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), it can lead to a rapid onset of confusion, headache, and fever. This chemical meningitis produces an encephalopathy a few hours after intrathecal administration and is associated with a cerebrospinal fluid pleiocytosis. This illness is severe enough to be confused with bacterial meningitis, although the temporal association with methotrexate injection usually makes the diagnosis obvious. Several days after the third or fourth weekly treatment with the drug, multiple fluctuating focal deficits (said to be “strokelike”) may occur. Recovery is usually full and the disorder does not usually recur. A delayed encephalopathy affects up to 25% of long-term adult survivors of primary cerebral lymphoma treated with methotrexate and radiotherapy. This may cause progressive dementia, gait disturbance, seizures, and focal neurological deficits. White matter changes are found on magnetic resonance imaging.

A delayed reversible myelopathy can be seen after several intrathecal injections with methotrexate.

Cytosine Arabinoside

Cytosine arabinoside (Ara-C or cytarabine) is used for hematological malignancies, breast cancer, and occasionally is given intrathecally for leptomeningeal carcinomatosis. High-dose Ara-C causes a reversible cerebellar syndrome in 10% to 20% of patients. It usually starts a few days after treatment, peaks at 2 to 3 days, and then resolves within 2 weeks of treatment, although the resolution may be incomplete. Occasionally, a more diffuse encephalopathy occurs with seizures. Intrathecal therapy can lead to a chemical meningitis and myelopathy. Neuropathy is rarely reported, especially where Ara-C is used with other drugs.

5-Fluorouracil

5-FU is used for gastrointestinal, head and neck, and breast cancers. In people with reduced activity of the enzyme dihydropyrimidine dehydrogenase, it may cause confusion or coma. The most common neurological toxicity, however, is a subacute reversible cerebellar syndrome. If 5-FU is used in combination with levamisole, a more severe encephalopathy may develop with seizures. Magnetic resonance imaging scans in these patients may show multiple enhancing white matter lesions.

Taxol (Paclitaxel) and Taxotere (Docetaxel)

Paclitaxel is extracted from the bark of the Pacific yew and docetaxel from the needles of the English yew. Taxenes promote and stabilize microtubular assembly, which seems to inhibit fast axonal transport leading to axonal dysfunction. Paclitaxel is used for the treatment of breast, ovarian, and lung cancers. About one half of patients treated with taxol in doses over 200 mg/m² develop a sensory neuropathy involving all sensory modalities. Symptoms usually begin within 1 to 2 days of treatment. Patients develop paraesthesia and some unsteadiness on walking due to a mild sensory ataxia. A few patients may develop weakness. Examination reveals signs of a neuropathy with a mild ataxia from proprioceptive loss. Perioral numbness may also occur. Nerve conduction studies and sural nerve biopsy confirm an axonal neuropathy with some segmental demyelination. The neuropathy is usually partially reversible once the treatment is stopped. Taxol can cause Lhermitte’s phenomenon.

Ifosfamide

Ifosfamide is used in the treatment of sarcoma, lymphoma, myeloma, and ovarian and testicular cancers. It is an alkylating agent that is hydroxylated in the liver to its active metabolite. It may lead to an acute encephalopathy with cerebellar and extrapyramidal symptoms with hallucinations and seizures possibly related to mitochondrial toxicity. This usually occurs in between 11% and 60% of patients and begins within 24 hours of treatment and resolves within a median of 3 to 4 days but can persist for 7 to 10 days. Severe encephalopathy occurs in less than 5%. Methylene blue can be used both as treatment and as prophylaxis for this encephalopathy. Thiamin infusions (100 mg diluted in 100 mL of normal saline every 4 hours) has also been found to reverse neurological symptoms.

Intracarotid Therapies

Intracarotid carmustine (BCNU) or cisplatin is usually associated with local eye pain and can lead to optic neuropathy with reduction in visual acuity, color vision, and occasionally complete unilateral blindness. A retinal vasculitis is reported in 10% of patients. Intra-arterial BCNU can cause cerebral parenchymal damage in the territory of the anterior choroidal artery and lead to an encephalopathy.

Intratumoral Therapies for Brain Tumors

BCNU-impregnated wafers (Gliadel), biological response modifiers, immunotherapy, and gene therapy reduce the toxic systemic effects but are associated with an increased frequency of local effects (edema, cerebritis, raised intracranial pressure) that may manifest with seizures or focal deficits.

Tamoxifen

Tamoxifen interferes with the activity of estrogen and slows or stops the growth of cancer cells that have estrogen receptors. Ocular toxicity develops in 12% of those on long-term tamoxifen in the form of blurred vision as a result of keratopathy or change in color vision as a pigmentary retinopathy or optic neuropathy. These visual symptoms are reversible on discontinuation of the drug.

Corticosteroids

Corticosteroids are used to reduce peritumoral edema in patients with brain and spinal tumors, as oncolytic agents, and with systemic chemotherapy to reduce nausea and vomiting. An acute myopathy can come on within a week of starting high-dose corticosteroids and can involve respiratory muscles. Some patients develop myopathy after using low doses of steroids for a period as short as a month, but more commonly this occurs after prolonged use. They usually result in a painless weakness of the pelvic girdle leading to difficulty rising from a chair or climbing stairs. Occasionally, the pectoral girdle and neck muscles may also be involved. The only treatment is drug withdrawal. Steroids also cause changes in mood with occasional psychosis, insomnia, tremor, and disturbances in smell. Steroid withdrawal can produce headaches, lethargy, myalgia, arthralgia, or postural hypotension.

Early Radiation Side Effects

Patients with aggressive large intracerebral tumors who have not been given adequate doses of steroids are at increased risk of acute encephalopathy. Symptoms usually develop within 1 or 2 days of radiotherapy treatment and are usually at their worst within the first 2 weeks. Patients develop headaches, nausea and vomiting, and worsening of existing neurological deficits. Magnetic resonance imaging may reveal localized peritumoral white matter edema and mass effect (Fig. 100-1). Symptoms usually resolve after the steroid dose is increased.

Figure 100-1 Magnetic resonance imaging of early delayed radiation-induced white matter in normal brain showing white matter edema and downward displacement of the ventricle 2 months after radiation therapy for a recurrent falcine atypical meningioma.

Early Delayed Radiation Side Effects

This starts a few weeks to a few months after completion of cranial irradiation. Patients notice a slowly developing lethargy and problems with concentration and memory. Occasionally there may be worsening of existing focal neurological symptoms. Early delayed reaction is very common (greater than 50%) and is believed to represent the direct effects of radiation on the more radiation sensitive myelin and glial cells. In 15%, early delayed side effects may mimic tumor recurrence. A brainstem encephalopathy may develop after irradiation of the posterior fossa. Rarely, patients treated with concurrent chemotherapy or elderly patients develop an early severe leukoencephalopathy, which is sometimes permanent. Minor symptoms can be monitored, but if severe, treatment with small doses of dexamethasone for 1 to 2 months and then slowly tapering them over 2 to 4 weeks is usually sufficient. In almost all patients, symptoms have settled by 3 to 4 months after completion of radiation therapy.

Late Effects of Radiation

Radiation Necrosis

Radiation necrosis occurs in patients treated with high focal doses of radiation. Patients present from several months to 10 years after cranial radiation. In 2.8% of patients treated for malignant glioma, focal radiation necrosis develops, but among those surviving a year as many as 9% develop the condition. The most important factor is the total dose of radiation given equal to or greater than 6000 cGy. The clinical and radiological presentation is similar to that of recurrent intracerebral tumor, with progressive focal neurological signs associated often with headaches, papilloedema, and seizures, usually close to the original tumor site. Computed tomography and magnetic resonance imaging can be indistinguishable from tumor progression (Fig. 100-2). Single-photon emission computed tomography with thallium or positron emission tomography with ¹⁸F-FDG can help distinguish tumor from radionecrosis. Increased uptake supports active tumor and low uptake suggests radionecrosis. Pathological examination shows white matter necrosis and, in more severe cases, necrosis of gray and white matter. There is often extensive vascular damage with endothelial proliferation, fibrosis/fibrinoid necrosis, and luminal occlusion (Fig. 100-3). Treatment of radiation necrosis with high-dose oral steroids may produce an improvement in symptoms and imaging. Surgical debulking of the mass is justified in some patients, first, to confirm the diagnosis and, second, to reduce mass effect. The use of anticoagulants and hyperbaric oxygen is reported to be successful in case reports, although they are not routinely used in clinical practice.

Figure 100-2 Magnetic resonance imaging scan/histology of a case with radiation necrosis and mass effect with contrast enhancement and central necrosis consistent with tumor recurrence 3 years following 60Gy in 30 fractions given to patient with anaplastic astrocytoma.

Figure 100-3 Histology of the brain showing changes of radiation necrosis with hyalinization of vessel walls.

Dementia Due to Radiation-Induced Leukoencephalopathy

Up to one fifth of long-term survivors of cancer who have had cranial radiation therapy suffer from a slow or stepwise dementia with apraxia and ataxia, mimicking normal pressure hydrocephalus. This is one of the most common reasons for poor quality of life in long-term survivors of malignant glioma. It causes a subcortical dementia with slowness of thought, apathy, and unsteady walking (apraxia). It is sometimes severe enough to inhibit the patient initiating gait or even standing. Later, incontinence develops. Although it has been reported as occurring as early as 6 months after radiation, the more characteristic course is starting 2 to 3 years after radiation therapy and slowly deteriorates over the next 5 to 10 years, until the patient is totally dependent on caregivers. Imaging shows marked atrophy of the brain with enlargement of the ventricles or diffuse white matter changes, most marked on magnetic resonance imaging (Fig. 100-4). Later, there may be dystrophic calcification in the brain (Fig. 100-5).

Figure 100-4 Severe radiation-induced leukoencephalopathy following radiation for a left frontoparietal anaplastic astrocytoma.

Figure 100-5 Late radiation-induced diffuse calcific microangiopathy (A) and a radiation-induced meningioma in the falx (B), occurring 20 years after treatment with radiation therapy for medulloblastoma.

Pathology shows a disseminated necrotizing leukoencephalopathy with demyelination in the subcortical and periventricular white matter sparing the gray matter and the basal ganglia. There may also be a mineralizing microangiopathy with calcium deposition in and around vessels leading to occlusion and dystrophic calcification within the brain. There is no effective treatment.

Cavernous Angiomas

Cavernous angiomas are small capillary dilatations in the brain that may develop 4 to 8 years after cranial irradiation. They may manifest as asymptomatic abnormalities on imaging or may be associated with seizures or headache. They may be difficult to distinguish from tumor recurrence in some situations on computed tomography scanning, but magnetic resonance imaging demonstrates the lesion has no mass effect and there is a characteristic hemosiderin ring around them (Fig. 100-6).

Figure 100-6 Cavernous hemangiomas (dark circular areas) in the temporal lobe and pons years after radiation therapy for a craniopharyngioma.

Early Local Neurological Complications of Radiotherapy

Positioning for radiation or insufficient padding can be associated with nerve trauma, either as a result of compression of the nerves (brachial plexus, radial nerve, ulnar nerve) or due to a brachial neuritis. Nerve compression is apparent immediately after the treatment session and is often confined to one nerve. Brachial neuritis can mimic an acute cervical disc. It is usually preceded by very severe “boring” scapular or shoulder pain, which then eases off over a number of days or weeks to leave muscle wasting proximally, often with winging of the scapula. Its onset and severity are too acute to mimic direct nerve invasion from cancer. The condition improves spontaneously with time.

Acute Radiation Myelopathy

This can occur within days of starting radiation for a spinal cord or epidural tumor. Treatment is with steroids.

Early Delayed Radiation Myelopathy

Subacute transient myelopathy is common after radiotherapy of the spine. It may occur in up to 5% to 15% of patients treated for Hodgkin’s disease where the cord is in the field. The only symptom experienced may be Lhermitte’s phenomenon. There are rarely findings on imaging, but some develop high signal in the cord with contrast enhancement (Fig. 100-7). The symptoms improve after 1 to 9 months. Steroids are rarely required.

Figure 100-7 T1-weighted gadolinium-enhanced magnetic resonance imaging of the cord showing contrast-enhanced area appearing some weeks after radiation therapy for a spinal metastatic deposit.

Delayed Progressive Myelopathy

This occurs in 1% to 12% of long-term survivors after radiation for esophageal, lung, lymphoma, and head and neck cancers, when the spinal cord is in the radiotherapy field. The peak incidence is between 1 and 2 years after treatment. It usually causes numbness in the legs and abdomen below the level of the radiation field, which may be asymmetrical at the beginning. Sometimes a Brown-Sequard syndrome is seen, and there may also be autonomic features. Slowly progressive sensory and motor symptoms may lead to paraparesis in about one half of patients. Magnetic resonance imaging shows low-intensity signal on T1-weighted images and high-intensity signal on T2-weighted scans, occasionally with contrast enhancement. There may be some swelling of the cord, although later in the course of the illness the cord becomes atrophic. Paraparesis is usually irreversible when it occurs.

Lower Motor Neuron Syndrome

This may occur between 4 months and many years after radiation therapy. It is slowly progressive; causes weakness, wasting, fasciculation, and reflex loss mainly in the legs; and may mimic motor neuron disease. There is no sensory loss or sphincter dysfunction. The condition progresses over several months, but stabilization may then occur. Magnetic resonance imaging is usually normal or shows some cord atrophy.

Brachial and Lumbosacral Plexopathies

Radiation-induced plexopathies usually begin years after treatment and have a progressive course. They are usually associated with breast cancer or lymphoma. Brachial neuropathies usually manifest with numbness or paraesthesia of the fingers, followed by pain and sometimes weakness. The symptoms may stabilize, although they can progress. The condition is believed to be due to fibrosis of tissues surrounding the plexus and perhaps radiation-induced vascular occlusion of vessels supplying the plexus or nerves leading to nerve infarction. Distinguishing these plexopathies from tumor involvement or other causes of brachial plexopathy can be difficult, although Horner’s syndrome and early, severe pain are found more frequently in brachial plexus metastasis. Myokymia (spontaneous, semirhythmical bursts of electrical potentials) is found in about one half of patients with radiation-induced plexopathy. Lumbosacral plexopathy has similar clinical features but involves the lower limbs.

Malignant nerve sheath tumors of the brachial plexus, Lumbosacral plexus, or peripheral nerves can rarely complicate radiotherapy.