Neuropathy

Neuropathies in patients with systemic cancer may be associated with dietary deficiency or cachexia but are also the commonest neurological side effect of anticancer drugs (Table 100-1). People with preexisting neuropathies, diabetes, or alcohol abuse are more prone to the chemotherapy-induced neuropathy. Drug-induced neuropathies develop during chemotherapy or within a few months (usually less than 4 months) after completion of chemotherapy. Neuropathies may progress after discontinuation of treatment for up to 2 to 3 months and then often stabilize or recover to some degree over the ensuing months or years. Acute severe neuropathies, leading to a Guillain-Barré–like syndrome, have been reported rarely after the administration of suramin and tacrolimus.

Encephalopathy

Confusion is a common occurence in cancer patients undergoing treatment. Treatable reversible causes of confusion, such as metabolic encephalopathy, infection, endocrine (hypothyroid, diabetes) deficiency states (vitamin B₁₂/folate), and drug-related causes (e.g., tricyclics, anxiolytics, analgesics), must be sought. Most chemotherapeutic agents in usual dosages have limited penetration across the blood-brain barrier. Symptoms of encephalopathy are more likely to occur when high doses of drugs are used (e.g., methotrexate, cytosine arabinoside, 5-fluorouracil [5-FU]), when drugs are administered locally to brain tissue (e.g., Gliadel wafers, biological response modifiers, gene therapy), intrathecally (e.g., methotrexate, cytosine arabinoside, thiotepa) intra-arterially (e.g., nitrosourea or cisplatin), or if the blood-brain barrier is already damaged such as by a brain tumor (Table 100-2). Frequency of confusion is also associated with the mode of drug delivery (intratumoral > intrathecal > intracarotid > oral or intravenous) and the dose given. A more specific condition, reversible posterior leukoencephalopathy (RPLE), can be caused by immunosuppression or some chemotherapy agents (cyclosporin, tacrolimus, interferon α, L-asparginase, vincristine, and high-dose methotrexate). Patients develop confusion, visual disturbance, seizures, and hypertension, which may progress to blindness and coma. White matter changes in the posterior brain on magnetic resonance imaging are diagnostic of RPLE. Elimination of the offending drug and treatment of hypertension can result in recovery without residual neurological signs over a 2- to 3-week period.

TABLE 100-2 Clinical Neurological Syndrome by Drug

Seizures

Most patients with cancer who develop seizures have either a direct cause for it (e.g., metastasis, carcinomatous meningitis) or an encephalopathy. Drug-related seizures are rare but have been reported. Tonic-clonic seizures on the background of cognitive disturbance suggest a toxic encephalopathy.

Stroke

Strokes are more common in people with cancer than in the general population. The most common cause in cancer patients is nonbacterial thrombotic endocarditis (especially in adenocarcinoma). Myelosuppression or coagulopathy contributes to the increased frequency of cerebral hemorrhage or infarction. Strokes can occur with cisplatin or with L-asparginase therapy. There is insufficient evidence to associate stroke strongly with other chemotherapeutic agents. Radiotherapy may induce accelerated atherosclerosis of intracranial or extracranial vessels, which can lead to embolic or ischemic stroke (see later).

Cisplatin

Cisplatin is an alkylating agent that damages rapidly dividing cells by inhibiting DNA synthesis and separation by formation of links within and between strands of DNA. It is used mainly to treat ovarian, testicular, bladder, and small cell lung cancers. The main neurological side effect of cisplatin is a dose-related sensory neuropathy that can affect up to 80% of patients who complete six courses of treatment. Symptoms start after a cumulative dose of 300 to 400 mg/m². Platinum-containing drugs accumulate in the dorsal root ganglia, where they have a toxic effect, which causes an ataxic sensory neuropathy. They also affect large myelinated fibers in the peripheral nerves, causing axonal loss and demyelination. Patients complain of paraesthesia, numbness, and pain in the toes and fingers that subsequently spread proximally to affect the arms and legs. Proprioception is impaired and reflexes are lost. Strength, pain, and temperature sensation are usually spared. Nerve conduction studies demonstrate decreased amplitude of sensory action potentials. The neuropathy may become severe enough to stop treatment with cisplatin. In 30% of patients with neuropathy, symptoms progress for 2 to 6 months after stopping treatment. The neuropathy is irreversible in many cases.

One fifth of patients given cisplatin develop symptomatic high tone deafness and tinnitus, due to damage to the cochlear hair cells. Deafness is rarely severe enough to interfere with speech perception, but tinnitus can seriously affect quality of life. Infrequently, cisplatin can produce vertigo and unsteadiness. About one third of patients develop Lhermitte’s phenomenon (electric shock–like sensations on neck flexion). Rarely, cisplatin causes a reversible posterior leukoencephalopathy. Intra-arterial cisplatin can cause optic neuropathy. Carboplatin and oxaliplatin have similar side effects but are less neurotoxic.

Vinca Alkaloids

Vinca alkaloids bind to tubulin and prevent its depolymerization from microtubules to dimers, disrupting normal spindle function and thus preventing cell division. This tubular toxic effect is believed to inhibit fast axonal transport and leads to axonal degeneration. Vincristine causes the most severe neuropathy, is usually the dose-limiting side effect, and occurs to some degree in all patients. Vindesine, vinblastine, and vinorelbine usually only give rise to mild neuropathies. Vincristine is used in the treatment of hematological malignancies, sarcomas, and brain tumors. After the administration of vincristine, mild paraesthesias in the fingertips and feet and muscle cramps are experienced, followed by weakness. Sural nerve biopsy shows primary axonal degeneration accompanied by segmental demyelination and reduction in both large and small fiber densities. It is usually slowly reversible months to years after withdrawal. Vincristine can cause an autonomic neuropathy, with abdominal pain and constipation (30%), urinary retention, or postural hypotension. Life-threatening paralytic ileus may occur. Some patients develop cranial nerve palsies, bilateral foot drop, or wrist drop, which can be severe and incompletely reversible. Vincristine administration intrathecally produces a fatal encephalopathy.

Methotrexate

Methotrexate is used for hematological malignancies, breast cancer, and occasionally intrathecally for malignant meningitis. It is an antifolate agent, inhibiting dihydrofolate reductase, hence reducing purine and thymidine synthesis. Folinic acid after treatment reduces frequency of neurological toxicity. Oral methotrexate rarely causes neurotoxicity. When administered into the cerebrospinal fluid or given in high doses intravenously (>1 g/m²