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3601_e20_p438-453 2/19/02 8:59 AM Page 438 Seizures and Syncope in the Cancer Patient 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- 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 noobservers 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; Rogers et al., 1993). Patients with seizures caused bybrain tumors present with generalized tonic-clonicseizures or simple or complex partial seizures, with or SEIZURES
without secondary generalization. Unfortunately, attimes 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 anearlier 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- 3601_e20_p438-453 2/19/02 8:59 AM Page 439 Seizures and Syncope in the Cancer Patient Table 20–1. Etiology of Seizures in Cancer Patients
Primary tumors (gliomas), metastatic tumors Primary tumors (meningiomas), metastatic tumors Primary tumors (meningeal gliomatosis), metastatic tumors (meningeal carcinomatosis, Platinum, methotrexate, cytarabine, busulfan, L-asparaginase, 5-fluorouracil, ifosfamide, paclitaxel IL-2, interferon, lymphokine-activated killer cells, granulocyte-macrophage colony-stimulating factor Radiologic contrast media used for CT scanning Volume depletion, overhydration, syndrome of inappropriate antidiuretic hormone secretion Malnutrition, pancreatic tumors, total parenteral nutrition withdrawal Nutritional, secondary to chemotherapy (cisplatin) Drug-related (chemotherapy—cisplatin, amphotericin B), hypoparathyroidism Pulmonary fibrosis (chemotherapy related), pulmonary embolism, lung cancer Stroke (thrombotic, embolic), vasculitis (paraneoplastic, treatment induced) Post-traumatic, due to thrombocytopenia, after spinal taps Spontaneous, due to thrombocytopenia or coagulopathy Herpes simplex, herpes zoster, cytomegalovirus Common pathogens, Listeria, Mycobacterium 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 Biron, 1989; Flowers and Levin, 1993; Rosner et al., 3601_e20_p438-453 2/19/02 8:59 AM Page 440 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT 1986). As time of survival increases with the use of 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- 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 small cerebral tumor metastases were present in thepatient 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 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 in conjunction with RT (Weiss et al., 1974; Feun etal., 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 acutely during RT because of increased cerebraledema. With the use of corticosteroids to controledema 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 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 be an ef- ity and leakage of irritative chemical products; no fective treatment for methotrexate-induced subacute connection has been made with prior external beam neurotoxicity (Bernini et al., 1995).
radiation, use of corticosteroids, target volume, iso-dose, or pretreatment edema (Werner-Wasik et al., Cisplatin. Seizures following intravenous cisplatin are mainly due to hypomagnesemia and hypocalcemia 3601_e20_p438-453 2/19/02 8:59 AM Page 441 Seizures and Syncope in the Cancer Patient and thus are easily prevented by magnesium and, if of interferon, interleukin-2 (IL-2), lymphokine-acti- necessary, calcium supplementation during the che- vated killer cells, and some colony-stimulating fac- motherapy infusion (Bachmeyer et al., 1996; Fuse- tors (Dierckx et al., 1985; Karp et al., 1996; Meyers et al., 1991). Transient lesions in the occipital poles,cerebellum, and centrum semiovale have been de- 5-Fluorouracil. Severe neurotoxicity with seizures, scribed in patients treated with IL-2 who developed encephalopathy, syncope, ataxia, motor neuropathy, focal neurologic problems, including seizures (Karp and demyelinating lesions evident on MRI scan has been reported in patients treated with 5-fluorouracil(5-FU). These patients had an underlying dihydropy- Intratumoral Therapies. Intratumoral therapies rimidine dehydrogenase deficiency, an enzyme that is seek to decrease systemic toxicity of a chemother- responsible for the rate-limiting step of 5-FU catabo- apeutic agent through a high level of regional drug lism. This deficiency increased binding of 5-FU to delivery. However, the risk of causing seizures is thymidylate synthetase and incorporation into RNA higher in those patients with a prior history of tumor-related seizures. Increased frequency of Pre-existing renal disease, which alters the clear- seizures was noted in patients treated with intratu- ance of chemotherapeutic agents, has been impli- moral BCNU Wafers (Gliadel) (Brem et al., 1995); cated in neurotoxicity, with seizures caused by treat- seizures typically occurred in the first 5 days after ment with chlorambucil and cytosine arabinoside. surgery, although they were also observed at 20 to Decreasing the dose of the chemotherapeutic agent is recommended for such patients (Salloum et al.,1997; Smith et al., 1997).
Ifosphamide (ifosfamide). Ifosphamide, commonlyused to treat sarcomas, medulloblastoma, and other Narcotics. Cancer patients often require narcotics pediatric and adult tumors, can cause severe neuro- for control of pain. Narcotics occasionally cause toxicity manifested by coma and seizures (Bhardwaj neurotoxicity and seizures. Specific drugs associated and Badesha, 1995; Gieron et al., 1988).
with the occurrence of seizures are meperidine (De-merol Hydrochloride), propoxyphene (Darvon), Paclitaxel (Taxol). Paclitaxel is highly active against and, rarely, morphine sulfate. In the case of meperi- ovarian, breast, and other cancers (lung, uterine). It dine, the metabolite normeperidine has been im- is a mitotic spindle inhibitor, and it exerts its major plicated. Renal dysfunction may contribute to, but neurotoxic effect on peripheral nerves. Recent re- is not the determining factor for, the accumulation ports link paclitaxel-induced encephalopathy with and neuroexcitatory effect of normeperidine (Goet- seizures, particularly in those patients treated with ting and Thirman, 1985; Kaiko et al., 1983; Szeto et high doses (Nieto et al., 1999; Perry and Warner, al., 1977). Seizures have been reported in patients 1996). Reversible encephalopathy and seizures have who have been treated with an intravenous mor- also been reported with vincristine. A brain biopsy phine solution containing sodium bisulfate as a specimen in one reported case revealed neurotubu- preservative (Meisel and Welford, 1992). An in- lar dissociation (Hurwitz et al., 1988).
trathecal or intraventricular morphine bolus canalso cause seizures (Kronenborg et al., 1998). Cyclosporin. Immunosuppressant drugs such as cy- Propoxyphene has been reported to cause status closporin are given to bone marrow transplant re- cipients to prevent rejection. These agents have beenreported to induce seizures in patients pretreated with Antiemetics. Some neuroleptics used as antiemetics busulfan or platinum compounds (Ghany et al., in conjunction with chemotherapy (phenothiazines, butyrophenones) have been reported to induceseizures. This phenomenon appears to be dose re- Biologic Response Modifiers. Encephalopathy and lated. The newer antiemetics, such as ondansetron, seizures have been reported after the administration 3601_e20_p438-453 2/19/02 8:59 AM Page 442 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT Antibiotics. Many cancer patients with neutropenia (Avrahami et al., 1987), particularly in those patients and depressed immune systems due to malignancy who have primary or metastatic brain tumors. Con- and chemotherapy receive broad-spectrum antibiot- trast-induced seizures are caused by an increased ics or multiple antibiotics. Some of these have been susceptibility to seizures and increased permeability associated with encephalopathy and seizures. Most of- of the blood–brain barrier in these patients, and they ten implicated are the quinolones and betalactams.
are possibly a direct toxic effect of the agents used The neurotoxicity of the quinolones is dose related.
(Avrahami et al., 1989; Fischer, 1980).
Experimental studies have shown that this is becausegamma-aminobutyric acid–like substituents in the structure of quinolones act as antagonists at the gamma-aminobutyric acid receptors (Akahane et Metabolic abnormalities are the most common cause al., 1989). Renal failure and the presence or history of altered levels of consciousness in cancer patients.
of brain metastases are contributing factors (Walton Hyponatremia, hypoglycemia, hypomagnesemia, hypocalcemia, and hypoxia lower the seizure thresh- Of the betalactams, imipenem/cilastatin (Pri- old. Seizures caused by metabolic abnormalities tend maxin) is the most neurotoxic. Betalactam neurotox- to be generalized. The accompanying cerebral dys- icity seems to be due to an increased concentration function is diffuse, even in the rare case of a focal or of the drug in brain tissue when it is given in high complex partial seizure (Cascino, 1993; Stein and doses or given to patients with impaired renal func- tion or caused by alterations in the blood–brain bar-rier due to infection or malignancy (Bodey et al., Hyponatremia. Hyponatremia in cancer patients 1987). An impaired mechanism for clearance of the can be caused by volume depletion or volume over- drug from brain tissue may be involved, but this has load, by drugs, or by a malignancy, such as occurs not yet been documented (Schliamser et al., 1991).
with paraneoplastic syndrome. Intravascular volumedepletion occurs as a result of poor fluid intake, fluid Methylphenidate (Ritalin). Patients with brain tu- loss with emesis, or retention of fluid in the abdom- mors or systemic cancer often experience fatigue, inal cavity (ascites), either neoplastic or due to con- lethargy, depressed mood, and overall neurobehav- gestive heart failure. Aggressive hydration to enhance ioral slowing. These symptoms can be caused by the the renal clearance of some chemotherapeutic drugs brain tumor itself or by the effects of RT and che- (platinum, methotrexate) causes dilutional hypona- motherapy. Methylphenidate has been shown to im- prove patients’ energy level and function (Meyers et The syndrome of inappropriate antidiuretic hor- al., 1998; Weitzner et al., 1995). There is some con- mone (SIADH) is another common cause of hypona- cern, however, that the drug may increase the fre- tremia in patients with cancer. As in paraneoplastic quency of seizures in patients who have a history of syndrome, it occurs most commonly in patients with epilepsy or seizures due to the presence of brain tu- small cell lung carcinoma and also in those with mor. This association has been demonstrated by re- Hodgkin’s lymphoma, non–small cell lung carci- sults from studies of children with epilepsy and at- noma, and cancer of the pancreas, colon, prostate, tention deficit hyperactivity disorder (Gross-Tsur et or adrenal cortex. Small cell lung carcinoma cells al., 1997). In contrast, a study of patients with brain produce arginine-vasopressin–like and atrial natri- injury and epilepsy suggests that methylphenidate uretic–like factors, two hormones implicated in para- may actually decrease the frequency of seizures neoplastic SIADH (Franck et al., 1987; Vanhees et al., (Wroblewski et al., 1992). In sum, the benefit of 2000). For other types of cancer, the production of methylphenidate therapy for cancer patients with neu- ectopic hormones is less well documented.
robehavioral slowing outweighs the remote risk of SIADH also occurs in those patients with lep- tomeningeal metastases, tumors involving the hypo-thalamus, and basilar meningitis. Drugs that can Radiologic Contrast Medium. Intravenous contrast cause the syndrome are carbamazepine, neuroleptics media used for CT scans of the brain have been re- (haloperidol [Haldol]), tricyclic antidepressants, and ported to trigger either focal or generalized seizures cytotoxics (Vinca alkaloids, cyclophosphamide). Cis- 3601_e20_p438-453 2/19/02 8:59 AM Page 443 Seizures and Syncope in the Cancer Patient platin can cause SIADH with secondary seizures syncope, massive pneumonitis, rapid progression of (Ritch, 1988). Diagnosis is made on the basis of lab- lung tumors, or metastatic lymphangitic spread. Pa- oratory findings of hyponatremia, hypo-osmolality of tients with pulmonary fibrosis secondary to chemo- the serum, and increased urine osmolality. Renal, he- therapy (bleomycin, nitrosoureas) or RT are also at patic, adrenal, and pituitary function are normal.
It is important to correctly diagnose the cause of hyponatremia to treat it appropriately. Hydration with normal saline solution corrects the problem of fluiddepletion. Fluid restriction, sodium supplementation, Cancer patients are very susceptible to infections, and and sometimes diuretics are indicated to treat fluid seizures occur in those patients who have systemic overload. The treatment of SIADH consists of re- infections or infectious processes in the CNS. Patients stricting fluids, administering demeclocycline, and undergoing high-dose chemotherapy with bone mar- identifying and, if possible, removing the cause. Para- row transplant are at particular risk. Central nervous neoplastic SIADH usually resolves if the tumor can be system infections associated with seizures can removed or if it responds to radiation or chemo- be caused by viruses (herpes simplex virus, cy- therapy. The syndrome may recur, indicating tumor tomegalovirus, herpes zoster virus); bacteria, includ- recurrence (McDonald and Dubose, 1993; Richard- ing common pathogens and opportunistic agents (Listeria, Mycobacterium); fungi (Aspergillus,Cryptococcus); or parasites (Toxoplasma) (Bosi Hypoglycemia. Hypoglycemia occurs in cancer pa- et al., 1998; Pruitt, 1991). Clinically, patients with tients who receive total parenteral nutrition and re- seizures caused by infections present with confusion, sults from either the insulin in the solution or with- altered level of consciousness (encephalitis), menin- drawal of total parenteral nutrition. Other causes are gitic signs, or, in the case of abscess, focal findings.
malnutrition and pancreatic tumors (insulinoma)(Daggett and Nabarro, 1984; Hazard et al., 1985).
Seizures can occur with blood glucose levels below40 mg/dL; they are usually preceded by diaphoresis, Cancer patients have both embolic and thrombotic tremor, a sensation of hunger, and nervousness.
strokes. The pathogenesis of cerebrovascular eventsin these patients includes cancer- and treatment- Hypocalcemia and Hypomagnesemia. Hypocalcemia related causes (Graus et al., 1985).
and hypomagnesemia are two electrolyte abnormali-ties that have similar effects on the nervous system.
Embolic Stroke. Embolic events can occur in the Hypocalcemia and hypomagnesemia occur in patients presence of cardiac arrhythmia, which occurs in pa- who receive intensive chemotherapy, especially cis- tients treated with paclitaxel, in those with cardiomy- platin, with overhydration (Bachmeyer et al., 1996; opathy secondary to doxorubicin, and in cancer- Fuse-Nagase et al., 1997). Hypocalcemia has also associated marantic endocarditis (Rosen and Arm- been reported in patients treated with amphotericin B. It occurs less commonly with malnutrition or inpatients with secondary hypoparathyroidism follow- Thrombotic Stroke. Thrombotic strokes are ob- ing treatment for thyroid cancer. Seizures are a com- served in patients who have hypercoagulability syn- mon manifestation of hypocalcemia because of the in- dromes, paraneoplastic phenomena associated with creased excitability of the cerebral cortex. Other pancreatic cancer, breast carcinoma, and other ma- clinical manifestations of hypocalcemia and hypo- lignancies (Collins et al., 1975; Patronas and Argy- magnesemia, including tremor, carpopedal spasm ropoulou, 1992). Stroke in cancer patients can be (tetany), and myoclonus, can sometimes be confused caused by carotid artery stenosis following RT to the neck for treatment of head and neck tumors or bycompression from neoplastic adenopathy. Radiother- Hypoxia. Hypoxia is another potential, although less apy to the brain can induce vasculopathy, another po- common, cause of seizures in cancer patients. Acute tential cause of ischemic stroke. Thrombotic and he- hypoxia occurs with pulmonary embolism, prolonged morrhagic strokes with secondary seizures have been 3601_e20_p438-453 2/19/02 8:59 AM Page 444 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT reported in children whose leukemias were treated tient immediately before the seizure, the duration of with L-asparaginase. L-asparaginase causes deficien- the event and of the post-ictal period, and whether or cies of antithrombin, plasminogen, fibrinogen, and not there are residual mental status changes or focal factors IX and XI (Priest et al., 1980). Chemother- neurologic deficits. The clinician should also try to apy-induced vascular events may be transient, and obtain information about the administration of all MRI scans may show areas of ischemia in the water- medications before the seizure and the presence of shed distribution (Pihko et al., 1993).
any signs of infection. It is important to elicit the pastmedical history, focusing on prior history of seizures, Venous Sinus Thromboses. Venous sinus throm- cardiac disease, pulmonary disease, diabetes, and boses can occur with the secondary venous infarc- head trauma. Common symptoms associated with tions that can be caused by tumor invasion or meta- seizures are headache, paresthesias, diaphoresis, dif- static or infectious meningitis. Venous infarctions are ficulty breathing, gastric discomfort, and occasionally The physical and neurologic examinations will Parenchymal and Intratumoral Hemorrhage. New- help to identify the cause(s) of the seizure. The pres- onset seizure or an increase in seizure frequency oc- ence of focal neurologic deficits suggests that the pa- curs in those patients with hemorrhage into a primary tient has a focal intracranial lesion (parenchymal or or metastatic brain tumor. Of the metastatic tumors, dural/meningeal), either neoplastic, infectious (ab- melanoma, renal cell carcinoma, and choriocarci- scess, empyema), hemorrhagic, or vascular. Focal noma are most commonly associated with hemor- leukoencephalopathy secondary to RT or chemo- therapy can also present with focal deficits. Alteredlevel of consciousness, myoclonus, and asterixis sug- Spontaneous Subarachnoid Hemorrhage. While subarachnoid hemorrhage may occur in patients who The first seizure in a cancer patient should prompt have a malignancy, it may not always be possible to laboratory tests, including complete blood cell count, elucidate the pathogenesis of the process. One cause with differential and platelet counts; chemistry pro- for subarachnoid hemorrhage or small cortical file; assay of magnesium level; blood and urine cul- parenchymal hemorrhage is CNS aspergillosis. It is tures; and blood levels for drugs such as cyclosporin, important to appreciate that subarachnoid hemor- methotrexate, aminophylline, ethanol, and, if appro- rhages can recur along with seizures as part of their Contrast-enhanced gadopentetic acid–enhanced MRI scan or CT scan of the brain can usually iden- Traumatic Subdural or Subarachnoid Hemor- tify intracranial lesions, leptomeningeal disease, rhage. These hemorrhages can occur in cancer pa- strokes, and hemorrhages. The extent of edema and tients who are thrombocytopenic or who develop a low-grade disseminated intravascular coagulation Lumbar puncture is indicated for the diagnosis syndrome. In such cases, even minor trauma may of meningitis, leptomeningeal metastases, and sub- arachnoid hemorrhage. It must be performed withgreat caution in patients who have an intracerebralmass or thrombocytopenia. Platelet transfusion may Diagnosis
The diagnosis of seizures in cancer patients is made Electroencephalography helps to identify the sei- on the basis of a detailed history, physical and neu- zure focus and differentiate between disease pro- rologic examinations, laboratory tests, neuroimaging cesses. Specific findings on electroencephalograms results, and electroencephalographic findings. When occur in herpesvirus encephalitis (periodic lateral- taking the patient’s history, the clinician must try to ized epileptiform discharges in the temporal lobes) obtain an accurate description of the ictal event: tim- and in some metabolic encephalopathies (triphasic ing of the event in relation to the diagnosis of tumor and the treatment for cancer, the presence or absence The differential diagnosis must be made with other of aura, elements of focality, the behavior of the pa- paroxysmal events, such as syncope, myoclonic jerks, 3601_e20_p438-453 2/19/02 8:59 AM Page 445 Seizures and Syncope in the Cancer Patient tetany, transient encephalopathy, transient ischemic mal lesions. The use of prophylactic antiepileptic attacks, and panic attacks, which can all mimic drugs in patients with brain tumors who do not have seizures is controversial (Cohen et al., 1988). In suchpatients, antiepileptic drugs may cause adverse ef-fects. Whether or not to use antiepileptic drugs is de- Treatment
termined by the patient’s condition and hepatic and An algorithm for the management of seizures in can- renal function and by the concurrent administration cer patients is presented in Figure 21–1. To decide of drugs that interfere with antiepileptic drugs’ me- which therapy to use for ictal events, the neurologist must answer two important questions: whether the In patients with altered mental status, antiepilep- event was a seizure and whether anticonvulsants are tic drugs must be administered parenterally. The drugs of choice are benzodiazepines, phenytoin, or If the patient is in status epilepticus, efforts should focus on stopping the seizures. Airway patency must For treatment of generalized seizures, phenytoin is be established, and intravenous therapy with benzo- usually the first drug administered. For complex par- diazepines (lorazepam, diazepam) and antiepileptic tial seizures, carbamazepine may be the first-line drugs (phenytoin, phenobarbital) must be initiated.
drug. Phenobarbital is the drug of choice for chil- If the work-up indicates a toxic or metabolic cause for the status epilepticus, antiepileptic drugs can bediscontinued once the seizures have stopped and their cause has been eliminated. Any drugs known to beepileptogenic must be discontinued, the metabolic Phenytoin is the most widely used antiepileptic drug abnormalities must be corrected, and appropriate an- in the United States. A known effective anticonvul- tibiotic therapy must be instituted for infection, avoid- sant, it has several advantages: It can be adminis- tered by multiple routes (oral, intravenous, through Long-term anticonvulsant treatment is indicated a gastric tube in its elixir form); it has a long half- for patients with a pre-existing seizure disorder, pri- life, which allows once-a-day dosing; and it is inex- mary or metastatic brain tumors, or other parenchy- Figure 20–1. An algorithm for the management of seizures in the neuro-oncologic patient.
3601_e20_p438-453 2/19/02 8:59 AM Page 446 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT Problems associated with phenytoin are related to therapy with busulfan (Fitzsimmons et al., 1990).
its pharmacokinetics. It is metabolized in the liver, Phenytoin was also shown to selectively enhance the and its serum levels are influenced by liver disease cytotoxicity of microtubule inhibitors, such as Vinca (metastatic or noncancer related) as well as by its alkaloids; this activity is presently under investigation multiple drug interactions (DeMonaco and Lawless, for potential clinical use (Ganapathi et al., 1993).
1983; Gattis and May, 1996; Ghosh et al., 1992). Dex-amethasone, commonly used in patients with primary and metastatic brain tumors as well as an adjuvantantiemetic in patients receiving chemotherapy, has Carbamazepine and its newer derivative oxcar- been demonstrated to lower phenytoin levels (Gattis bazepine (Trileptal) is the anticonvulsant of choice and May, 1996; Lackner, 1991). Platinum-containing for patients with complex partial seizures, and it is chemotherapy regimens have been reported to de- used as a second-line antiepileptic drug for patients crease phenytoin levels to as low as 25% of the ini- with generalized seizures who either did not have ad- tial therapeutic level, with return to baseline after equate seizure control with phenytoin or developed discontinuation of chemotherapy. Procarbazine, a allergic reactions to it. When administered together chemotherapeutic agent related to disulfiram, can with phenytoin, carbamazepine decreases the pheny- increase the level of phenytoin. Anticonvulsants also toin level. It can only be administered orally or increase the risk of procarbazine hypersensitivity re- through a gastrostomy tube and therefore cannot be actions (Lehmann et al., 1997). The phenytoin dose used in emergency situations. The main difficulty with needs to be adjusted and the levels monitored closely using carbamazepine in cancer patients is its myelo- in those patients receiving chemotherapy to avoid un- toxic effect, which causes neutropenia, lymphopenia, der dosing and toxic effects (Neef and de Voogd-van and aplastic anemia (Silverman and Chapron, 1995).
der Straaten, 1988; Grossman et al., 1989; Ghosh et These problems limit its use in patients who are re- al., 1992). Phenytoin also increases clearance and ceiving chemotherapy. Furthermore, carbamazepine may thus decrease the efficacy of chemotherapeutic levels are decreased by chemotherapeutic drugs such agents such as busulfan, paclitaxel, topotecan and re- as platinum (Jain, 1993). Carbamazepine also causes lated drugs (Grossman et al., 1998; Hassan et al., SIADH. Like phenytoin, carbamazepine can cause 1993; Zamboni et al., 1998). Because of decreased allergic reactions, including Stevens-Johnson syn- protein binding and increased free plasma drug lev- els, the dose must be decreased for patients who arebeing treated with warfarin or cimetidine.
Both total and free phenytoin levels should be monitored in patients who have impaired renal func- Valproic acid and its derivative divalproex sodium tion because phenytoin excretion may be impaired.
(Depakote) are used for patients with seizures that Seizures can occur in cancer patients receiving are not controlled by phenytoin. The drugs are ad- phenytoin when subtherapeutic levels of the drug are ministered orally and are metabolized in the liver.
administered, and they can also occur as a manifes- When administered together with phenytoin, val- tation of phenytoin toxicity. Phenytoin can cause al- proate can either decrease or increase phenytoin lev- lergic reactions, usually a cutaneous rash. Severe re- els. Methotrexate has been reported to cause an acute actions, including Stevens-Johnson syndrome, have decline in the level of serum valproate (Schroeder been described in patients being weaned from corti- and Ostergaard, 1994). Reported toxic effects that costeroids while receiving RT to the brain (Delattre limit its use in cancer patients are hepatotoxicity, pro- longed bleeding time, and dose-dependent thrombo- In vitro, but not in vivo, studies indicated a possi- ble radiosensitizing effect of phenytoin on astrocy-toma cells (Lordo et al., 1987). Phenytoin and other enzyme inducers were reported to have a protectiveeffect in patients receiving busulfan, reducing its neu- Phenobarbital remains the drug of choice for con- rotoxicity and myelotoxicity. Phenytoin is now used trolling seizures in children. It is mainly used as an for seizure prophylaxis in patients receiving chemo- adjunct to phenytoin or for adult patients for whom 3601_e20_p438-453 2/19/02 8:59 AM Page 447 Seizures and Syncope in the Cancer Patient other anticonvulsants have failed. Its main side effect vulsants and as adjuncts for better seizure control by is somnolence, although some patients experience patients who fail anticonvulsant monotherapy.
Conclusions
Seizures are a common neurologic problem in pa- A new class of antiepileptic drug, GABA agonists, has tients with systemic and CNS malignancies and may recently been released to the marketplace, and there have multiple etiologies. Examination should be is not much experience with their use by cancer pa- aimed at identifying and treating all of its possible tients. Neurontin is purported to cause fewer side ef- causes. The treatment of seizures in cancer patients fects than conventional antiepileptic drugs, but there must be individualized, and metabolic factors and have been no studies to evaluate its interactions, if drug interactions must be taken into consideration any, with chemotherapeutic agents. Because it has so when anticonvulsant therapy is initiated.
few side effects, it is commonly used in combinationwith phenytoin, carbamazepine, or valproate for braintumor patients with refractory complex partial Syncope is defined as a sudden transient loss of con-sciousness and postural tone with spontaneous re- covery. The frequency of syncope in cancer patients Lamotrigine is a new, structurally unique, anticon- is not well documented. Presyncope, with premoni- vulsant that acts on voltage-dependent sodium chan- tory symptoms but without loss of consciousness nels, resulting in decreased release of excitatory neu- (“faint feeling”), is probably even more common rotransmitters. It is indicated for treatment of partial (Plum and Posner, 1982). Syncope occurs because seizures but can cause severe dermatologic side ef- of a transient interruption of cerebral blood flow.
fects and myelotoxicity. It has known interactions with Common presyncopal symptoms are dizziness, light- other anticonvulsants, but to date there are no re- headedness, palpitations, diaphoresis, and, occa- ports of interactions with chemotherapeutic drugs.
Lamotrigine is a dehydrofolate reductase inhibitorand should not be used by patients treated with Etiology
methotrexate and other antimetabolites.
The etiology of syncope in cancer patients is pre-sented in Table 20–2. As in the case of seizures, sev- eral etiologic factors may contribute to syncope in Topiramate is another new anticonvulsant used as ad- cancer patients, the most common being orthostatic junctive therapy for partial seizures. It acts on sodium hypotension, with cardiac causes assuming a sec- channels and as a GABA agonist. It produces no sig- ondary role. Other causes are drugs, vasovagal reac- nificant drug interactions, and its main side effect is tions, and cerebrovascular disease (Kapoor, 1991, psychomotor slowing. Topamax may cause leuko- Orthostatic hypotension is commonly present in the Gabitril is another new GABA-ergic anticonvulsant, terminal stages of cancer in those patients who are which is indicated as an adjunctive treatment of com- suffering from malnutrition and dehydration. It also plex partial seizures. It has no significant drug inter- occurs in those who become dehydrated from eme- actions, and it can be safely used with enzyme- sis caused by chemotherapy. Patients with severe ane- inducing drugs. Rarely, it may cause anemia and mia often present with syncope or presyncope caused thrombocytopenia. These new drugs can be used by by insufficient oxygenation of the brain rather than patients with known allergy to the first-line anticon- from volume depletion. The drop in blood pressure 3601_e20_p438-453 2/19/02 8:59 AM Page 448 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT Table 20-2. Etiology of Syncope in Patients with Malignancy
Platinum compounds, Vinca alkaloids, taxanes, diabetes Tricyclic antidepressants, vasodilators, diuretics Chemotherapeutic agents (fluorouracil, Vinca alkaloids, platinum compounds, taxanes), CNS depressants (barbiturates), biologic response modifiers Nutritional, pancreatic tumors (insulinoma) Parapharyngeal tumors, radiation therapy to neck Myocardial ischemia (mediastinal radiation, atherosclerosis), cardiomyopathy (adriamycin, Chemotherapy (paclitaxel, interleukin-2), mediastinal radiation, pre-existing cardiac disease Micturition, coughing, swallowing, strong emotional stimuli with change in position is accompanied by an in- Syncope is also part of the spectrum of direct neu- creased heart rate. Chemotherapeutic agents such as rotoxic effects of chemotherapeutic drugs such as flu- cisplatin and Vinca alkaloids cause a peripheral neu- orouracil (Hook et al., 1992; Shehata et al., 1999).
ropathy with dysautonomia. The heart rate does not Biologic response modifiers and colony-stimulating increase significantly with the drop in blood pressure factors also cause hypotension with syncope or near- in patients who have this condition.
Another common cause of orthostatic hypotension in cancer patients is related to drugs such as diuret- ics and antidepressants. The pathogenetic mechanismof orthostasis in patients taking diuretics is intravas- Syncope in hypoglycemic patients has a fairly typical cular volume depletion, whereas antidepressants, clinical presentation, which suggests its diagnosis. It neuroleptics, and some antiemetics cause an anti- is preceded by a sensation of hunger. The patient be- cholinergic effect. Hypotension with possible presyn- comes irritable, tremulous, and diaphoretic and may cope or syncope is a common side effect of biologic complain of dimming vision. The skin becomes pale.
agents such as interferon, IL-2, and tumor necrosis Loss of consciousness is brief and is usually not fol- factor. Orthostatic presyncope and syncope also oc- lowed by confusion; however, with severe hypo- cur in patients with severe infections that cause high glycemia, there may be associated seizure activity. Hy- poglycemia occurs in patients who have insulinoma,malnutrition, and insulin-dependent diabetes and canbe caused by insulin overdosing from total parenteral nutrition. The symptoms of patients with insulinoma Syncope can be a side effect of medications, even in typically occur in the morning, before breakfast, or the absence of other etiologic factors. The mechanisms between meals (Daggett and Nabarro, 1984; Hazard are orthostatic hypotension either through volume de- pletion (diuretics, mannitol), vasopressor effects (bi-ologic response modifiers), anticholinergic effects (antidepressants), cardiac arrhythmia (paclitaxel, in-travenous phenytoin), or peripheral neuropathy (vin- Syncope is a common manifestation of cardiac dis- cristine, paclitaxel, platinum compounds).
ease. Cancer patients can experience the same prob- 3601_e20_p438-453 2/19/02 8:59 AM Page 449 Seizures and Syncope in the Cancer Patient lems that patients without malignancy do. The main neuralgia–asystole syndrome, carotid sinus syndrome, pathogenetic mechanisms for syncope of cardiac ori- and glossopharyngeal-related reflex cardiogenic gin are pump failure, heart blocks, and arrhythmias.
syncope without neuralgic pain (Cicogna et al., 1993; Pump failure occurs in myocardial infarction or Dykman et al., 1981; Wang and Ng, 1995). Na- cardiomyopathy. In cancer patients, cardiomyopathy sopharyngeal and parapharyngeal carcinomas cause can be caused by chemotherapy with anthracyclines, these syndromes. In these patients, syncope does not especially daunorubicin, which may be irreversible.
respond to medical management or in some cases to Other cardiotoxic chemotherapeutic agents are mi- pacemaker insertion. Syncope may resolve after treat- toxantrone and estramustin. The risk for cardiac ment of the tumor or may require intracranial inter- disease increases if such drugs are administered fol- vention to resect the glossopharyngeal nerve.
lowing RT to the chest and mediastinum. Viral my-ocarditis in the immunosuppressed patient and graft-versus-host disease following allogeneic bonemarrow transplant are other causes of heart failure.
Vasovagal syncope is one of the most common types Heart failure patients usually have symptoms sugges- of syncope in young adults, and patients usually pres- tive of myocardial ischemia before syncope: chest ent with a history of prior syncopal episodes. Vaso- pain, dyspnea, and signs of heart failure.
vagal syncope occurs in response to stress, pain, Heart blocks and cardiac arrhythmias in cancer fear, and heat and is preceded by symptoms such as patients are usually caused by a pre-existing cardiac palpitations, queasiness, nausea, diaphoresis, and condition. Arrhythmias do occasionally result from abdominal discomfort. Incontinence is uncommon.
paclitaxel or IL-2 therapy. Several case reports of syn- The underlying pathophysiologic mechanism is cope describe cardiac arrhythmias, coronary artery thought to be a reflex withdrawal of sympathetic tone stenosis, and defective cardiovascular reflexes in pa- (Bezold-Jarisch reflex), indicated clinically by tachy- tients who were treated with RT to the mediastinum cardia, followed by bradycardia, pallor, and hy- or neck (de Waard et al., 1996; Mary-Rabine et al., potension. Syncope that occurs during micturition or 1980; Shapiro et al., 1996). Syncope occasionally oc- defecation (situational syncope), typically after a curs after obstruction of pulmonary flow caused by long period of bed rest, is more common in men Diagnosis
Syncope can be a manifestation of cerebrovascular The diagnosis of syncope is made primarily on disease in the anterior or posterior circulation and the basis of the patient’s clinical presentation (if the may or may not be associated with focal neurologic episode is witnessed) or an accurate and detailed his- deficits. Possible causes of altered cerebral blood tory. The history should include data on the patient’s flow in cancer patients include compression of the complaints before the loss of consciousness, appear- carotid artery by tumor, stenosis of the subclavian or ance of the patient (skin pale or flushed, diaphore- carotid arteries following RT to the chest or neck, and sis, breathing pattern), duration of the episode, thrombotic or embolic events. When syncope occurs associated seizure activity, incontinence, and the after elevation or exertion of the left arm, a subcla- presence or absence of confusion. Information vian steal must be suspected, and blood pressure should also be obtained about the patient’s past med- ical history with regard to cardiac disease, hyperten-sion or hypotension, diabetes and hypoglycemia, typeof cancer, psychiatric history, medications, and cir- cumstances of the event (micturition or defecation, Patients with head and neck tumors, thyroid tumors, crowded or overheated area, pain, stress). The phys- and cervical lymphadenopathy can develop recurrent ical and neurologic examinations, if feasible at or syncope related to carotid sinus hypersensitivity. Syn- near the time of the event, can reveal the presence of cope in patients with head and neck tumors can oc- hypotension, arrhythmia, or focal findings suggestive cur through several mechanisms: glossopharyngeal of a vascular or neoplastic brain lesion.
3601_e20_p438-453 2/19/02 8:59 AM Page 450 SYMPTOMS SECONDARY TO CANCER AND ITS TREATMENT Examination should include measurement of blood Treatment
pressure and heart rate in both supine and standing Syncope is a brief, usually fully reversible, episode of positions and in both arms to determine the presence loss of consciousness that generally does not require of position hypotension or the subclavian steal syn- specific treatment. However, when the cause of syn- drome. Auscultation of the heart can reveal arrhyth- cope is a life-threatening condition such as a heart mias and/or cardiac valve abnormalities. Cardiac block, malignant arrhythmia, or pulmonary embolus, monitoring, echocardiogram, and laboratory tests close monitoring and urgent appropriate treatment also help the clinician make the diagnosis. Labora- must be instituted. Insertion of a cardiac pacemaker tory tests should include hemoglobin, hematocrit, and, in some cases, intracranial section of the glos- white blood cell count, differential count, and platelet sopharyngeal nerve are necessary. In simple syncope, count to rule out anemia and infection; electrolyte, the elimination of the causative agent(s) usually pre- glucose, calcium, and magnesium levels; drug levels vents further occurrences. Supportive therapy, main- when appropriate (psychotropics and antidepres- tenance of good nutritional status, hydration or blood sants, opiates, barbiturates); and blood and urine cul- transfusions to maintain adequate intravascular vol- ume, correction of hypoglycemia and electrolyte ab- When focal neurologic deficits are present, a CT normalities, and discontinuation of offending drugs or MRI scan of the brain is indicated. Electroen- can prevent the occurrence of syncope in cancer pa- cephalography is helpful in the differential diagnosis tients (Benitez del Rosario and Salinas Martin, 1997).
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