3601_e20_p438-453 2/19/02 8:59 AM Page 438 20 Seizures and Syncope in the Cancer Patient ALEXANDRA FLOWERS Neurologic complications in cancer patients com- may be present in a patient, so an accurate evalua- monly involve altered levels of consciousness. This tion will require a comprehensive work-up of each chapter discusses seizures and syncope, two prob- patient. lems in cancer patients that can have multiple causes. Whereas normally it is easy to distinguish between Primary and Metastatic Brain Tumors these two conditions, occasionally when there are no observers of the event, it can be difficult for the clin- Primary and metastatic brain tumors can present with ician to be certain whether a seizure or syncope has focal or generalized seizures. Among infiltrating occurred. It is hoped that the sections that follow will gliomas, low-grade gliomas, particularly those involv- help clarify the etiologies, presentations, and treat- ing the temporal lobe, are the most likely to cause ments for seizures and syncope in cancer patients, in- seizures, usually with onset in childhood or in the teen- cluding those caused by drugs given for cancer age years (Bartolomei et al., 1997; Britton et al., 1994; therapy. Rogers et al., 1993). Patients with seizures caused by brain tumors present with generalized tonic-clonic seizures or simple or complex partial seizures, with or SEIZURES without secondary generalization. Unfortunately, at times the seizures are difficult to treat. Additionally, an Seizures are the first clinical manifestation in ap- increased frequency of seizures in a patient with a proximately 30% of patients with primary or meta- known low-grade brain tumor may indicate tumor static brain tumors (Cascino, 1993; Stein and Cham- transformation to a more malignant histology. berlain, 1991). In patients who have systemic cancer In general, patients with primary brain tumors who without brain metastases, the incidence of ictal phe- present with seizures but do not have magnetic res- nomena is not well documented. In fact, there onance imaging (MRI) or computerized tomography have been no prospective or retrospective studies of (CT) confirmation of tumor at their initial evaluation seizures in this group, and some seizures in these pa- have a better prognosis. This fact may reflect an ear- tients are not recognized as such (e.g., complex par- lier diagnosis of tumor and/or lower grade of malig- tial seizures). On occasion, non-ictal, abnormal nancy. Improvement in MRI scanning techniques al- movements may be confused with seizures. lows these patients to be diagnosed with tumor at an earlier time. Surgery, when feasible, is a desired therapeutic ap- Etiology proach for both tumor removal and seizure control The etiology of seizures in cancer patients is pre- (Britton et al., 1994). Modern techniques, such sented in Table 20–1. More than one etiologic factor as brain mapping and intraoperative electroen- 438 3601_e20_p438-453 2/19/02 8:59 AM Page 439 Seizures and Syncope in the Cancer Patient 439 Table 20–1. Etiology of Seizures in Cancer Patients Etiologic Factors Causes Intracranial tumors Parenchymal Primary tumors (gliomas), metastatic tumors Meningeal Mass lesions Primary tumors (meningiomas), metastatic tumors Diffuse Primary tumors (meningeal gliomatosis), metastatic tumors (meningeal carcinomatosis, lymphomatosis) Systemic cancer Treatment-related Radiation therapy Increased edema, radiation necrosis Chemotherapy Platinum, methotrexate, cytarabine, busulfan, L-asparaginase, 5-fluorouracil, ifosfamide, paclitaxel Intratumoral chemotherapy Biologic agents IL-2, interferon, lymphokine-activated killer cells, granulocyte-macrophage colony-stimulating factor Other drugs Narcotics Meperidine, morphine, propoxyphene Neuroleptics Haloperidol, phenothiazine Antidepressants Tricyclics, Prozac, Wellbutrin Antibiotics Betalactams, quinolones IV contrast media Radiologic contrast media used for CT scanning Metabolic Hyponatremia Volume depletion, overhydration, syndrome of inappropriate antidiuretic hormone secretion Hypoglycemia Malnutrition, pancreatic tumors, total parenteral nutrition withdrawal Hypocalcemia Nutritional, secondary to chemotherapy (cisplatin) Hypomagnesemia Drug-related (chemotherapy—cisplatin, amphotericin B), hypoparathyroidism Hypoxia Pulmonary fibrosis (chemotherapy related), pulmonary embolism, lung cancer (primary or metastatic) Vascular Stroke (thrombotic, embolic), vasculitis (paraneoplastic, treatment induced) Hemorrhagic Parenchymal Tumor, mycotic aneurysms, aspergillomas Subdural Post-traumatic, due to thrombocytopenia, after spinal taps Subarachnoid Spontaneous, due to thrombocytopenia or coagulopathy Infectious Viral Herpes simplex, herpes zoster, cytomegalovirus Bacterial Common pathogens, Listeria, Mycobacterium Fungal Aspergillus, Cryptococcus Parasitic Toxoplasmosis cephalography, allow accurate identification of the Systemic cancers most likely to metastasize to the seizure focus (Lim et al., 1991; Cascino, 1990; Smith brain are melanoma, lung carcinoma, renal cell car- et al., 1991). When surgical resection is not feasible, cinoma, breast carcinoma, cancers of the gastroin- radiation therapy (RT) can help control the seizures testinal tract, and choriocarcinoma (Trillet and (Rogers et al., 1993). Biron, 1989; Flowers and Levin, 1993; Rosner et al., 3601_e20_p438-453 2/19/02 8:59 AM Page 440 440 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT 1986). As time of survival increases with the use of Seizures Related to Chemotherapy chemotherapy, other types of cancer are thus given Seizures occur in fewer than 1% of patients treated more time to develop and can also metastasize to the with systemic chemotherapy and can occur as a man- brain. Seizures can also occur secondary to ifestation of the neurotoxicity of chemotherapeutic parenchymal brain metastases and with dural and lep- agents. In general, chemotherapy-associated neuro- tomeningeal metastases (Wasserstrom et al., 1982; toxicity is related to specific drugs or drug combina- Blaney et al., 1991). tions, dose intensity, and route of administration (Weiss et al., 1974). Because the early studies pre- Seizures Related to Paraneoplastic dated both the CT and MRI era, it is possible that Syndromes small cerebral tumor metastases were present in the patient population reported. The chemotherapeutic Although rare, paraneoplastic encephalomyeloneuri- agents most commonly reported to cause central ner- tis can manifest with complex partial or generalized vous system (CNS) toxicity are cisplatin, methotrex- seizures, and these occur most frequently with anti- ate, L-asparaginase, and busulfan. Neurotoxicity is Hu–associated paraneoplastic encephalomyeloneuri- also caused by high doses of busulfan, which is ad- tis in patients with small cell lung carcinoma. Occa- ministered to recipients of bone marrow transplants sionally seizures occur in patients with paraneoplastic (Antonini et al., 1998; Kramer et al., 1997; Snider et encephalomyeloneuritis associated with prostate or al., 1994; Tahsildar et al., 1996). renal cell carcinoma (Dalmau et al., 1992; Drislane, The frequency of neurologic toxic effects increases 1994; Franck et al., 1987; de Toffol et al., 1997). with intra-arterial or intrathecal administration, and Paraneoplastic temporal lobe epilepsy has even been blood–brain barrier modification and also when che- reported in a patient with testicular cancer (Ahern et motherapy (especially methotrexate) is administered al., 1994). in conjunction with RT (Weiss et al., 1974; Feun et al., 1991; Stewart et al., 1992; Newelt and Dahlborg, Seizures Related to Radiation Therapy 1987). Seizures have also been induced by fat em- boli during the intra-arterial administration of cis- The frequency of preexisting seizures may increase platin (Menendez et al., 1990). acutely during RT because of increased cerebral edema. With the use of corticosteroids to control edema and careful monitoring of antiepileptic drug Methotrexate. Moderate and high doses of intra- levels, this is a rather infrequent occurrence. Seizures venous methotrexate can cause leukoencephalopathy may also occur as a result of radiation-induced brain with seizures and other neurologic symptoms (Gen- necrosis or vasculopathy, which are delayed effects vresse et al., 1999). Methotrexate increases the con- of RT (Ciaudo-Lacroix and Lapresle, 1985; Rider, centration of homocysteine, which is oxidatively 1963; Spencer, 1998). Positron emission tomography metabolized to the excitatory amino acid neurotrans- and single-photon emission computed tomography mitters homocisteic acid and cysteine sulfinic acid. scans of the brain can help to distinguish brain tu- Homocysteine also damages the vascular endothelium mors from radiation-induced necrosis, although ac- (Quinn et al., 1997). Seizures have been reported tive epileptogenic foci caused by radiation necrosis with intrathecal and intraventricular administration of can demonstrate hyperperfusion and hypermetabo- methotrexate and cytosine arabinoside as well (Lee lism (Sasaki et al., 1996). et al., 1997; Resar et al., 1993). Neuroimaging stud- Seizures have been reported as immediate side ies, particularly MRI scans of the brain, show diffuse effects (occurring within the first 2 weeks) in pa- white matter lesions, some of which may enhance, or tients treated with radiosurgery. This may be due to may demonstrate a more focal pattern (Lovblad et al., a direct effect of irradiation on cellular permeabil- 1998). Aminophylline has been reported to