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Home , Cerebrovascular disease, Focal neurologic signs, Stroke

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21

Cerebrovascular

LISA R. ROGERS

Cerebrovascular disease is an important cause of neu- and its treatment. disorders, toxicity of rologic morbidity and mortality in patients with can- antineoplastic treatment, and direct effects of cere- cer, and its presence must be considered in any can- bral tumor are the most common causes of in cer patient who experiences cerebral symptoms. It is this group. studies are helpful in iden- the second most common cause of pathologically de- tifying the type and location of stroke, but the most finable central (CNS) disease found in important clues to its etiology in patients are cancer patients at and is often symptomatic. An the type and extent of systemic cancer, the presence autopsy study from the Memorial Sloan-Kettering Can- of CNS metastasis, and the type of antineoplastic ther- cer Center identified in 500 apy. This chapter reviews the cerebral hemorrhage (14.6%) of 3426 cancer patients at autopsy (Graus et and cerebral syndromes that occur in can- al., 1985). Of those patients in whom cerebrovascular cer patients, with emphasis on the clinical settings in disease was identified, 51% had experienced clinical which they occur and current methods of diagnosis symptoms related to the disease. and treatment. Identifying cerebrovascular disease in the cancer patient is important because identification and treat- ment of the disorder can sometimes ameliorate neu- CEREBRAL HEMORRHAGE rologic symptoms and prevent subsequent episodes. Even when a stroke occurs in the setting of advanced Pathophysiology and cancer, treatment can improve the patient’s quality of Clinical Presentation life. If a stroke occurs when cancer is limited, failure to identify and treat the cerebrovascular disease un- Table 21–1 lists the etiologies of the most common derlying the stroke may doom an otherwise success- cerebral hemorrhage syndromes that occur in cancer ful outcome of the cancer treatment. In a small per- patients. Hemorrhage is usually caused by coagulation centage of patients, stroke is the presenting sign of abnormalities, metastasis, or a combination of cancer, and identification of cerebrovascular disease the two. Hemorrhage typically occurs in the brain pa- in this subset may lead to the diagnosis of cancer. renchyma, but associated intraventricular or sub- Identifying cerebrovascular disease in the patient arachnoid hemorrhage may also occur, depending on with cancer presents a challenge to the clinician, as the location of the primary hemorrhage. Primary sub- the pathogenesis is often unique to this group of pa- dural or is uncommon. tients. In cancer patients, the common risk factors Cerebral hemorrhage occurs more often in patients for stroke, such as systemic and cerebral atheroscle- with leukemia than in those with lymphoma or solid rosis, , and advanced age, are over- tumors and is more common in acute than in chronic shadowed by the pathophysiologic effects of cancer leukemias and in myelogenous rather than lymphocytic

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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 of coagulation promyelocytic leukemia Thrombocytopenia Intraparenchymal hemorrhage Leukemia, usually at relapse or the failure to induce remission Subdural or subarachnoid hemorrhage Leukemia, often associated with disseminated intravascular coagulation or sepsis Tumor related Hemorrhage into parenchymal Intraparenchymal hemorrhage Melanoma, germ cell tumors, cancer brain metastases Ruptured neoplastic Intraparenchymal and subarachnoid Cardiac myxoma, choriocarcinoma, lung hemorrhage cancer , leukemic nodules Intraparenchymal hemorrhage Leukemia with hyperleukocytosis Dural metastases Subdural hemorrhage Carcinoma, leukemia, lymphoma Treatment related L-asparaginase Intraparenchymal hemorrhage Acute lymphocytic leukemia during induction therapy Hemolytic uremic-like syndrome Intraparenchymal hemorrhage Adenocarcinoma treated with chemotherapy, especially mitomycin C Miscellaneous Idiopathic thrombocytopenic Intraparenchymal hemorrhage Lymphoma, multiple myeloma, or chronic purpura, dysfunction, myeloproliferative disorders hyperviscosity, acquired von Willebrand’s disease Hypertensive cerebrovascular disease Intraparenchymal hemorrhage Solid tumors

leukemias. The symptoms of intraparenchymal hem- (1) acute disseminated intravascular coagulation orrhage may be acute or gradual and include one or (DIC), (2) the presence of liver metastasis, (3) sep- more of the following: , vomiting, reduced sis, and/or (4) thrombocytopenia induced by tumor level of , , , invasion of the or effects on the bone and . The symptoms of subdural marrow of radiation or chemotherapy. Coagulation in cancer patients are typically confusion and lethargy, disorders are the most frequent cause of cerebral and these are usually acute. Rarely, there may be focal hemorrhage in patients with leukemia, and hemor- neurologic signs (e.g., , , rhages in these patients are usually symptomatic. In monoparesis). Subdural hemorrhage is less often fatal patients with acute promyelocytic leukemia, a subtype than parenchymal hemorrhage (Graus et al., 1996). of acute myelogenous leukemia, DIC is triggered by Subarachnoid or intraventricular hemorrhage usually release of procoagulant material from the granules in produces rapid deterioration in the level of con- the progranulocytes. The coagulopathy worsens after sciousness, resulting in . the 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- Coagulopathy dence of DIC is detected in as many as one-third of In cancer patients, abnormal coagulation that pre- patients early in the course of acute lymphoblastic disposes to cerebral hemorrhage is typically due to leukemia, but is rarely associated with clinically sig- 3601_e21_p454-469 2/19/02 9:01 AM Page 456

456 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

nificant hemorrhage (Higuchi et al., 1998). Dissem- 2000). Figure 21–1 shows a postmortem example of inated intravascular coagulopathy may become symp- fatal bilateral hemorrhagic caused by su- tomatic in these patients during induction chemo- perior sagittal in a patient with adeno- therapy, especially in the presence of very low levels carcinoma and coagulopathy. In patients with solid of fibrinogen (Sarris et al., 1996). Cerebral hemor- tumors, symptomatic parenchymal brain hemorrhage rhage is usually a late of other types of resulting from coagulopathy is rare and it is usually leukemia and occurs at relapse or when remission a terminal event. cannot be induced. In the late stages of those leuke- mias, the pathogenesis of hemorrhage is multifacto- Hemorrhage Associated with rial. Disseminated intravascular coagulopathy may be Cerebral Tumor present, but is often accompanied by infection, liver disease, and/or hematologic complications of che- Hemorrhage into parenchymal metastatic brain tu- motherapy. mor is the most common type of brain hemorrhage Primary subdural hemorrhage occurs in leukemia in patients with solid tumors. It occurs most fre- patients when there is severe and refractory throm- quently in patients with metastatic melanoma, germ bocytopenia. In some patients, DIC, sepsis, and cell tumors (especially choriocarcinoma), and car- meningeal leukemia are contributing factors to hem- cinoma of the lung or kidney. It is caused by necro- orrhage (Pitner and Johnson, 1973). Subdural hem- sis of tumor and the rupture of newly formed blood orrhage is more common in patients with acute myel- vessels or by invasion of blood vessels in the adjacent ogenous leukemia after autologous rather than brain parenchyma (Kondziolka et al., 1987). In rare allogeneic bone marrow transplant (Graus et al., instances, especially with metastasis from malignant 1996). An unusual cause of brain hemorrhage is ve- melanoma or choriocarcinoma, the metastasis un- nous infarction due to cerebral sinus thrombosis as- derlying vascular invasion is microscopic. In more sociated with coagulopathy, typically occurring in pa- than one-half of patients, symptoms are acute and may tients who have leukemia (Raizer and DeAngelis, be the first clinical sign of metastasis

Figure 21–1. Bilateral cerebral hemorrhagic infarctions caused by nonmetastatic superior sagittal sinus thrombosis. 3601_e21_p454-469 2/19/02 9:01 AM Page 457

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(Lieu et al., 1999). In other patients, the symptoms that are filled with leukemic blasts (leukostasis) and are superimposed on chronic or progressive symp- adjacent to leukemic nodules (Freireich et al., 1960). toms of brain metastasis. Blast cells have less deformation than red blood cells; Ruptured neoplastic are a rare cause of thus hyperviscosity, vascular endothelial damage, and and predominantly occur in competition with host cells to produce local patients who have cardiac myxoma, lung carcinoma, might result in hemorrhage. or choriocarcinoma (Kalafut et al., 1998). These Leukemic nodules enlarge and invade cerebral aneurysms develop when tumor embolic material in- vessels. Leukostasis is more intense in the white mat- vades a cerebral vessel wall. After recanalization, the ter, periventricular regions, and leptomeninges than damaged wall dilates and ruptures (Murata et al., in the cortex (Nowacki et al., 1995). Intracerebral 1993). Rarely, aneurysms develop as a result of vas- hemorrhages associated with hyperleukocytosis are cular invasion by a parenchymal metastasis. Neoplas- usually multiple and are located in the . aneurysms are typically located in distal arterial Intraventricular or subarachnoid hemorrhage may branches, usually those of the middle cerebral . also occur. In contrast with patients who have hem- Symptomatic subdural hemorrhage associated orrhage caused by coagulopathy, only moderate with tumor metastasis to the dura is uncommon. thrombocytopenia is usually present, which would not Dural metastasis develops from hematogenous spread be expected to cause spontaneous hemorrhage. A of tumor to the dura or from skull metastasis that in- rare cause of intraparenchymal hemorrhage is cere- vades the dura. Figure 21–2 shows a subdural he- bral perivascular infiltration of leukemic cells in lep- matoma that was caused by dural metastasis of breast tomeningeal leukemia, resulting in the rupture of carcinoma. The subdural hemorrhage may be due to cerebral . Subarachnoid hemorrhage can the rupture of vessels from vascular congestion by also occur in patients with diffuse leptomeningeal tu- tumor or due to spontaneous hemorrhage of tumor. mor when there is thrombocytopenia. In some patients, there may be an effusion from tu- mor in the dura. The tumors that most commonly un- Treatment-Related Hemorrhage derlie subdural hemorrhage associated with dural metastasis are carcinomas (especially gastric, breast, The use of L-asparaginase in induction therapy for or prostate); leukemia and lymphoma are less com- acute lymphocytic leukemia results in cerebral hem- mon (McKenzie et al., 1990). In some instances, a orrhage or thrombosis in a small percentage of pa- superimposed coagulopathy contributes to the hem- tients (Urban and Sager, 1981; Gugliotta et al., 1992). orrhage (Minette and Kimmel, 1989). Signs of sub- L-asparaginase is known to promote and dural hemorrhage usually develop gradually, and to deplete plasma proteins involved in coagulation, there may be focal neurologic signs in addition to but the precise mechanism of thrombosis and hem- headache. due to dural or skull orrhage is unknown. In some cases, cerebral hem- metastasis is rare (McIver et al., 2001). orrhage is due to venous infarction from thrombosis If DIC associated with acute promyelocytic leukemia of the superior sagittal sinus. is excluded, hyperleukocytosis (peripheral blast cell A hemolytic uremic–like syndrome is reported in count in excess of 100,000/mm3) is the most common patients with adenocarcinoma, sometimes develop- cause of intracerebral hemorrhage at the time of di- ing after the administration of chemotherapy. The agnosis of leukemia. Hyperleukocytosis occurs most clinical manifestations are thought to be due to frequently in patients with acute myelogenous leuke- endothelial damage and include microangiopathic mia, especially the monocytic variant (Wurthner et al., hemolytic , thrombocytopenia, pulmonary 1999). Patients with hyperleukocytosis experience in- edema, and renal insufficiency. Similar to the de tracerebral hemorrhage in association with infiltration novo hemolytic uremic syndrome, the neurologic of cerebral capillaries by blast cells, but the pathogen- signs include headache, confusion, hemiparesis, and esis of hemorrhage is controversial. In one series hem- coma. Originally reported as a complication of mit- orrhage occurred while the white count was omycin C, it has now been associated with several declining following chemotherapy administration antineoplastic agents, including bleomycin and cis- (Wurthner et al., 1999). Postmortem studies reveal platin (Gordon and Kwaan, 1997). The onset after hemorrhage adjacent to dilated and thin-walled vessels chemotherapy administration is highly variable and 3601_e21_p454-469 2/19/02 9:01 AM Page 458

458 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

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

ranges from days to months. In other cancer patients, Miscellaneous intracerebral hemorrhage occurs as a terminal event in the setting of severe thrombocytopenia induced by Hypertension is a rare cause of symptomatic intra- bone marrow failure from chemotherapy, radiation, cerebral hemorrhage in cancer patients (Graus et al., or metastasis. 1985). It occurs primarily in patients with solid tu- 3601_e21_p454-469 2/19/02 9:01 AM Page 459

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mors. A high percentage of patients with chronic hemorrhage into parenchymal brain metastasis. Clues myeloproliferative disorders, especially chronic myel- to intratumoral hemorrhage include a multiplicity of ogenous leukemia and osteomyelofibrosis, experi- hemorrhages, brain locations other than those usu- ence intraparenchymal hemorrhage. Hemorrhage ally found with hypertensive hemorrhage, and early may coexist with intracerebral thromboses (Buss et edema and enhancement adjacent to the hemorrhage al., 1985), and these tend to occur early in the dis- (Atlas et al., 1987). If an intratumoral brain hemor- ease (Wehmeier et al., 1991). In patients with lym- rhage is suspected but the patient is not known to phoma, intracerebral hemorrhage may be related to have cancer, biopsy of the hematoma wall is indicated severe thrombocytopenia from idiopathic thrombo- to establish the diagnosis. Parenchymal hemorrhages cytopenic purpura or to an acquired form of von associated with ruptured neoplastic aneurysms may Willebrand’s disease. In patients with myeloma, in- be single or multiple. Cerebral in neo- tracerebral hemorrhage may be related to thrombo- plastic aneurysms can reveal filling defects, fusiform cytopenia and serum hyperviscosity. Primary sub- and saccular aneurysms, and occluded vessels, but arachnoid hemorrhage is sufficiently rare in cancer the sensitivity of angiography is unknown; in some in- patients so that congenital aneurysms should be con- stances, the hematoma obliterates the aneurysm and sidered. Among 24 patients with cancer and primary angiographic findings are normal. subarachnoid hemorrhage in the series by Graus et In patients with subdural , CT and MRI al. (1985), 4 had ruptured congenital aneurysms. brain scans can show acute or chronic subdural fluid collections. If dural metastasis is present, there may be Diagnosis evidence of adjacent skull metastasis and dural en- hancement after injection of a contrast agent such as Coagulopathy gadolinium. However, histologic examination of the The stage of the leukemia and associated clinical fac- dural membrane or subdural fluid may be necessary tors such as degree of thrombocytopenia and the pres- to establish the diagnosis of dural metastasis. Lep- ence of sepsis can suggest the cause of brain hemor- tomeningeal metastasis is suggested by leptomeningeal rhage in patients with leukemia. The diagnosis of enhancement on neuroimaging studies after injection intracerebral hemorrhage is established by MRI or CT of a contrast agent such as gadolinium and proven by scans of the brain that reveal single or multiple hem- identification of malignant cells in orrhages. Patients who have acute DIC may also have or in leptomeningeal biopsy specimens. systemic thrombosis, including , pulmonary , or , and sys- Treatment-Related Hemorrhage temic hemorrhage, including hemorrhage in the mu- cosal surfaces, retinae, , genitourinary and gas- Cerebral hemorrhage can occur during or immedi- trointestinal tracts, and at the site of venipuncture or ately after induction therapy with L-asparaginase in bone marrow aspiration. Laboratory studies to confirm patients with acute lymphocytic leukemia. Brain MRI acute DIC include measurement of , prothrom- and magnetic resonance can be diagnos- bin time, activated partial thromboplastin time, fibrino- tic of venous occlusion. Systemic signs of a hemolytic gen, fibrin split products, fibrinopeptide A, the D-dimer uremic–like syndrome in conjunction with severe he- assay, and the presence of schistocytes on the periph- molytic anemia and thrombocytopenia associated eral blood smear. In many patients with cancer, labo- with the administration of chemotherapy for adeno- ratory tests reveal evidence of chronic DIC, but this con- carcinoma suggest this diagnosis. dition is rarely symptomatic; results of laboratory tests of coagulation function in all patients must be carefully Miscellaneous interpreted in their clinical context. Laboratory tests that reveal evidence of extreme thrombocytosis, impaired platelet function, or hyper- Hemorrhage Associated with viscosity can be helpful in identifying the cause of Cerebral Tumor cerebral hemorrhage in patients with chronic myelo- Computed or MRI scans of the brain re- proliferative disorders, lymphoma, and multiple veal single or multiple hemorrhages when there is myeloma. 3601_e21_p454-469 2/19/02 9:01 AM Page 460

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Treatment Therapy for subdural hemorrhage associated with dural metastasis is generally palliative and includes Coagulopathy brain irradiation and drainage of subdural fluid. The Successful therapy for acute DIC is multifaceted and use of antimetabolites and leukapheresis reduces controversial. Evacuation of an intracerebral hemor- the frequency of brain hemorrhage in acute leukemia rhage in the setting of coagulopathy is difficult, and in patients presenting with hyperleukocytosis (Wurthner patients with cancer who have cerebral hemorrhage et al., 1999). caused by DIC treatment should be directed at con- trolling the systemic tumor and the associated medical Treatment-Related Hemorrhage conditions that contribute to the coagulopathy, such as sepsis. Treatment with and fresh-frozen plasma The chances for neurologic recovery in patients ex- can control DIC in some patients. Other therapies in- periencing L-asparaginase–induced thrombosis or clude replacement of clotting factors with blood prod- hemorrhage are generally good (Feinberg and Swen- ucts such as cryoprecipitate and platelet concentrations son, 1988), and cerebrovascular events do not usu- and antifibrinolytic agents. In patients with acute ally recur after re-treatment. Fresh-frozen plasma may promyelocytic leukemia and DIC, it is controversial be beneficial for patients with , but whether prophylactic heparin as an adjunct to induc- it is not known if anticoagulation is necessary. The tion chemotherapy can reduce the incidence of in- for patients with the hemolytic uremic–like tracerebral hemorrhage. Chemotherapy, however, can syndrome induced by chemotherapy is poor, but increase the lysis of blast cells and aggravate DIC. All- steroids and plasma exchange may prolong survival trans retinoic acid administered for remission induc- (Gordon and Kwaan, 1997). tion therapy of acute promyelocytic leukemia can dif- ferentiate abnormal promyelocytes into mature Miscellaneous granulocytes, which improves coagulation function and results in a slight decrease of early brain hemorrhage Conventional cytoreductive therapy reduces the inci- (Tallman et al., 1997). Most patients with subdural he- dence of cerebral ischemic or hemorrhagic events in matoma caused by coagulopathy can be successfully patients with chronic myeloproliferative disorders managed without (Graus et al., 1996). (Wehmeier et al., 1991).

Hemorrhage Associated with Cerebral Tumor Survival of patients with massive intratumoral par- As is the case with cerebral hemorrhage, the risk fac- enchymal brain hemorrhage or ruptured neoplastic tors for cerebral infarction in patients with cancer are aneurysms is poor, especially for those who have an usually different from those in patients without can- acute onset of symptoms (Graus et al., 1985). These cer. Table 21–2 lists the causes of cerebral infarc- patients may die as a direct result of the hemorrhage. tion in cancer patients. Coagulation disorders, infec- In some patients, resection of a single large hema- tion, the direct effects of CNS metastasis, and toma is life saving (Little et al., 1979). The clinical complications of antineoplastic treatment are the course in patients with hemorrhage into brain me- most common causes. Symptomatic cerebral infarc- tastasis who have a stable neurologic condition is no tion is more common in patients who have lymphoma different from that of patients with nonhemorrhagic and carcinoma than it is in those with leukemia, in brain metastasis. These patients should receive radi- whom cerebral hemorrhage predominates. ation therapy directed to the underlying brain metas- Two clinical factors make the identification of tasis. For patients with ruptured neoplastic cerebral cerebral infarction in cancer patients and the deter- aneurysms, therapy should be directed to the systemic mination of its cause difficult. First, cerebral infarc- tumor (appropriate antineoplastic therapy in the case tions in cancer patients are often multifocal, and the of systemic cancer and removal of the cardiac tumor resulting multifocal neurologic signs are difficult to in the case of cardiac myxoma). Brain irradiation is distinguish from those caused by . indicated for neoplastic aneurysms that arise from Therefore, the possibility of cerebral infarction must systemic carcinoma. be considered for all cancer patients who experience 3601_e21_p454-469 2/19/02 9:01 AM Page 461

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Table 21–2. Pathophysiology of Cerebral Infarction in Patients with Cancer Etiology Pathology Tumor Type and Setting Coagulopathy Nonbacterial thrombotic Cerebral infarction Adenocarcinoma, usually widespread Cerebral intravascular Cerebral infarction, petechial hemorrhage Lymphoma, leukemia, breast cancer, in coagulation 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, lymphoma adjacent 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 with L-asparaginase Chemotherapy Cerebral infarction Breast cancer during multi-agent chemotherapy and hormonal therapy; other solid tumors during cisplatin-based chemotherapy Miscellaneous 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

encephalopathy. Second, proving a link between co- bosis of or veins in the systemic or cerebral agulation abnormalities and cerebral infarction can circulation. There are multiple risk factors for coag- be difficult because many cancer patients have ab- ulopathy and thrombosis, including a complex inter- normalities of coagulation function that are revealed action between tumor cells and their products with by laboratory tests but are not clinically significant. host cells, cancer treatment including single- or mul- The most important clues to the etiology of cerebral tiple-agent chemotherapy, hormonal therapy, and he- infarction are the type of cancer, the extent of sys- matopoietic growth factors. Nonbacterial thrombotic temic metastasis, the presence of CNS metastasis, and endocarditis is the result of a hypercoagulable state the type of antineoplastic treatment. and is characterized by the development of sterile platelet-fibrin vegetations on cardiac valves. Nonbacterial thrombotic endocarditis is the most Pathophysiology and common cause of symptomatic cerebral infarction Clinical Presentation in cancer patients (Graus et al., 1985). Figure 21–3 shows cardiac nonbacterial thrombotic endocarditis Coagulopathy in a patient with lung adenocarcinoma. Patients with The majority of patients with advanced solid tumors cerebral infarction caused by nonbacterial throm- have laboratory evidence of clotting activation that is botic endocarditis usually experience focal neuro- usually asymptomatic. In a small percentage of pa- logic signs, and angiography in these patients typi- tients, however, the coagulopathy results in throm- cally shows multiple branch occlusions of the middle 3601_e21_p454-469 2/19/02 9:01 AM Page 462

462 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

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

cerebral artery. Focal signs may be preceded by tran- sometimes transient, focal neurologic signs (Collins et sient ischemic attacks. Some patients also develop en- al., 1975). The clinical course is progressive. Typically, cephalopathy because of multifocal infarctions. Post- multiple vessels in more than one major vessel territory mortem studies suggest that cerebral infarctions are of the brain and leptomeninges—usually small arter- caused by embolization of cardiac vegetations to the ies, arterioles, capillaries, or venules—are occluded brain, cerebral intravascular thromboses that result with fibrin. Figure 21–4 shows fibrin occlusions of lep- from the associated coagulation disorder, or both tomeningeal vessels in association with cerebral infarc- (Reagan and Okazaki, 1974; Rogers et al., 1987). tions in a patient with breast cancer and cerebral Nonbacterial thrombotic endocarditis occurs most intravascular coagulation. Cerebral intravascular coag- commonly in patients with adenocarcinoma, espe- ulation is reported in patients with leukemia, breast can- cially mucin-producing carcinomas of the lung or cer, and lymphoma, usually in the setting of advanced gastrointestinal tract. It usually develops in patients disease and sepsis. Amico et al. (1989) reported sys- with advanced cancer, but can occur in patients with temic and cerebral infarctions in six patients with mu- early-stage cancer and can even be the presenting sign cinous . At autopsy, mucin was present within of cancer (Rogers et al., 1987). Evidence of systemic vessels, macrophages, and areas of infarction. It is thrombosis or hemorrhage suggests the presence of unknown whether mucin deposition results from me- nonbacterial thrombotic endocarditis. tastasis or is associated with a cancer-related coagu- Cerebral intravascular coagulation is due to throm- lopathy. botic occlusion of small cerebral vessels caused by a Nonmetastatic occlusion of large cerebral venous coagulopathy unaccompanied by nonbacterial throm- structures in cancer patients is caused by a coagula- botic endocarditis. It is the second most common cause tion disorder associated with cancer or with chemo- of symptomatic cerebral infarction in patients with can- therapy. The most common cerebral venous structure cer (Graus et al., 1985). Patients with cerebral in- affected is the superior sagittal sinus, and the under- travascular coagulation develop encephalopathy, and lying tumor is usually leukemia (Raizer and DeAnge- approximately one-half of patients have superimposed, lis, 2000). The incidence of this disorder is unknown 3601_e21_p454-469 2/19/02 9:01 AM Page 463

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

because the sinus occlusion can recanalize and is, in those with lymphoma or carcinoma. Common sites therefore, underreported in autopsy series. The on- of entry are the lower respiratory tract for Aspergillus set of symptoms from nonmetastatic superior sagittal and the gastrointestinal or genitourinary tracts or in- sinus thrombosis is typically sudden headache; dwelling venous catheters for Candida species. Cere- seizures, focal neurologic signs, or encephalopathy bral infarctions associated with cerebral infection are develop if there is brain hemorrhage or infarction. often multiple and may be hemorrhagic (Walsh et Superior sagittal sinus occlusion is associated with in- al., 1985). The neurologic signs usually consist of duction therapy that includes the administration of seizures, focal cerebral signs, or encephalopathy. L-asparaginase to patients with acute lymphocytic leu- Acute focal signs and seizures are more common in kemia (see “Treatment-Related Cerebral Infarction” patients with Aspergillus infection, and encephalopa- in this chapter). In other patients with lymphoma or thy is more common in patients with Candida infec- solid tumors, it usually occurs in the setting of wide- tion. is rarely present. spread systemic metastatic disease. Infarction Associated with Cerebral Tumor Infarction Associated with Skull or dural tumor that infiltrates or compresses Cerebral Infection the superior sagittal sinus can produce venous stasis Cancer patients are predisposed to systemic infections and thrombosis. In contrast to patients with non- because of immunosuppression caused by the tumor metastatic superior sagittal sinus thrombosis, patients or by treatment with radiation, chemotherapy, broad- with the metastatic type of thrombosis develop suba- spectrum antibiotics, or immunosuppressants. Cere- cute symptoms resulting from increased intracranial bral infarction associated with infection is most com- pressure (typically headache, vomiting, and pa- monly caused by fungal septic emboli, typically of pilledema). Focal neurologic signs or encephalopa- Aspergillus and Candida species. Fungal sepsis oc- thy may be present if there is cerebral infarction. It curs more commonly in patients with leukemia than occurs most commonly in patients with neuroblas- 3601_e21_p454-469 2/19/02 9:01 AM Page 464

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toma, lung cancer, and lymphoma, but is reported in Potential mechanisms for abnormal coagulation a variety of tumors. function in patients receiving chemotherapy include Another mechanism for tumor-related cerebral in- alterations in coagulation factors or farction is embolism of a tumor fragment to the brain. proteins and endothelial damage produced by these This can produce focal or multifocal cerebral signs, agents. Because of the small number of events oc- sometimes preceded by transient ischemic attacks curring in individual treatment studies and the lack (O’Neill et al., 1987). Embolism of a tumor fragment of uniform reporting of thromboembolism, including to the brain is reported exclusively in patients with stroke, the evidence for a causal relationship with an- solid tumors, usually those with a primary or meta- tineoplastic agents, regardless of other risk factors, static cardiac or lung tumor that is the source of the is weak (Lee and Levine, 1999). The best-recognized . Cerebral embolism can occur at the time of cerebrovascular complication of chemotherapy is ve- manipulation of the lung in patients with lung tumor nous thrombosis caused by L-asparaginase used in undergoing thoracotomy (Lefkovitz et al., 1986; combination induction chemotherapy for patients O’Neill et al., 1987). It can be the presenting sign of with acute lymphocytic leukemia (Lee and Levine, cardiac tumor, especially cardiac myxoma. Lep- 1999; Gugliotta et al., 1992). L-asparaginase pro- tomeningeal metastasis is a rare cause of cerebral in- motes fibrinolysis and causes a depletion of plasma farction. Infarction may be the sole manifestation of proteins involved in coagulation. There may be pro- this disorder, or there may be accompanying typical motion of thrombosis by a transient increase in un- signs, including headache, cranial nerve palsies, and usually large plasma von Willebrand’s factor multi- radiculopathies. Postmortem studies suggest that in- mers (Pui et al., 1987). There are also uncommon farction occurs because tumor infiltrates the cerebral reports of systemic and cerebral venous and arterial arteries in the Virchow-Robin spaces and causes vas- thromboembolic complications in women with breast cular occlusion or spasm (Klein et al., 1989). The in- cancer receiving multiagent chemotherapy (Wall et farctions may be multifocal. al., 1989), especially when chemotherapy is com- bined with hormonal therapy (Saphner et al., 1991). Complications usually occur early in treatment. Treatment-Related Infarction A rare neurologic complication of chemotherapy Neck radiation administered for head and neck can- is cerebral embolization from a ventricular mural cer or lymphoma can produce delayed extracranial that forms in association with cardiomy- carotid or occlusion. In a prospective study opathy resulting from chemotherapy with doxoru- of carotid duplex ultrasound performed in 240 pa- bicin (Adriamycin) (Schachter and Freeman, 1982). tients with head and neck cancer who received ra- Transient focal neurologic signs suggesting transient diation to the cervical region, a greater than 70% ischemic attacks can occur during interleukin-2 ther- stenosis of the common and/or internal carotid apy (Bernard et al., 1990). artery was detected in 28 patients (11.7%) (Cheng et al., 1999). Histologic examination of the diseased Miscellaneous artery suggests that radiation produces or acceler- ates atherosclerosis. Patients may develop transient Atherosclerosis is the most common cause of cere- ischemic attacks, including , or bral infarction found at autopsy in patients with can- cerebral infarction. Murros and Toole (1989) re- cer, but it accounts for only 14% of symptomatic in- ported a wide interval between and farctions (Graus et al., 1985). The most common the development of this complication, with a mean tumors associated with symptomatic cerebral infarc- interval of 19 years. Carotid artery rupture is a po- tion from atherosclerosis are head and neck cancers tentially fatal complication of head and neck tumor and lung cancer. A less common cause of sympto- resection and neck irradiation. It is usually associ- matic cerebral infarction is granulomatous angiitis ated with orocutaneous , necrosis of the skin occurring in patients with Hodgkin’s disease or leu- flap, and infection (McCready et al., 1983). Patients kemia (Inwards et al., 1991; Lowe and Russell, may die from exsanguination. If the carotid rupture 1987). Signs include headache, fever, confusion, is detected and the artery is ligated, there is a sig- seizures, obtundation, or hemiparesis. Patients with nificant chance of cerebral infarction and chronic myeloproliferative disorders who have ex- (Razack and Sako, 1982). treme thrombocytosis can experience cerebral arte- 3601_e21_p454-469 2/19/02 9:01 AM Page 465

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rial or venous thromboembolic events (Randi et al., giography is a sensitive test for the diagnosis of cere- 1998). These complications are most common in pa- bral infarction from nonbacterial thrombotic endo- tients with and essential thrombo- carditis. In these patients, typ- cythemia and occur more often in older patients ically shows multiple branch occlusions of the middle (Jabaily et al., 1983; Wehmeier et al., 1991). Platelet cerebral artery (Rogers et al., 1987). Many patients thromboembolism is likely caused by inherent alter- with cerebral intravascular coagulation have systemic ations of platelet function in addition to the exces- , but results of laboratory tests of coagula- sively high number of platelets. Neurologic symptoms tion function are nonspecific. In a study by Collins et are most common before and shortly after the diag- al. (1975), neuroimaging studies performed in a nosis of chronic myeloproliferative disorders, prob- small number of patients were normal. There is no ably because cytoreductive therapy administered af- method currently known to diagnose this syndrome ter the diagnosis is effective (Michiels et al., 1993). aside from postmortem examination. In patients with essential , symp- Magnetic resonance imaging of the brain is the toms are usually transient and are poorly localized; imaging procedure of choice to detect superior sagit- they include unsteadiness, , and . tal sinus thrombosis caused by coagulopathy. It can Focal symptoms such as transient monocular blind- document the lack of normal flow void within the oc- ness or limb weakness are less common. They are of cluded sinus and can reveal enlarged collateral veins sudden onset and are often accompanied by head- (Sze et al., 1988). Adjacent cerebral hemorrhage or ache. Systemic arterial or venous thrombosis may also infarction can also be visualized. When MRI is non- occur. Patients with Hodgkin’s disease who are in re- diagnostic, magnetic resonance venography can be mission or cured can experience episodic neurologic diagnostic (Fig. 21–5). dysfunction that resembles transient ischemic attacks (Feldmann and Posner, 1986). The cause of these symptoms is unknown. Infarction Associated with Infection Computed tomography and MRI brain scans can re- veal infarctions in patients with septic cerebral em- Diagnosis bolism. Focal enhancement may appear later if the Coagulopathy infarctions evolve into abscesses. Cerebrospinal fluid examination is generally nondiagnostic because usu- Patients with stroke caused by coagulation disorders ally only mild pleocytosis and protein elevation are may have evidence of systemic thrombosis or present. Cultures are typically negative. Hemorrhagic hemorrhage. Particularly, patients with nonbacterial cerebrospinal fluid can be a clue to Aspergillus in- thrombotic endocarditis may have systemic bleeding, fection (Walsh et al., 1985). Blood cultures are of- limb thrombophlebitis arterial occlusion, pulmonary ten negative, but clinical or radiographic evidence of embolism, or myocardial infarction (Reagan and pulmonary infection suggests systemic Aspergillus in- Okazaki, 1974; Rogers et al., 1987). Laboratory tests fection. Aspergillus can be isolated from respiratory may reveal evidence of DIC in some patients (Rogers secretions or open lung biopsy specimens, but open et al., 1987), but in many patients abnormalities on lung biopsy is potentially hazardous in many cancer coagulation function tests are indistinguishable from patients because of coexisting thrombocytopenia the abnormalities commonly associated with cancer. (Walsh et al., 1985). These abnormalities include markers of clotting ac- tivation, such as abnormal –antithrombin complex, prothrombin fragment F 1 2, and D- Infarction Associated with Cerebral Tumor dimer. Cardiac murmurs are rare, and transthoracic echo- Brain MRI and magnetic resonance venography are cardiography is usually nondiagnostic because of the the methods of choice to diagnose metastatic supe- small size of the cardiac vegetations. Transesophageal rior sagittal sinus occlusion and to reveal associated can be diagnostic (Blanchard et cerebral infarction. In patients with superior sagittal al., 1992). Computed tomography or MRI scans of sinus occlusion due to skull or dural tumor, MRI may the brain may reveal cerebral infarction. In patients also reveal evidence of adjacent skull or dural me- who experience focal neurologic signs, cerebral an- tastasis. Dural or leptomeningeal metastasis will usu- 3601_e21_p454-469 2/19/02 9:01 AM Page 466

466 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT

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

ally enhance after injection of gadolinium. In patients or extensive stenosis of the with tumor embolic infarctions, the infarctions can that is confined to the field of irradiation. The length be seen on CT or MRI scans, and angiography may of stenosis in these patients is typically greater than reveal vascular occlusions (Marazuela et al., 1989; it is in patients with atherosclerosis not associated O’Neill et al., 1987); however, these findings are not with irradiation (Fig. 21–6). Little information is specific, and a definitive diagnosis of tumor embolism available on neuroimaging abnormalities in patients can be established only if there is a simultaneous pe- who experience cerebral infarction related to che- ripheral arterial embolism that can be examined his- motherapy administration except for patients with su- tologically. Patients in whom tumor embolic infarc- perior sagittal sinus occlusion. There are no labora- tion is suspected should undergo serial CT or MRI tory tests that can diagnose chemotherapy-induced brain scans for evaluation of growth of the brain me- coagulation abnormalities. tastasis. Clinical clues to the presence of primary or metastatic cardiac tumor include a new onset of con- Miscellaneous gestive failure, , rapid car- diac enlargement, or that are difficult to Atherosclerotic brain infarction is suggested by the control. Echocardiography is diagnostic. patient’s age and the presence of typical risk factors for atherosclerosis. Granulomatous angiitis is sug- gested by the presence of cerebral infarctions, hem- Treatment-Related Infarction orrhages, or contrast-enhancing masses on CT or MRI Carotid angiography in patients with radiation-in- brain scans in patients with lymphoma or leukemia. duced carotid artery disease usually reveals occlusion Angiography may show a classic beading pattern but 3601_e21_p454-469 2/19/02 9:01 AM Page 467

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Treatment Coagulopathy Effective therapy for coagulation disorders must be directed to the underlying tumor, to associated med- ical conditions such as sepsis that predispose the pa- tient to the disorder, and to the coagulation disorder itself. Management decisions for coagulopathy are still controversial, and therapy must be individualized. Low-molecular-weight heparin or low-dose can reduce the risk of systemic venous thromboem- bolism in cancer patients (Levine and Lee, 2001), but their role in the prophylaxis of stroke is unknown. Pa- tients who experience cerebral infarction from non- bacterial thrombotic endocarditis may benefit from anticoagulation therapy. In the series by Rogers et al. (1987), heparin therapy was effective in reducing ischemic symptoms in some patients with cerebral in- farction, and the incidence of hemorrhagic infarction and cerebral hemorrhage, possible side effects of this therapy, was no greater than in patients who were not anticoagulated. However, anticoagulation must be un- dertaken judiciously because of the risk of systemic and cerebral hemorrhage in patients with this disor- der. Appropriate therapy for cerebral intravascular coagulation is not known. Heparin and urokinase are reported to be beneficial in reducing the morbidity of superior sagittal sinus thrombosis in patients without cancer (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 should be treated with antifungal therapy, but the prognosis Figure 21–6. Cerebral angiography in a patient with laryn- for recovery and survival is poor (Walsh et al., 1985). 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 diffuse Infarction Associated with Cerebral Tumor irregularity and severe stenosis alternating with zones of di- Patients with metastatic superior sagittal sinus occlu- latation in the proximal internal and external carotid arteries. The area of involvement of the common, internal, and exter- sion should be treated with irradiation of the brain. nal carotid arteries corresponds to the field of radiation. It is not known whether anticoagulation therapy is ef- fective in treating this disorder. In patients with em- bolic infarction from malignant tumors, the brain may be nonspecifically abnormal or normal. The most should also be irradiated. In those patients with car- definitive method for diagnosis of granulomatous diac tumors, removal of the cardiac tumor will angiitis is biopsy, but its sensitivity is low (Inwards et prevent subsequent embolization. Patients with lep- al., 1991). The association of cerebral infarction with tomeningeal metastasis should be treated with radia- thrombocythemia can be determined by measuring tion to the symptomatic areas of the neuraxis and with the platelet count. systemic or intraventricular chemotherapy. 3601_e21_p454-469 2/19/02 9:01 AM Page 468

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Treatment-Related Infarction Cheng SW, Wu LL, Ting AC, Lau H, Lam LK, Wei WI. 1999. Ir- radiation-induced extracranial carotid stenosis in patients Patients with symptomatic or high-grade radiation-in- with head and neck malignancies. Am J Surg 178:323–328. duced carotid stenosis can be effectively treated with Citardi MJ, Chaloupka JC, Son YH, Ariyan S, Sasaki CT. 1995. ; the long-term patency rates are sim- Management of carotid artery rupture by monitored en- ilar to those in nonirradiated patients (Kashyup et al., dovascular therapeutic occlusion (1988–1994). Laryngo- scope 105:1086–1092. 1999). Endovascular occlusion is a safe and effective Collins RC, Al-Mondhiry H, Chernik NL, Posner JB. 1975. Neu- method to avoid carotid artery ligation and prevent rologic manifestations of intravascular coagulation in pa- cerebral infarction in patients with carotid artery rup- tients with cancer: a clinicopathologic analysis of 12 cases. ture (Citardi et al., 1995). If carotid ligation is re- 25:795–806. quired, low-dose heparin may reduce the risk of cere- De Bruijn SF, Stam J. 1999. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight bral infarction (Leikensohn et al., 1978). There is no heparin for cerebral sinus thrombosis. Stroke 30:484–488. effective therapy known for the vascular complica- Einhaupl KM, Villringer A, Meister W, et al. 1991. Heparin treat- tions of chemotherapy, although Feinberg and Swen- ment in sinus venous thrombosis. Lancet 338:597–600. son (1988) suggest that prophylactic fresh-frozen Feinberg WM, Swenson MR. 1988. Cerebrovascular compli- cations of L-asparaginase therapy. Neurology 38:127–133. plasma be administered to patients receiving L-as- Feldmann E, Posner JB. 1986. Episodic neurologic dysfunc- paraginase. In other situations, the benefits of che- tion in patients with Hodgkin’s Disease. 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