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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Nonmetastatic Complications

, MD and , MD.

Complications of Cancer Therapy

Many cancer treatments are neurotoxic (Table 146-10). Some drugs (eg, vincristine) cause neurotoxicity even at low doses, while others (eg, cytarabine) cause neurotoxicity only during intensive therapy. Neurologic toxicity is a dose-limiting factor in several cancer treatments, such as RT, and patients may suffer more from these toxicities than from the cancer itself.100–102 The more commonly encountered neurologic toxicities from cancer treatment are discussed below.

Table 146-10. Neurotoxicity of Agents Commonly Used in Cancer Patients.

Table 146-10

Neurotoxicity of Agents Commonly Used in Cancer Patients.

Chemotherapy

Vinca Alkaloids

Vinca alkaloids cause nerve damage by binding tubulin in peripheral nerves, disrupting the formation of microtubules that mediate fast axonal transport. Neurotoxicity is a dose-limiting side effect of all the vinca alkaloids, but especially of vincristine. Central neurotoxicity is rare because vincristine does not penetrate the normal blood-brain barrier103; however, accidental instillation directly into the CSF causes rapid axonal damage, which is usually fatal.104

Vinca alkaloid neurotoxicity is age (more severe in adults) and dose dependent, and appears to be more prominent in patients with hepatic dysfunction,105 and in those who have received other potentially neurotoxic therapies.106 Tingling paresthesias develop in the fingertips, and usually in the toes, of virtually all patients treated with vincristine, although clinically detectable sensory loss is often absent. Loss of ankle stretch reflexes is an early and almost universal sign, and with continued therapy, all reflexes may diminish or disappear. Weakness may occur as therapy continues. Weakness is of two types: (1) A generalized distal axonal neuropathy is the more common. When that weakness is mild, patients lose the ability to walk on their heels and lose strength in wrist extensors. More severely affected patients develop foot drop and slap their feet when they walk. Weakness can become severe enough to render the patient immobile or bed bound, but the drug should be discontinued prior to the development of such marked weakness. Preexisting peripheral nerve diseases, especially Charcot-Marie-Tooth neuropathy107 and probably other neuropathies (eg, diabetic polyneuropathy), increase the severity of vincristine neuropathy. (2) Some patients develop focal weakness, for example, unilateral foot drop or cranial nerve palsies, such as ptosis or extraocular muscle, facial, or laryngeal paralysis.108 Although symptomatic toxicity is usually reversible after discontinuation of the drug, significant weakness may persist in severely affected patients. Autonomic dysfunction, particularly abdominal cramping and constipation, often occurs within hours to days of each dose. Adynamic ileus may result and can be life-threatening. A prophylactic bowel regimen or metoclopramide may reduce the severity of this complication. Impotence has been reported.

Less-common complications of vincristine administration include aching bone pain, sharp stabbing pain in the jaw or throat, or an increase in any preexisting pain. These symptoms typically occur within hours of injection and subside over several days. The symptoms appear with the first or second dose, and rarely recur with subsequent doses.109 Hyponatremia from inappropriate secretion of antidiuretic hormone occurs within days of drug administration, and may recur with subsequent doses.106 Encephalopathy and seizures not related to hyponatremia have been reported to occur after vincristine administration, but are very rare. There is no effective treatment.

Methotrexate

There are several clinically distinct forms of MTX toxicity.100 An acute reaction with meningismus, confusion, fever, and CSF pleocytosis occurs 4 to 6 h after intrathecal injection and resolves over several days. This syndrome is often confused with infectious meningitis, but the onset is too rapid after the injection for bacterial contamination; antibiotics are unnecessary unless Gram stain or cultures demonstrate organisms. Dexamethasone may relieve some of these symptoms. Mild acute toxicity occurs in as many as 10% of patients, but further doses of intrathecal MTX are usually uneventful. The cause of this syndrome is not known, although high CSF MTX levels may accompany the reaction. Cytarabine can have a similar acute reaction, particularly the new liposomal preparation (DepoCyt).77

An early delayed reaction follows high-dose intravenous infusion of MTX in about 4% of patients so treated.110,111 The disorder usually occurs 7 to 10 days after the third or fourth treatment and is characterized by stupor or coma, often associated with multifocal neurologic signs that change from hour to hour. Most patients recover completely and the disorder usually does not recur even if MTX is reinstituted. The pathogenesis of this syndrome is unknown.

Paraplegia may follow instillation of MTX or cytarabine by lumbar puncture.112 The disorder is characterized by weakness and sensory loss in the legs, which evolve over several days to complete transverse myelopathy. Some patients recover, but most remain paraplegic. Extensive necrosis of the spinal cord is found at autopsy. The pathogenesis of the disorder is unknown, but it appears to be idiosyncratic rather than dose related.

MTX leukoencephalopathy occurs in patients who have received a high cumulative dose of intrathecal or systemic MTX113 or MTX in combination with cranial RT.47 Symptoms begin weeks or months after treatment and appear as focal neurologic deficits that sometimes progress to seizures, coma, and death. Such a severe outcome is uncommon and tends to occur in the pediatric population. More commonly in adults, progressive cognitive impairment in the absence of lateralizing signs may be seen in patients who survive ≥ 6 months following treatment with systemic or intrathecal MTX ± RT. Leukoencephalopathy is always found on neuroimaging of these patients, but occasionally it may be found on MRI or at autopsy in asymptomatic patients. The neuropathologic findings consist of multifocal areas of coagulative necrosis in the white matter, often with extensive calcification. Unlike cerebral radionecrosis, fibrinoid necrosis of blood vessels is absent. The areas of necrosis may be randomly distributed in the white matter or be predominantly periventricular. The latter pattern may occur when MTX is injected into the ventricles of patients with abnormal outflow of ventricular CSF. Alternatively, focal leukoencephalopathy may develop around the catheter track.114 When MTX is injected into ventricles with elevated pressure, the drug tracks along the catheter, producing focal leukoencephalopathy which mimics a mass lesion; MRI may show a hypointense enhancing mass (Figure 146-7). This may resolve on its own or require removal of the catheter.

Figure 146-7. Gadolinium enhanced T1-weighted A, and T2-weighted B, MR images of focal leukoencephalopathy in a patient with a malfunctioning Ommaya reservoir.

Figure 146-7

Gadolinium enhanced T1-weighted A, and T2-weighted B, MR images of focal leukoencephalopathy in a patient with a malfunctioning Ommaya reservoir. This reservoir was obstructed but unrecognized. Multiple courses of methotrexate were instilled into the (more...)

Platins

Peripheral neuropathy is a dose-limiting toxicity of some platins, particularly cisplatin100 and oxaliplatin.115 Neuropathic symptoms begin as tingling paresthesias in the toes and fingers; loss of stretch reflexes and reduced vibratory and position sensation are found. Pain and temperature sensation and strength are unaffected. These findings and loss of sural (sensory) nerve conduction with preservation of motor nerve conduction indicate a large, myelinated sensory fiber neuropathy. Symptoms often begin after treatment has been completed and progress for months before stabilizing. Severe, disabling sensory ataxia may result. Gradual resolution follows, although some patients are permanently disabled. Neurotrophic agents and amifostine116 have both been reported to decrease cisplatin neurotoxicity, but the data are inconclusive.117 Lhermitte sign, an electric sensation in the arms, back, or legs upon neck flexion, is an occasional manifestation of either drug.115 Oxaliplatin may cause cold-induced paresthesias either during or shortly after an infusion.118

Ototoxicity caused by cisplatin is a result of damage of the organ of Corti. Toxicity severe enough to interfere with speech perception is uncommon, but hearing loss may or may not resolve. Cisplatin has been associated with optic neuropathy, especially after intracarotid infusion. Seizures and encephalopathy have been reported in patients receiving cisplatin. Cisplatin induces renal magnesium and calcium wasting, and although these disorders must be excluded when seizures or encephalopathy occur, they rarely contribute to platinum neurotoxicity.

Vascular disease producing neurologic symptoms has been reported as a late delayed effect of cisplatin-based chemotherapy. Many such patients develop Raynaud phenomenon, and a few have developed transient ischemic attacks or cerebral infarctions. Other platinum drugs are less neurotoxic.119

5-Fluorouracil

High-dose 5-fluorouracil (5-FU) is associated with pancerebellar dysfunction that begins during or following therapy and gradually resolves over several weeks.120 The syndrome may or may not recur with retreatment, but it does not occur with the doses of 5-FU now used. Generalized encephalopathy has been seen in association with severe systemic toxicity during therapy, and may indicate an inherited deficiency of dihydropyrimidine dehydrogenase, the enzyme responsible for pyrimidine catabolism.121

Cytosine Arabinoside

Intravenous high-dose ara-C (eg, 3 g/m2 every 12 h for six doses) causes neurotoxicity in 10% to 25% of patients. The common form is pancerebellar dysfunction122 starting several days after the initiation of therapy and worsening for several more days. Gradual recovery begins about 2 weeks after its onset, but recovery may be incomplete in approximately 20% of patients, especially those in whom the neurologic disorder was severe. Pathologic changes include loss of cerebellar Purkinje cells and neurons in the deep cerebellar nuclei. Encephalopathy and seizures also occur, usually in the setting of cerebellar toxicity.123 Neurotoxicity has been documented with minimum cumulative doses of 18 g/m2, but higher doses (eg, 30 to 40 g/m2) are associated with increasingly severe toxicity. Age older than 50 years and renal insufficiency predispose patients to more severe toxicity. A recrudescence of neurologic symptoms may occur with retreatment. Peripheral neuropathy is also a rare complication of high-dose ara-C; in most patients, high-dose cytarabine was given with other potentially neurotoxic agents, such as fludarabine.124

Other Drugs

Other commonly used drugs that cause neurotoxicity include the taxanes, suramin, and procarbazine, all of which can cause peripheral neuropathy, although procarbazine rarely does so. High-dose busulfan therapy, used to prepare children for bone marrow transplantation, can cause seizures. At standard doses the drug is not neurotoxic. Gemcitabine, in combination with abdominal radiation, has been reported to cause myositis with acute muscle pain and tenderness. It is responsive to steroids.125 The drug has also been reported to cause a reversible posterior encephalopathy,126 but this syndrome, characterized by headache, somnolence, seizures, and posterior hemisphere hyperintensities on MRI scans, is associated with a number of anticancer agents, including vincristine and cyclosporin. The clinical symptoms, which are usually reversible, are often associated with the development of severe hypertension that is likely critical to the pathophysiology of this disorder often termed hypertensive encephalopathy.

Corticosteroids

Corticosteroids are used extensively in cancer therapy, either as oncolytic agents or to reduce edema associated with CNS metastases. In addition to their systemic toxicities—such as diabetes, immune suppression, GI perforation or hemorrhage, and osteoporosis—corticosteroids cause neurotoxicity in the form of myopathy127 and alterations of mental status.128 Myopathy affects most patients taking steroids for brain or spinal cord metastases. Patients develop symmetric, proximal weakness in their arms and legs within weeks after the institution of steroids. The weakness may progress, but very rarely renders the patient nonambulatory. Early symptoms include difficulty arising from chairs or toilet seats and climbing stairs. Muscle stretch reflexes are normal and sensation and bowel and bladder function are not affected. Respiratory function may be compromised127 and often causes exercise intolerance. The serum creatine phosphokinase (CPK) is not elevated. The differential diagnosis includes hypokalemia, thyroid dysfunction, polymyositis, Lambert-Eaton myasthenic syndrome (LEMS), and spinal cord compression. The only treatment is reduction or discontinuation of the steroids. Exercise and adequate protein intake may help.129 Patients with hypoalbuminemia may be at higher risk for steroid myopathy.

Psychosis, delirium, euphoria, or dysphoria may complicate steroid therapy. Dose reduction or discontinuation is usually necessary, although neuroleptics or sedatives can be used in patients for whom continued therapy is critical. Gastrointestinal perforation, particularly of the sigmoid colon, may complicate steroid treatment, especially of constipated patients. The steroids may mask the symptoms, delaying appropriate diagnosis.

Radiation Therapy

Despite the fact that cells in the CNS turn over slowly or not at all, the brain, spinal cord, and, to a lesser degree, peripheral nerves are susceptible to damage by ionizing radiation that usually causes symptoms months or years after the radiation has been completed (Table 146-11).100,130–132 With patients living longer after initial treatment, the problem of delayed radiation damage to the CNS is increasingly important.

Table 146-11. Neurologic Complications of Central Nervous System Irradiation.

Table 146-11

Neurologic Complications of Central Nervous System Irradiation.

Brain Toxicity

Acute reactions, occurring within hours of a dose of RT, are rare with current fractionation schedules when patients are pretreated with dexamethasone.1 Patients with large or multifocal tumors and cerebral edema, especially those already exhibiting symptoms and signs of increased intracranial pressure, are more likely to experience this side effect. Symptoms and signs include worsening of existing deficits, headache, nausea and vomiting, lethargy, and somnolence. These are usually transient and respond to increased doses of corticosteroids. The etiology has been ascribed to radiation-induced disruption of the blood-brain barrier with resulting cerebral edema. Occasionally, worsening perilesional edema may be seen on MRI scan.

Early delayed encephalopathy occurs a few weeks to a few months after RT. Patients may develop worsening of lateralizing signs, or somnolence or diminished cognition133 in the absence of focal deficits; the former predominates in adults treated for brain tumors and the latter in children treated prophylactically. Symptoms may persist for days to weeks, and are often relieved by corticosteroids; complete resolution is usual. Early delayed encephalopathy is often confused with progression of the primary brain tumor or metastasis being irradiated. An MRI scan reveals an enhancing lesion indistinguishable from progressive tumor. Clinical suspicion and resolution of symptoms over time may be the only real clue to the cause of the deterioration. The pathogenesis of early delayed encephalopathy is probably demyelination resulting from radiation injury to oligodendroglia.134

Delayed encephalopathy is the most serious complication of brain RT,135,136 and radionecrosis is its most common late delayed complication, arising months to years after treatment.137 In one study, cerebral radionecrosis occurred in 6% of patients treated with 4,500 cGy or more.138 The total dose is the most important factor in the development of cerebral radionecrosis; there is a threshold near 6,000 cGy above which radionecrosis becomes common. However, high daily fraction schedules also carry increased risk for radionecrosis. Headache, focal deficits and seizures are the usual symptoms. CT/MRI reveals a contrast-enhancing lesion with surrounding edema producing mass effect; this radiographic appearance is indistinguishable from CNS tumor. PET or single-photon emission computed tomography (SPECT) scans may differentiate tumor that is hypermetabolic from necrosis that is hypometabolic. However, the differentiation between radionecrosis and tumor is often difficult, and biopsy may be required. Marked symptomatic improvement follows treatment with dexamethasone, and some patients remain well after steroids are discontinued. Surgical resection of the necrotic material is often necessary. Reports that anticoagulation139 or hyperbaric oxygen140 relieve symptoms require confirmation. Radiation may also cause dementia unassociated with evidence of necrosis.141,142 The MRI may show only ventricular dilatation, sulcal atrophy, and white matter hyperintensity. Some of these patients respond to ventriculoperitoneal shunting143 albeit incompletely and temporarily. This disorder is most common in patients who have received both RT and intensive systemic chemotherapy, and is likely a variant of delayed leukoencephalopathy.

Cerebral infarction may result from occlusion of cervical or intracranial arteries that have received large doses of RT.144 Vascular malformations may appear and bleed many years after brain radiation therapy.145 Complicated migraine-like episodes may occur in children after cranial irradiation.146 Endocrinologic dysfunction may arise years after RT, resulting from either hypothalamic or pituitary failure.147 Brain tumors may occur decades after cranial RT or radiosurgery148 administered in adulthood, but latency is often much shorter (median 6 years) in those irradiated in childhood. Radiation-induced brain tumors include meningioma, sarcoma, and malignant glioma.149,150

Spinal Cord Toxicity

Spinal cord damage caused by RT is uncommon. Transient, electric shock-like sensations following neck flexion (Lhermitte sign) may occur weeks to months after RT to the cervical cord,151 including mantle RT for Hodgkin disease. Spontaneous resolution is the rule. Progressive radiation myelopathy, on the other hand, is a devastating complication with onset months to years (median 20 months) following RT.152 The incidence of radiation myelopathy is affected by the total RT dose and dose per fraction; an estimate of the ED5 (5% incidence of complication) is between 5,700 and 6,100 cGy for RT delivered in 200 cGy fractions. Symptoms of radiation myelopathy usually begin with sensory changes in the legs and gradually progress to sensory loss, weakness, and sphincter dysfunction. Pain may be present at the level of the cord damage. Dysesthetic pain below the level of cord injury may be prominent. Unlike epidural spinal cord compression, sensory and motor findings are often asymmetric at the beginning. A Brown-Séquard syndrome is often present. The MRI scan reveals either a normal, enlarged, or atrophic cord that may contrast-enhance, but extrinsic compression is absent (Figure 146-8). Steroids do not reverse the neurotoxic deficits. Anticoagulants and hyperbaric oxygen have been reported to be effective, but this has not been verified.153,154 Spontaneous improvement sometimes occurs.152 A lower motor neuron syndrome with weakness and muscle atrophy can occur after irradiation of the spinal cord. Although weakness is prominent, patients usually remain ambulatory; spontaneous improvement is occasionally seen.155 Radiation-induced plexopathies were discussed in a previous section (see brachial plexopathy).

Figure 146-8. An MRI scan demonstrating radiation myelopathy.

Figure 146-8

An MRI scan demonstrating radiation myelopathy. The hypodense thoracic vertebral body is the site of a bone metastasis from breast cancer for which the patient was radiated. Some months later, the patient developed a myelopathy, and the contrast-enhancing (more...)

Cerebrovascular Complications of Cancer

Cerebrovascular lesions are the second most common neuropathologic finding, after metastases, in postmortem studies of cancer patients. Of 3,426 brains studied by the MSKCC autopsy service, 15% contained vascular lesions.156,157

Cerebral hemorrhage can develop in any metastasis.158,159 It is most commonly seen in lung cancer, but occurs proportionately more frequently in melanoma, thyroid, renal, and germ cell metastases. Intracerebral hemorrhages that are not associated with metastases are seen in patients with leukemia, thrombocytopenia, or coagulopathy. Intravascular leukostasis is not required for hemorrhage in leukemic patients. Subdural hemorrhage may occur in association with dural metastases or coagulopathy. A hemorrhage may result in abrupt neurologic deterioration or may be unsuspected prior to obtaining a brain scan. With large hemorrhages, patients experience an abrupt onset of headache, vomiting, lethargy, and focal deficits. For patients with intracerebral hemorrhage resulting from coagulopathy or thrombocytopenia, the underlying problem should be treated and the patient observed. Subdural hematomas and some hemorrhages into metastases may respond to surgical evacuation. Corticosteroids are useful in those patients who hemorrhage into an underlying brain metastasis but probably do not help hemorrhage into an otherwise normal brain.

Cerebral infarction is as common as hemorrhage.156,160 Infarctions secondary to accelerated atherosclerosis take place decades following RT that has included cervical or cerebral vessels in the field.161 Radiation therapy for head and neck cancer predisposes to carotid stenosis, and intracranial arterial stenosis with subsequent infarction may occur following cranial RT. Septic cerebral infarction is usually secondary to Aspergillus, Candida, or Mucor. These opportunistic organisms produce a secondary vasculitis. The infarctions are often multiple and hemorrhagic. Aspergillus is the most common causative agent and is always associated with pulmonary infection; discovery of the latter may be a clue to the correct diagnosis. Antifungal therapy is rarely successful, and the outcome is usually fatal.

Cerebral venous thrombosis (eg, superior sagittal sinus thrombosis) may result from compression or invasion of vascular structures by a metastasis, or from a coagulopathy.163 Clinical features include worsening headache, focal deficits, and seizures. The diagnosis can be made by MRI combined with magnetic resonance venography. Lumbar puncture reveals an elevated opening pressure, and frequently red cells in the CSF. Spontaneous resolution usually occurs unless dural metastasis is the cause, in which case RT is required. Anticoagulation is safe and should be considered for progressive neurologic symptoms; however, most patients recover fully without treatment.

Cerebral embolism can result from nonbacterial thrombotic endocarditis (NBTE, marantic endocarditis).164 Lung and GI carcinomas are the primary cancers most commonly associated with NBTE. Infarctions in patients with NBTE are often multiple and hemorrhagic. Diffuse encephalopathy and focal deficits usually coexist. Approximately one-third of patients with NBTE also have laboratory evidence of disseminated intravascular coagulation (DIC). Two-dimensional echocardiography is rarely helpful, but transesophageal echocardiography can demonstrate the valvular vegetations.165 Cerebral angiography demonstrates multiple arterial branch occlusions. Anticoagulation with heparin should be considered. Anecdotal evidence suggests that warfarin is not helpful. Tumor emboli166 originate from pulmonary metastases in most circumstances. The patient develops a neurologic deficit, followed weeks to months later by progressive deficits referable to the same area of brain due to growth of the embolized tumor.

DIC may result in cerebrovascular thrombosis.8 DIC is associated with severe systemic infection as well as leukemia and lymphoma, breast, prostate, and GI carcinomas. Neurologic symptoms, which usually begin abruptly with diffuse encephalopathy and fluctuating multifocal deficits, often precede laboratory evidence of DIC. Enhanced MRI is usually negative, although small foci of ischemia are occasionally seen and may be evident on diffusion weighted sequences. Anticoagulation with heparin, but not warfarin, may prevent progressive neurologic dysfunction.162

Metabolic Encephalopathy

Diffuse ence- phalopathy with or without focal signs is a common and prominent sign of many of the neurologic complications of cancer,167–170 including brain (usually multiple) or leptomeningeal metastases; neurotoxicity of many chemotherapeutic agents; vascular complications, particularly DIC; intracranial infections, and some paraneoplastic syndromes. However, most patients with encephalopathy do not suffer from one of these causes; instead, the disorder results from metabolic or nutritional abnormalities related to the underlying cancer or its treatment. Table 146-12 lists some of the causes of diffuse encephalopathy in cancer patients, but in most instances the disorder is either multifactorial or the underlying cause is never identified. Opioids or sedative drug overdose, hypoxia, or vital organ failure are the most frequently identified causes. In patients with multiple contributory causes, effective treatment of one factor may reverse the encephalopathy even though others cannot be treated. In patients in whom the cause is not identified, the symptoms often resolve spontaneously; however, the presence of delirium is associated with an overall poor prognosis.171

Table 146-12. Causes of Encephalopathy in Cancer Patients.

Table 146-12

Causes of Encephalopathy in Cancer Patients.

Metabolic encephalopathy usually causes global impairment of attention, alertness, and cognition in the absence of lateralizing signs.172,173 Focal neurologic findings may occur in metabolic encephalopathy, but their presence should prompt a search for structural lesions. The possibility of structural disease even in nonfocal, encephalopathic cancer patients should always be kept in mind; for example, multiple brain metastases may present only as a recent change in mental status. Nonconvulsive status epilepticus may cause encephalopathy without focal signs,174 although careful observation will usually detect repetitive movements of eyes or extremities.

Investigation and treatment should proceed simultaneously. When the history does not immediately suggest the etiology (eg, opioid toxicity, sepsis), a stepwise investigation should be carried out to identify the cause. If the examination reveals focal neurologic findings, or if the patient is stuporous, an MRI with and without contrast should be obtained. Otherwise the scan may be deferred until the laboratory evaluation is available. The tests should cover each of the areas listed in Table 146-12. If no cause is apparent from these tests, a lumbar puncture should be considered.

Simultaneously with evaluation, treatment should be undertaken. General medical measures of oxygenation, blood pressure, temperature control, and hydration often improve mental function. In diabetic patients, dextrose should be administered while awaiting the results of laboratory tests. Medications that are not critical should be stopped. During the initial evaluation, symptomatic treatment with sedatives or neuroleptics should be avoided when possible, because these agents cloud the clinical picture and, therefore, may hamper diagnosis. Haloperidol or risperidone may help to control symptoms of agitation and hallucinations, if present, but should not be used in alcohol or sedative withdrawal (risk of seizures) or in anticholinergic intoxication. Benzodiazepines can be used in the former conditions and physostigmine in the latter. If opioid intoxication is suspected, and the patient's respiratory status is not compromised, it is best to let the intoxication resolve without specific treatment because naloxone administration may precipitate severe, abrupt withdrawal and its effect is short-lived. If naloxone is administered, the initial dose should be 0.2 mg (one-half vial) diluted in saline and administered slowly. Thiamine should be given intravenously to patients with severe malnutrition. Once identified, the underlying cause of the encephalopathy should be promptly treated. However, improvement of the encephalopathy may lag behind improvement in laboratory values, especially if the abnormality was gradual in development.

Paraneoplastic Neurologic Syndromes

Paraneoplastic syndromes refer to disorders of unknown etiology that occur with increased frequency in patients with cancer.1,9 Compared with known complications of cancer, paraneoplastic syndromes are rare, seen in less than 1% of cancer patients. Although rare, they are important to patients afflicted with them and to their physicians. As paraneoplastic syndromes precede the diagnosis of cancer in about two-thirds of cases, prompt recognition may lead to early diagnosis and cure of the underlying neoplasm. These disorders often debilitate the patient to a greater degree than does the malignancy, but some of the syndromes are improved with successful treatment of the cancer. Table 146-13 lists some paraneoplastic syndromes. The primary cancers most commonly associated with each syndrome are also listed, but these associations are not absolute, because each syndrome has been observed with a variety of cancer types.

Table 146-13. Paraneoplastic Neurologic Syndromes.

Table 146-13

Paraneoplastic Neurologic Syndromes.

The etiologies of these syndromes are not well understood, but most are suspected to have an autoimmune basis. The strongest evidence for an autoimmune disorder is for the Lambert- Eaton myasthenic syndrome, in which autoantibodies inhibit the function of presynaptic calcium channels at the neuromuscular junction, resulting in weakness. Examination demonstrates an increase in muscle power after repetitive muscle contraction (the opposite of myasthenia gravis), and absent deep tendon reflexes. These findings, along with autonomic and sensory complaints of dry mouth, impotence, and thigh paresthesias, point to a nerve disorder. Electrodiagnostic tests of repetitive nerve stimulation reveal an increasing amplitude of the muscle action potential, which is pathognomonic. Several other paraneoplastic syndromes are associated with the presence of specific antibodies, including subacute sensory neuronopathy, limbic encephalitis, subacute cerebellar degeneration, and gammopathy-associated neuropathies. These specific antibodies serve as markers that not only identify the syndrome as paraneoplastic, but suggest the site of the underlying tumor.9 The antibodies have not been proved to have an etiologic role in the pathogenesis of such syndromes.

A variety of therapies directed at immunomodulation, including plasmapheresis, corticosteroids and intravenous immunoglobin, have failed to reverse the neurologic impairment associated with paraneoplastic disorders. The exception is the Lambert-Eaton myasthenic syndrome, which responds well to immunosuppressive treatments. Some patients with paraneoplastic neurologic disorders have reversal or stabilization of their neurologic dysfunction when the underlying malignancy is effectively treated and this should be therapeutic priority for all these patients.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12946

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