors

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nificant hemorrhage (Higuchi et al., 1998). Dissem-inated intravascular coagulopathy may become symp-tomatic in these patients during induction chemo-therapy, especially in the presence of very low levelsof fibrinogen (Sarris et al., 1996). Cerebral hemor-rhage is usually a late complication of other types ofleukemia and occurs at relapse or when remissioncannot be induced. In the late stages of those leuke-mias, the pathogenesis of hemorrhage is multifacto-rial. Disseminated intravascular coagulopathy may bepresent, but is often accompanied by infection, liver disease, and/or hematologic complications of che-motherapy.

Primary subdural hemorrhage occurs in leukemiapatients when there is severe and refractory throm-bocytopenia. In some patients, DIC, sepsis, andmeningeal leukemia are contributing factors to hem-orrhage (Pitner and Johnson, 1973). Subdural hem-orrhage is more common in patients with acute myel-ogenous leukemia after autologous rather thanallogeneic bone marrow transplant (Graus et al.,1996). An unusual cause of brain hemorrhage is ve-nous infarction due to cerebral sinus thrombosis as-sociated with coagulopathy, typically occurring in pa-tients who have leukemia (Raizer and DeAngelis,

2000). Figure 21–1 shows a postmortem example offatal bilateral hemorrhagic infarctions caused by su-perior sagittal thrombosis in a patient with adeno-carcinoma and coagulopathy. In patients with solidtumors, symptomatic parenchymal brain hemorrhageresulting from coagulopathy is rare and it is usuallya terminal event.

Hemorrhage Associated with Cerebral Tumor

Hemorrhage into parenchymal metastatic brain tu-mor is the most common type of brain hemorrhagein patients with solid tumors. It occurs most fre-quently in patients with metastatic melanoma, germcell tumors (especially choriocarcinoma), and car-cinoma of the lung or kidney. It is caused by necro-sis of tumor and the rupture of newly formed bloodvessels or by invasion of blood vessels in the adjacentbrain parenchyma (Kondziolka et al., 1987). In rareinstances, especially with metastasis from malignantmelanoma or choriocarcinoma, the metastasis un-derlying vascular invasion is microscopic. In morethan one-half of patients, symptoms are acute and maybe the first clinical sign of brain tumor metastasis

456 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

Figure 21–1. Bilateral cerebral hemorrhagic infarctions caused by nonmetastatic superior sagittal sinus thrombosis.

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(Lieu et al., 1999). In other patients, the symptomsare superimposed on chronic or progressive symp-toms of brain metastasis.

Ruptured neoplastic aneurysms are a rare cause ofintracerebral hemorrhage and predominantly occur inpatients who have cardiac myxoma, lung carcinoma,or choriocarcinoma (Kalafut et al., 1998). Theseaneurysms develop when tumor embolic material in-vades a cerebral vessel wall. After recanalization, thedamaged wall dilates and ruptures (Murata et al.,1993). Rarely, aneurysms develop as a result of vas-cular invasion by a parenchymal metastasis. Neoplas-tic aneurysms are typically located in distal arterialbranches, usually those of the middle cerebral artery.

Symptomatic subdural hemorrhage associatedwith tumor metastasis to the dura is uncommon.Dural metastasis develops from hematogenous spreadof tumor to the dura or from skull metastasis that in-vades the dura. Figure 21–2 shows a subdural he-matoma that was caused by dural metastasis of breastcarcinoma. The subdural hemorrhage may be due tothe rupture of vessels from vascular congestion bytumor or due to spontaneous hemorrhage of tumor.In some patients, there may be an effusion from tu-mor in the dura. The tumors that most commonly un-derlie subdural hemorrhage associated with duralmetastasis are carcinomas (especially gastric, breast,or prostate); leukemia and lymphoma are less com-mon (McKenzie et al., 1990). In some instances, asuperimposed coagulopathy contributes to the hem-orrhage (Minette and Kimmel, 1989). Signs of sub-dural hemorrhage usually develop gradually, andthere may be focal neurologic signs in addition toheadache. Epidural hematoma due to dural or skullmetastasis is rare (McIver et al., 2001).

If DIC associated with acute promyelocytic leukemiais excluded, hyperleukocytosis (peripheral blast cellcount in excess of 100,000/mm3) is the most commoncause of intracerebral hemorrhage at the time of di-agnosis of leukemia. Hyperleukocytosis occurs mostfrequently in patients with acute myelogenous leuke-mia, especially the monocytic variant (Wurthner et al.,1999). Patients with hyperleukocytosis experience in-tracerebral hemorrhage in association with infiltrationof cerebral capillaries by blast cells, but the pathogen-esis of hemorrhage is controversial. In one series hem-orrhage occurred while the white blood cell count wasdeclining following chemotherapy administration(Wurthner et al., 1999). Postmortem studies revealhemorrhage adjacent to dilated and thin-walled vessels

that are filled with leukemic blasts (leukostasis) andadjacent to leukemic nodules (Freireich et al., 1960).Blast cells have less deformation than red blood cells;thus hyperviscosity, vascular endothelial damage, andcompetition with host cells to produce local hypoxiamight result in hemorrhage.

Leukemic nodules enlarge and invade cerebralvessels. Leukostasis is more intense in the white mat-ter, periventricular regions, and leptomeninges thanin the cortex (Nowacki et al., 1995). Intracerebralhemorrhages associated with hyperleukocytosis areusually multiple and are located in the white matter.Intraventricular or subarachnoid hemorrhage mayalso occur. In contrast with patients who have hem-orrhage caused by coagulopathy, only moderatethrombocytopenia is usually present, which would notbe expected to cause spontaneous hemorrhage. Arare cause of intraparenchymal hemorrhage is cere-bral perivascular infiltration of leukemic cells in lep-tomeningeal leukemia, resulting in the rupture ofcerebral capillaries. Subarachnoid hemorrhage canalso occur in patients with diffuse leptomeningeal tu-mor when there is thrombocytopenia.

Treatment-Related Hemorrhage

The use of L-asparaginase in induction therapy foracute lymphocytic leukemia results in cerebral hem-orrhage or thrombosis in a small percentage of pa-tients (Urban and Sager, 1981; Gugliotta et al., 1992).L-asparaginase is known to promote fibrinolysis andto deplete plasma proteins involved in coagulation,but the precise mechanism of thrombosis and hem-orrhage is unknown. In some cases, cerebral hem-orrhage is due to venous infarction from thrombosisof the superior sagittal sinus.

A hemolytic uremic–like syndrome is reported inpatients with adenocarcinoma, sometimes develop-ing after the administration of chemotherapy. Theclinical manifestations are thought to be due to endothelial damage and include microangiopathic hemolytic anemia, thrombocytopenia, pulmonaryedema, and renal insufficiency. Similar to the denovo hemolytic uremic syndrome, the neurologicsigns include headache, confusion, hemiparesis, andcoma. Originally reported as a complication of mit-omycin C, it has now been associated with severalantineoplastic agents, including bleomycin and cis-platin (Gordon and Kwaan, 1997). The onset afterchemotherapy administration is highly variable and


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ranges from days to months. In other cancer patients,intracerebral hemorrhage occurs as a terminal eventin the setting of severe thrombocytopenia induced bybone marrow failure from chemotherapy, radiation,or metastasis.

Miscellaneous

Hypertension is a rare cause of symptomatic intra-cerebral hemorrhage in cancer patients (Graus et al.,1985). It occurs primarily in patients with solid tu-


Figure 21–2. Postmortem examination of a subdural hematoma associated with nodular dural metastases (arrow) of breast car-cinoma.

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mors. A high percentage of patients with chronicmyeloproliferative disorders, especially chronic myel-ogenous leukemia and osteomyelofibrosis, experi-ence intraparenchymal hemorrhage. Hemorrhagemay coexist with intracerebral thromboses (Buss etal., 1985), and these tend to occur early in the dis-ease (Wehmeier et al., 1991). In patients with lym-phoma, intracerebral hemorrhage may be related tosevere thrombocytopenia from idiopathic thrombo-cytopenic purpura or to an acquired form of vonWillebrand’s disease. In patients with myeloma, in-tracerebral hemorrhage may be related to thrombo-cytopenia and serum hyperviscosity. Primary sub-arachnoid hemorrhage is sufficiently rare in cancerpatients so that congenital aneurysms should be con-sidered. Among 24 patients with cancer and primarysubarachnoid hemorrhage in the series by Graus etal. (1985), 4 had ruptured congenital aneurysms.

Diagnosis

Coagulopathy

The stage of the leukemia and associated clinical fac-tors such as degree of thrombocytopenia and the pres-ence of sepsis can suggest the cause of brain hemor-rhage in patients with leukemia. The diagnosis ofintracerebral hemorrhage is established by MRI or CTscans of the brain that reveal single or multiple hem-orrhages. Patients who have acute DIC may also havesystemic thrombosis, including deep vein thrombosis,pulmonary embolism, or myocardial infarction, and sys-temic hemorrhage, including hemorrhage in the mu-cosal surfaces, retinae, skin, genitourinary and gas-trointestinal tracts, and at the site of venipuncture orbone marrow aspiration. Laboratory studies to confirmacute DIC include measurement of platelets, prothrom-bin time, activated partial thromboplastin time, fibrino-gen, fibrin split products, fibrinopeptide A, the D-dimerassay, and the presence of schistocytes on the periph-eral blood smear. In many patients with cancer, labo-ratory tests reveal evidence of chronic DIC, but this con-dition is rarely symptomatic; results of laboratory testsof coagulation function in all patients must be carefullyinterpreted in their clinical context.


Computed tomography or MRI scans of the brain re-veal single or multiple hemorrhages when there is

hemorrhage into parenchymal brain metastasis. Cluesto intratumoral hemorrhage include a multiplicity ofhemorrhages, brain locations other than those usu-ally found with hypertensive hemorrhage, and earlyedema and enhancement adjacent to the hemorrhage(Atlas et al., 1987). If an intratumoral brain hemor-rhage is suspected but the patient is not known tohave cancer, biopsy of the hematoma wall is indicatedto establish the diagnosis. Parenchymal hemorrhagesassociated with ruptured neoplastic aneurysms maybe single or multiple. Cerebral angiography in neo-plastic aneurysms can reveal filling defects, fusiformand saccular aneurysms, and occluded vessels, butthe sensitivity of angiography is unknown; in some in-stances, the hematoma obliterates the aneurysm andangiographic findings are normal.

In patients with subdural hematomas, CT and MRIbrain scans can show acute or chronic subdural fluidcollections. If dural metastasis is present, there may beevidence of adjacent skull metastasis and dural en-hancement after injection of a contrast agent such asgadolinium. However, histologic examination of thedural membrane or subdural fluid may be necessaryto establish the diagnosis of dural metastasis. Lep-tomeningeal metastasis is suggested by leptomeningealenhancement on neuroimaging studies after injectionof a contrast agent such as gadolinium and proven byidentification of malignant cells in cerebrospinal fluidor in leptomeningeal biopsy specimens.


Cerebral hemorrhage can occur during or immedi-ately after induction therapy with L-asparaginase inpatients with acute lymphocytic leukemia. Brain MRIand magnetic resonance venography can be diagnos-tic of venous occlusion. Systemic signs of a hemolyticuremic–like syndrome in conjunction with severe he-molytic anemia and thrombocytopenia associatedwith the administration of chemotherapy for adeno-carcinoma suggest this diagnosis.

Miscellaneous

Laboratory tests that reveal evidence of extremethrombocytosis, impaired platelet function, or hyper-viscosity can be helpful in identifying the cause ofcerebral hemorrhage in patients with chronic myelo-proliferative disorders, lymphoma, and multiplemyeloma.


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Treatment

Coagulopathy

Successful therapy for acute DIC is multifaceted andcontroversial. Evacuation of an intracerebral hemor-rhage in the setting of coagulopathy is difficult, and inpatients with cancer who have cerebral hemorrhagecaused by DIC treatment should be directed at con-trolling the systemic tumor and the associated medicalconditions that contribute to the coagulopathy, such assepsis. Treatment with heparin and fresh-frozen plasmacan control DIC in some patients. Other therapies in-clude replacement of clotting factors with blood prod-ucts such as cryoprecipitate and platelet concentrationsand antifibrinolytic agents. In patients with acutepromyelocytic leukemia and DIC, it is controversialwhether prophylactic heparin as an adjunct to induc-tion chemotherapy can reduce the incidence of in-tracerebral hemorrhage. Chemotherapy, however, canincrease the lysis of blast cells and aggravate DIC. All-trans retinoic acid administered for remission induc-tion therapy of acute promyelocytic leukemia can dif-ferentiate abnormal promyelocytes into maturegranulocytes, which improves coagulation function andresults in a slight decrease of early brain hemorrhage(Tallman et al., 1997). Most patients with subdural he-matoma caused by coagulopathy can be successfullymanaged without surgery (Graus et al., 1996).


Survival of patients with massive intratumoral par-enchymal brain hemorrhage or ruptured neoplasticaneurysms is poor, especially for those who have anacute onset of symptoms (Graus et al., 1985). Thesepatients may die as a direct result of the hemorrhage.In some patients, resection of a single large hema-toma is life saving (Little et al., 1979). The clinicalcourse in patients with hemorrhage into brain me-tastasis who have a stable neurologic condition is nodifferent from that of patients with nonhemorrhagicbrain metastasis. These patients should receive radi-ation therapy directed to the underlying brain metas-tasis. For patients with ruptured neoplastic cerebralaneurysms, therapy should be directed to the systemictumor (appropriate antineoplastic therapy in the caseof systemic cancer and removal of the cardiac tumorin the case of cardiac myxoma). Brain irradiation isindicated for neoplastic aneurysms that arise fromsystemic carcinoma.

Therapy for subdural hemorrhage associated withdural metastasis is generally palliative and includesbrain irradiation and drainage of subdural fluid. Theuse of antimetabolites and leukapheresis reduces the frequency of brain hemorrhage in acute leukemiapatients presenting with hyperleukocytosis (Wurthneret al., 1999).


The chances for neurologic recovery in patients ex-periencing L-asparaginase–induced thrombosis orhemorrhage are generally good (Feinberg and Swen-son, 1988), and cerebrovascular events do not usu-ally recur after re-treatment. Fresh-frozen plasma maybe beneficial for patients with venous thrombosis, butit is not known if anticoagulation is necessary. Theprognosis for patients with the hemolytic uremic–likesyndrome induced by chemotherapy is poor, butsteroids and plasma exchange may prolong survival(Gordon and Kwaan, 1997).

Miscellaneous

Conventional cytoreductive therapy reduces the inci-dence of cerebral ischemic or hemorrhagic events inpatients with chronic myeloproliferative disorders(Wehmeier et al., 1991).

CEREBRAL INFARCTION

As is the case with cerebral hemorrhage, the risk fac-tors for cerebral infarction in patients with cancer areusually different from those in patients without can-cer. Table 21–2 lists the causes of cerebral infarc-tion in cancer patients. Coagulation disorders, infec-tion, the direct effects of CNS metastasis, andcomplications of antineoplastic treatment are themost common causes. Symptomatic cerebral infarc-tion is more common in patients who have lymphomaand carcinoma than it is in those with leukemia, inwhom cerebral hemorrhage predominates.

Two clinical factors make the identification ofcerebral infarction in cancer patients and the deter-mination of its cause difficult. First, cerebral infarc-tions in cancer patients are often multifocal, and theresulting multifocal neurologic signs are difficult todistinguish from those caused by encephalopathy.Therefore, the possibility of cerebral infarction mustbe considered for all cancer patients who experience


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encephalopathy. Second, proving a link between co-agulation abnormalities and cerebral infarction canbe difficult because many cancer patients have ab-normalities of coagulation function that are revealedby laboratory tests but are not clinically significant.The most important clues to the etiology of cerebralinfarction are the type of cancer, the extent of sys-temic metastasis, the presence of CNS metastasis, andthe type of antineoplastic treatment.

Pathophysiology and Clinical Presentation

Coagulopathy

The majority of patients with advanced solid tumorshave laboratory evidence of clotting activation that isusually asymptomatic. In a small percentage of pa-tients, however, the coagulopathy results in throm-

bosis of arteries or veins in the systemic or cerebralcirculation. There are multiple risk factors for coag-ulopathy and thrombosis, including a complex inter-action between tumor cells and their products withhost cells, cancer treatment including single- or mul-tiple-agent chemotherapy, hormonal therapy, and he-matopoietic growth factors. Nonbacterial thromboticendocarditis is the result of a hypercoagulable stateand is characterized by the development of sterileplatelet-fibrin vegetations on cardiac valves.

Nonbacterial thrombotic endocarditis is the mostcommon cause of symptomatic cerebral infarction in cancer patients (Graus et al., 1985). Figure 21–3shows cardiac nonbacterial thrombotic endocarditisin a patient with lung adenocarcinoma. Patients withcerebral infarction caused by nonbacterial throm-botic endocarditis usually experience focal neuro-logic signs, and angiography in these patients typi-cally shows multiple branch occlusions of the middle


Table 21–2. Pathophysiology of Cerebral Infarction in Patients with Cancer

Etiology Pathology Tumor Type and Setting

Coagulopathy

Nonbacterial thrombotic Cerebral infarction Adenocarcinoma, usually widespreadendocarditis

Cerebral intravascular Cerebral infarction, petechial hemorrhage Lymphoma, leukemia, breast cancer, incoagulation advanced disease and sepsis

Coagulopathy, etiology Superior sagittal sinus thrombosis with Lymphoma and solid tumors, usually in undetermined or without adjacent cerebral infarction advanced disease

Infection

Fungal sepsis Cerebral infarction Leukemia

Tumor-related

Skull or dural metastases Saggital sinus thrombosis with or without Lung cancer, neuroblastoma, lymphomaadjacent cerebral infarction

Tumor embolism Cerebral infarction Lung and cardiac tumors

Leptomeningeal metastasis Cerebral infarction Solid tumors

Radiation-induced vasculopathy Cerebral infarction Head and neck cancer, lymphoma

Chemotherapy Superior sagittal sinus occlusion Leukemia, during induction therapy withL-asparaginase

Chemotherapy Cerebral infarction Breast cancer during multi-agentchemotherapy and hormonal therapy;other solid tumors during cisplatin-basedchemotherapy

Miscellaneous

Atherosclerosis Cerebral infarction Head and neck and lung cancer

Granulomatous angiitis Cerebral infarction Hodgkin’s lymphoma, leukemia

Thrombocytosis Cerebral infarction Chronic myeloproliferative disorders,particularly essential thrombocytopenia

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cerebral artery. Focal signs may be preceded by tran-sient ischemic attacks. Some patients also develop en-cephalopathy because of multifocal infarctions. Post-mortem studies suggest that cerebral infarctions arecaused by embolization of cardiac vegetations to thebrain, cerebral intravascular thromboses that resultfrom the associated coagulation disorder, or both(Reagan and Okazaki, 1974; Rogers et al., 1987).Nonbacterial thrombotic endocarditis occurs mostcommonly in patients with adenocarcinoma, espe-cially mucin-producing carcinomas of the lung orgastrointestinal tract. It usually develops in patientswith advanced cancer, but can occur in patients withearly-stage cancer and can even be the presenting signof cancer (Rogers et al., 1987). Evidence of systemicthrombosis or hemorrhage suggests the presence ofnonbacterial thrombotic endocarditis.

Cerebral intravascular coagulation is due to throm-botic occlusion of small cerebral vessels caused by acoagulopathy unaccompanied by nonbacterial throm-botic endocarditis. It is the second most common causeof symptomatic cerebral infarction in patients with can-cer (Graus et al., 1985). Patients with cerebral in-travascular coagulation develop encephalopathy, andapproximately one-half of patients have superimposed,

sometimes transient, focal neurologic signs (Collins etal., 1975). The clinical course is progressive. Typically,multiple vessels in more than one major vessel territoryof the brain and leptomeninges—usually small arter-ies, arterioles, capillaries, or venules—are occludedwith fibrin. Figure 21–4 shows fibrin occlusions of lep-tomeningeal vessels in association with cerebral infarc-tions in a patient with breast cancer and cerebral intravascular coagulation. Cerebral intravascular coag-ulation is reported in patients with leukemia, breast can-cer, and lymphoma, usually in the setting of advanceddisease and sepsis. Amico et al. (1989) reported sys-temic and cerebral infarctions in six patients with mu-cinous cancers. At autopsy, mucin was present withinvessels, macrophages, and areas of infarction. It is unknown whether mucin deposition results from me-tastasis or is associated with a cancer-related coagu-lopathy.

Nonmetastatic occlusion of large cerebral venousstructures in cancer patients is caused by a coagula-tion disorder associated with cancer or with chemo-therapy. The most common cerebral venous structureaffected is the superior sagittal sinus, and the under-lying tumor is usually leukemia (Raizer and DeAnge-lis, 2000). The incidence of this disorder is unknown


Figure 21–3. Postmortem examination demonstrating vegetations of nonbacterial thrombotic endocarditis attached to all cuspsof the aortic valve. (The valve has been opened anteriorly.) The arrow indicates one area of vegetation.

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because the sinus occlusion can recanalize and is,therefore, underreported in autopsy series. The on-set of symptoms from nonmetastatic superior sagittalsinus thrombosis is typically sudden headache;seizures, focal neurologic signs, or encephalopathydevelop if there is brain hemorrhage or infarction.Superior sagittal sinus occlusion is associated with in-duction therapy that includes the administration of L-asparaginase to patients with acute lymphocytic leu-kemia (see “Treatment-Related Cerebral Infarction”in this chapter). In other patients with lymphoma orsolid tumors, it usually occurs in the setting of wide-spread systemic metastatic disease.

Infarction Associated with Cerebral Infection

Cancer patients are predisposed to systemic infectionsbecause of immunosuppression caused by the tumoror by treatment with radiation, chemotherapy, broad-spectrum antibiotics, or immunosuppressants. Cere-bral infarction associated with infection is most com-monly caused by fungal septic emboli, typically ofAspergillus and Candida species. Fungal sepsis oc-curs more commonly in patients with leukemia than

in those with lymphoma or carcinoma. Common sitesof entry are the lower respiratory tract for Aspergillusand the gastrointestinal or genitourinary tracts or in-dwelling venous catheters for Candida species. Cere-bral infarctions associated with cerebral infection areoften multiple and may be hemorrhagic (Walsh et al., 1985). The neurologic signs usually consist ofseizures, focal cerebral signs, or encephalopathy.Acute focal signs and seizures are more common inpatients with Aspergillus infection, and encephalopa-thy is more common in patients with Candida infec-tion. Meningitis is rarely present.

Infarction Associated with Cerebral Tumor

Skull or dural tumor that infiltrates or compressesthe superior sagittal sinus can produce venous stasisand thrombosis. In contrast to patients with non-metastatic superior sagittal sinus thrombosis, patientswith the metastatic type of thrombosis develop suba-cute symptoms resulting from increased intracranialpressure (typically headache, vomiting, and pa-pilledema). Focal neurologic signs or encephalopa-thy may be present if there is cerebral infarction. Itoccurs most commonly in patients with neuroblas-


Figure 21–4. Organizing fibrin thrombi (arrows) in small leptomeningeal arteries overlying an area of cerebral infarction in a patientwith disseminated breast carcinoma and cerebral intravascular coagulation. Hematoxylin and eosin; original magnification, �50.

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toma, lung cancer, and lymphoma, but is reported ina variety of tumors.

Another mechanism for tumor-related cerebral in-farction is embolism of a tumor fragment to the brain.This can produce focal or multifocal cerebral signs,sometimes preceded by transient ischemic attacks(O’Neill et al., 1987). Embolism of a tumor fragmentto the brain is reported exclusively in patients withsolid tumors, usually those with a primary or meta-static cardiac or lung tumor that is the source of theembolus. Cerebral embolism can occur at the time ofmanipulation of the lung in patients with lung tumorundergoing thoracotomy (Lefkovitz et al., 1986;O’Neill et al., 1987). It can be the presenting sign ofcardiac tumor, especially cardiac myxoma. Lep-tomeningeal metastasis is a rare cause of cerebral in-farction. Infarction may be the sole manifestation ofthis disorder, or there may be accompanying typicalsigns, including headache, cranial nerve palsies, andradiculopathies. Postmortem studies suggest that in-farction occurs because tumor infiltrates the cerebralarteries in the Virchow-Robin spaces and causes vas-cular occlusion or spasm (Klein et al., 1989). The in-farctions may be multifocal.

Treatment-Related Infarction

Neck radiation administered for head and neck can-cer or lymphoma can produce delayed extracranialcarotid stenosis or occlusion. In a prospective studyof carotid duplex ultrasound performed in 240 pa-tients with head and neck cancer who received ra-diation to the cervical region, a greater than 70%stenosis of the common and/or internal carotidartery was detected in 28 patients (11.7%) (Chenget al., 1999). Histologic examination of the diseasedartery suggests that radiation produces or acceler-ates atherosclerosis. Patients may develop transientischemic attacks, including amaurosis fugax, orcerebral infarction. Murros and Toole (1989) re-ported a wide interval between radiation therapy andthe development of this complication, with a meaninterval of 19 years. Carotid artery rupture is a po-tentially fatal complication of head and neck tumorresection and neck irradiation. It is usually associ-ated with orocutaneous fistulas, necrosis of the skinflap, and infection (McCready et al., 1983). Patientsmay die from exsanguination. If the carotid ruptureis detected and the artery is ligated, there is a sig-nificant chance of cerebral infarction and death(Razack and Sako, 1982).

Potential mechanisms for abnormal coagulationfunction in patients receiving chemotherapy includealterations in coagulation factors or anticoagulantproteins and endothelial damage produced by theseagents. Because of the small number of events oc-curring in individual treatment studies and the lackof uniform reporting of thromboembolism, includingstroke, the evidence for a causal relationship with an-tineoplastic agents, regardless of other risk factors,is weak (Lee and Levine, 1999). The best-recognizedcerebrovascular complication of chemotherapy is ve-nous thrombosis caused by L-asparaginase used incombination induction chemotherapy for patientswith acute lymphocytic leukemia (Lee and Levine,1999; Gugliotta et al., 1992). L-asparaginase pro-motes fibrinolysis and causes a depletion of plasmaproteins involved in coagulation. There may be pro-motion of thrombosis by a transient increase in un-usually large plasma von Willebrand’s factor multi-mers (Pui et al., 1987). There are also uncommonreports of systemic and cerebral venous and arterialthromboembolic complications in women with breastcancer receiving multiagent chemotherapy (Wall etal., 1989), especially when chemotherapy is com-bined with hormonal therapy (Saphner et al., 1991).Complications usually occur early in treatment.

A rare neurologic complication of chemotherapyis cerebral embolization from a ventricular muralthrombus that forms in association with cardiomy-opathy resulting from chemotherapy with doxoru-bicin (Adriamycin) (Schachter and Freeman, 1982).Transient focal neurologic signs suggesting transientischemic attacks can occur during interleukin-2 ther-apy (Bernard et al., 1990).

Miscellaneous

Atherosclerosis is the most common cause of cere-bral infarction found at autopsy in patients with can-cer, but it accounts for only 14% of symptomatic in-farctions (Graus et al., 1985). The most commontumors associated with symptomatic cerebral infarc-tion from atherosclerosis are head and neck cancersand lung cancer. A less common cause of sympto-matic cerebral infarction is granulomatous angiitisoccurring in patients with Hodgkin’s disease or leu-kemia (Inwards et al., 1991; Lowe and Russell,1987). Signs include headache, fever, confusion,seizures, obtundation, or hemiparesis. Patients withchronic myeloproliferative disorders who have ex-treme thrombocytosis can experience cerebral arte-


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rial or venous thromboembolic events (Randi et al.,1998). These complications are most common in pa-tients with polycythemia vera and essential thrombo-cythemia and occur more often in older patients(Jabaily et al., 1983; Wehmeier et al., 1991). Plateletthromboembolism is likely caused by inherent alter-ations of platelet function in addition to the exces-sively high number of platelets. Neurologic symptomsare most common before and shortly after the diag-nosis of chronic myeloproliferative disorders, prob-ably because cytoreductive therapy administered af-ter the diagnosis is effective (Michiels et al., 1993).In patients with essential thrombocythemia, symp-toms are usually transient and are poorly localized;they include unsteadiness, dysarthria, and scotomas.Focal symptoms such as transient monocular blind-ness or limb weakness are less common. They are ofsudden onset and are often accompanied by head-ache. Systemic arterial or venous thrombosis may alsooccur. Patients with Hodgkin’s disease who are in re-mission or cured can experience episodic neurologicdysfunction that resembles transient ischemic attacks(Feldmann and Posner, 1986). The cause of thesesymptoms is unknown.

Diagnosis

Coagulopathy

Patients with stroke caused by coagulation disordersmay have evidence of systemic thrombosis or hemorrhage. Particularly, patients with nonbacterialthrombotic endocarditis may have systemic bleeding,limb thrombophlebitis arterial occlusion, pulmonaryembolism, or myocardial infarction (Reagan andOkazaki, 1974; Rogers et al., 1987). Laboratory testsmay reveal evidence of DIC in some patients (Rogerset al., 1987), but in many patients abnormalities oncoagulation function tests are indistinguishable fromthe abnormalities commonly associated with cancer.These abnormalities include markers of clotting ac-tivation, such as abnormal thrombin–antithrombincomplex, prothrombin fragment F 1 � 2, and D-dimer.

Cardiac murmurs are rare, and transthoracic echo-cardiography is usually nondiagnostic because of thesmall size of the cardiac vegetations. Transesophagealechocardiography can be diagnostic (Blanchard etal., 1992). Computed tomography or MRI scans ofthe brain may reveal cerebral infarction. In patientswho experience focal neurologic signs, cerebral an-

giography is a sensitive test for the diagnosis of cere-bral infarction from nonbacterial thrombotic endo-carditis. In these patients, cerebral angiography typ-ically shows multiple branch occlusions of the middlecerebral artery (Rogers et al., 1987). Many patientswith cerebral intravascular coagulation have systemicbleeding, but results of laboratory tests of coagula-tion function are nonspecific. In a study by Collins etal. (1975), neuroimaging studies performed in asmall number of patients were normal. There is nomethod currently known to diagnose this syndromeaside from postmortem examination.

Magnetic resonance imaging of the brain is theimaging procedure of choice to detect superior sagit-tal sinus thrombosis caused by coagulopathy. It candocument the lack of normal flow void within the oc-cluded sinus and can reveal enlarged collateral veins(Sze et al., 1988). Adjacent cerebral hemorrhage orinfarction can also be visualized. When MRI is non-diagnostic, magnetic resonance venography can bediagnostic (Fig. 21–5).

Infarction Associated with Infection

Computed tomography and MRI brain scans can re-veal infarctions in patients with septic cerebral em-bolism. Focal enhancement may appear later if theinfarctions evolve into abscesses. Cerebrospinal fluidexamination is generally nondiagnostic because usu-ally only mild pleocytosis and protein elevation arepresent. Cultures are typically negative. Hemorrhagiccerebrospinal fluid can be a clue to Aspergillus in-fection (Walsh et al., 1985). Blood cultures are of-ten negative, but clinical or radiographic evidence ofpulmonary infection suggests systemic Aspergillus in-fection. Aspergillus can be isolated from respiratorysecretions or open lung biopsy specimens, but openlung biopsy is potentially hazardous in many cancerpatients because of coexisting thrombocytopenia(Walsh et al., 1985).


Brain MRI and magnetic resonance venography arethe methods of choice to diagnose metastatic supe-rior sagittal sinus occlusion and to reveal associatedcerebral infarction. In patients with superior sagittalsinus occlusion due to skull or dural tumor, MRI mayalso reveal evidence of adjacent skull or dural me-tastasis. Dural or leptomeningeal metastasis will usu-


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ally enhance after injection of gadolinium. In patientswith tumor embolic infarctions, the infarctions canbe seen on CT or MRI scans, and angiography mayreveal vascular occlusions (Marazuela et al., 1989;O’Neill et al., 1987); however, these findings are notspecific, and a definitive diagnosis of tumor embolismcan be established only if there is a simultaneous pe-ripheral arterial embolism that can be examined his-tologically. Patients in whom tumor embolic infarc-tion is suspected should undergo serial CT or MRIbrain scans for evaluation of growth of the brain me-tastasis. Clinical clues to the presence of primary ormetastatic cardiac tumor include a new onset of con-gestive heart failure, pericardial effusion, rapid car-diac enlargement, or arrhythmias that are difficult tocontrol. Echocardiography is diagnostic.


Carotid angiography in patients with radiation-in-duced carotid artery disease usually reveals occlusion

or extensive stenosis of the common carotid arterythat is confined to the field of irradiation. The lengthof stenosis in these patients is typically greater thanit is in patients with atherosclerosis not associatedwith irradiation (Fig. 21–6). Little information isavailable on neuroimaging abnormalities in patientswho experience cerebral infarction related to che-motherapy administration except for patients with su-perior sagittal sinus occlusion. There are no labora-tory tests that can diagnose chemotherapy-inducedcoagulation abnormalities.

Miscellaneous

Atherosclerotic brain infarction is suggested by thepatient’s age and the presence of typical risk factorsfor atherosclerosis. Granulomatous angiitis is sug-gested by the presence of cerebral infarctions, hem-orrhages, or contrast-enhancing masses on CT or MRIbrain scans in patients with lymphoma or leukemia.Angiography may show a classic beading pattern but


Figure 21–5. Nonmetastatic superior sagittal sinus occlusion (arrowhead) visible on two-dimensional time-of-flight magnetic res-onance venogram.

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may be nonspecifically abnormal or normal. The mostdefinitive method for diagnosis of granulomatousangiitis is biopsy, but its sensitivity is low (Inwards etal., 1991). The association of cerebral infarction withthrombocythemia can be determined by measuringthe platelet count.

Treatment

Coagulopathy

Effective therapy for coagulation disorders must bedirected to the underlying tumor, to associated med-ical conditions such as sepsis that predispose the pa-tient to the disorder, and to the coagulation disorderitself. Management decisions for coagulopathy arestill controversial, and therapy must be individualized.Low-molecular-weight heparin or low-dose warfarincan reduce the risk of systemic venous thromboem-bolism in cancer patients (Levine and Lee, 2001), buttheir role in the prophylaxis of stroke is unknown. Pa-tients who experience cerebral infarction from non-bacterial thrombotic endocarditis may benefit fromanticoagulation therapy. In the series by Rogers et al.(1987), heparin therapy was effective in reducingischemic symptoms in some patients with cerebral in-farction, and the incidence of hemorrhagic infarctionand cerebral hemorrhage, possible side effects of thistherapy, was no greater than in patients who were notanticoagulated. However, anticoagulation must be un-dertaken judiciously because of the risk of systemicand cerebral hemorrhage in patients with this disor-der. Appropriate therapy for cerebral intravascularcoagulation is not known. Heparin and urokinase arereported to be beneficial in reducing the morbidity ofsuperior sagittal sinus thrombosis in patients withoutcancer (Einhaupl et al., 1991; De Bruijn and Stam,1999; Philips et al., 1999), but no prospective stud-ies have been performed in patients with cancer.

Infarction Associated with Infection

Patients with fungal septic cerebral infarction shouldbe treated with antifungal therapy, but the prognosisfor recovery and survival is poor (Walsh et al., 1985).


Patients with metastatic superior sagittal sinus occlu-sion should be treated with irradiation of the brain.It is not known whether anticoagulation therapy is ef-fective in treating this disorder. In patients with em-bolic infarction from malignant tumors, the brainshould also be irradiated. In those patients with car-diac tumors, removal of the cardiac tumor will prevent subsequent embolization. Patients with lep-tomeningeal metastasis should be treated with radia-tion to the symptomatic areas of the neuraxis and withsystemic or intraventricular chemotherapy.


Figure 21–6. Cerebral angiography in a patient with laryn-geal cancer and radiation-induced carotid atherosclerosis re-veals irregularity and moderate stenosis of the distal left com-mon carotid artery. There is a long segment of diffuseirregularity and severe stenosis alternating with zones of di-latation in the proximal internal and external carotid arteries.The area of involvement of the common, internal, and exter-nal carotid arteries corresponds to the field of radiation.

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Patients with symptomatic or high-grade radiation-in-duced carotid stenosis can be effectively treated withendarterectomy; the long-term patency rates are sim-ilar to those in nonirradiated patients (Kashyup et al.,1999). Endovascular occlusion is a safe and effectivemethod to avoid carotid artery ligation and preventcerebral infarction in patients with carotid artery rup-ture (Citardi et al., 1995). If carotid ligation is re-quired, low-dose heparin may reduce the risk of cere-bral infarction (Leikensohn et al., 1978). There is noeffective therapy known for the vascular complica-tions of chemotherapy, although Feinberg and Swen-son (1988) suggest that prophylactic fresh-frozenplasma be administered to patients receiving L-as-paraginase. In other situations, the benefits of che-motherapy must be carefully weighed against the riskof recurrent thromboembolic events.

Miscellaneous

Granulomatous angiitis can respond to treatment di-rected to the underlying cancer (Hodgkin’s diseaseor leukemia) or to steroids and cytotoxic drugs ad-ministered for vasculitis (Inwards et al., 1991). As-pirin and cytostatic reduction of the platelet count areeffective in preventing recurrence of thromboticevents in patients with essential thrombocythemia(Michiels et al., 1993). The clinical course of patientswith Hodgkin’s disease who experience transient neu-rologic symptoms of unknown etiology is benign, andno treatment is indicated (Feldmann and Posner,1986).

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