Neurologic Complications
Summary of Key Points
Incidence of Chemotherapy- and Radiation Therapy–Induced Neurotoxicity
• The actual incidence of treatment-related neurotoxicity is unknown, but the frequency is increasing.
• Improvements in supportive care, but not neuroprotective regimens, have allowed dose escalation for many drugs, and thus neurotoxicity often is the dose-limiting factor.
• Increased survival from cancer has resulted in an increasing prevalence of late-onset neurotoxicity.
• Newer treatments directed at tumors in the central nervous system often result in neurotoxicity, particularly with therapies administered directly into the cerebrospinal fluid.
Etiology of Neurotoxicity
• Direct effects on neurons, myelin, and supporting glial cells have been implicated.
• Effects on neuronal cytoskeleton and axonal transport, neuronal metabolism, and neurotransmitter function are the most commonly hypothesized mechanisms of toxicity. Alterations in specific ion channels have been reported in some cases of chemotherapy-induced peripheral neuropathy.
Evaluation of the Patient
• In general, chemotherapy or radiation toxicity should be considered a diagnosis of exclusion.
• Specific diagnostic tests do not exist for treatment-induced toxicity from most agents and regimens in use.
• The diagnosis often is made by recognition of a neurotoxic syndrome temporally related to treatment and by exclusion of other causes of neurologic dysfunction.
Treatment
• With most neurotoxic syndromes, specific treatment is not available.
• Prevention or reduction of risk often is possible with proper monitoring or treatment planning.
• New agents are under development for management or prevention of neurotoxicity, but careful testing is required to ensure that the antineoplastic effect is not compromised.
1. Answer: A. Cytosine arabinoside, or cytarabine, can cause a wide range of neurotoxic effects. Systemic administration of high-dose (greater than 1 g/m2) intravenous ara-C can cause acute cerebellar toxicity. Acute encephalopathy, often accompanied by seizures, has been described less frequently than cerebellar dysfunction in patients receiving high-dose intravenous ara-C. Direct administration of ara-C into the lumbar thecal space has been reported to cause myeloradiculopathy. This complication is uncommon; it usually is found only after an extensive course of intrathecal chemotherapy. Peripheral neuropathy has also been reported after administration of high-dose ara-C.
2. Answer: A. The differential diagnosis of acute encephalopathy in patients with cancer includes an extensive array of potential causes. Most commonly, however, acute encephalopathy is caused by toxic or metabolic derangement. Frequent causes include narcotic effects, electrolyte abnormalities, hypoxia, and renal or hepatic dysfunction. Neoplastic meningitis frequently manifests as mental status changes. Likewise, brain metastasis can cause an acute change in mental status. A paraneoplastic syndrome, limbic encephalitis, can manifest as a progressive dementia, which often is subacute. Cancer treatment can directly or indirectly cause acute encephalopathy.
3. Answer: A. The most common neurotoxicity associated with cisplatin is peripheral neuropathy, which is so significant that it is a dose-limiting adverse effect. The neuropathy predominantly involves the large sensory fibers, which mediate vibration and proprioceptive function. Deep tendon reflexes are lost because of toxic effects on the large myelinated sensory fibers, which provide the afferent arm of the reflex arc. Involvement of motor function generally is mild and is seen only in patients with severe sensory neuropathy. Development of neuropathy is dose related.
