Neurologic complications of chemotherapy

Neurologic complications of chemotherapy have been reported with increasing frequency in cancer patients as a result of more powerful and aggressive antineoplastic therapy with neurotoxic agents and also because of prolonged patient survival. These complications may result from the direct toxic effects of the drug on the nervous system or indirectly from metabolic derangements, inflammatory responses, or cerebrovascular disorders induced by such anti-cancer drugs. Recognition of these complications is important because they may be confused with metastatic or recurrent disease and because discontinuation or dose reduction of the anti-cancer drug may prevent irreversible injury.

The neurologic complications of the more commonly used chemotherapeutic agents, antihormonal therapies, biological response modifiers, targeted molecular agents, immunotherapies, and CAR-T cell therapies in cancer patients will be discussed. This topic is covered in greater detail in a number of prior reviews (47; 162; 295; 52).

The neurologic complications of the most common systemic anti-cancer therapies are summarized in Table 1.

Table 1. Neurologic Complications of Systemic Anti-Cancer Therapies

Drugs that commonly cause neurotoxicity

Cisplatin. Cisplatin is an alkylating agent used to treat ovarian, testicular, cervical, bladder, lung, gastrointestinal, and head and neck cancers. It frequently causes neurotoxicity, especially peripheral neuropathies and ototoxicity.

Neuropathy. The main neurologic complication of cisplatin is a ganglionopathy affecting predominantly large diameter sensory neurons (126). Symptoms primarily result from injury to the dorsal root ganglion. The peripheral nerve may also be affected. The neuropathy is characterized by subacute development of nonpainful numbness and paresthesias in the extremities. Symptoms usually begin in the toes and then spread to the fingers and then, in ascending fashion, affect the proximal legs and arms. Proprioception is impaired and reflexes are lost, but pinprick sensation, temperature sensation, and power are often spared. Nerve conduction studies show decreased amplitude of sensory action potentials and prolonged sensory latencies consistent with a sensory axonopathy. Sural nerve biopsy may show both demyelination and axonal loss.

The main differential diagnoses include paraneoplastic neuropathies and neuropathies associated with autoimmune disorders such as in Sjögren syndrome. Paraneoplastic neuropathies tend to involve all sensory fibers and may progress despite discontinuation of cisplatin. Some patients test positive for antineuronal antibodies (anti-Hu) in serum. Patients with autoimmune neuropathies often have clinical features of the underlying connective tissue disease, and autoimmune antibodies are usually present in serum.

There is marked individual susceptibility to the development of cisplatin-induced neuropathies (168). Typically, neuropathies develop in patients following cumulative doses of cisplatin greater than 400 mg/m2 (25). Increased dose intensity of cisplatin administration does not appear to enhance the severity of the neuropathy (109; 110). Patients with mild neuropathies can continue to receive full doses of cisplatin. Once the neuropathy becomes more severe and begins to interfere with neurologic function, the clinician must decide whether to continue with therapy and risk potentially disabling neurotoxicity, reduce the dose of drug, or discontinue the drug and replace it with less neurotoxic agents. The most appropriate course of action varies with each patient and must take into account various factors, such as the severity of the neuropathy and the availability of less neurotoxic alternatives. After cessation of chemotherapy, the neuropathy usually continues to deteriorate for several months in 30% of patients, the so-called coasting phenomenon (249). Most patients eventually improve, although recovery is often incomplete (25).

Many agents have been tested for the prevention or treatment of chemotherapy-induced peripheral neuropathy, including neuropathy caused by cisplatin (03). The 2020 American Society for Clinical Oncology Clinical Practice guideline on chemotherapy-induced peripheral neuropathy does not recommend any agents for the prevention of neuropathy based on the paucity of high-quality data and lack of sufficient evidence (155). Regarding the treatment of existing chemotherapy-induced peripheral neuropathy, the best available data support a moderate recommendation for treatment with duloxetine (251; 155).

Cranial neuropathies. Cisplatin may cause ototoxicity, leading to high-frequency sensorineural hearing loss and tinnitus. The toxicity is due to peripheral receptor (hair) loss in the organ of Corti and is related to drug dose (175). Audiometric hearing loss is present in 74% to 88% of patients receiving cisplatin, and symptomatic hearing loss occurs in 16% to 20% of patients. Cranial irradiation probably increases the likelihood of significant hearing loss in patients also treated with platinum drugs. The hearing loss tends to be worse in children, although they have a slightly greater ability to improve after the drug has been discontinued. Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo, and can be associated with hearing loss. Previous use of aminoglycosides may exacerbate the vestibulopathy (18; 175). Intraarterial infusion of cisplatin for head and neck cancer produces cranial palsies in approximately 6% of patients (77). Intracarotid infusion of cisplatin may also cause ocular toxicity, although these complications rarely occur after intravenous administration of the drug (138). They include retinopathy, papilledema (191), optic neuritis (191), and disturbed color perception due to dysfunction of retinal cones (281). Other complications of intraarterial cisplatin include headaches, confusion, and seizures (262). Fortunately, such treatments are rarely considered nowadays.

Myelotoxicity (Lhermitte sign). This symptom, characterized by paresthesias localizing to the upper back and extremities with neck flexion, is seen in 20% to 40% of patients receiving cisplatin. Patients tend to develop this symptom after several weeks or months of treatment. Neurologic exam and MRI scans are usually normal and the Lhermitte sign often resolves spontaneously several months after the drug has been discontinued. It is thought to result from transient demyelination of the posterior columns or from Wallerian degeneration of the central projections of the dorsal root ganglion (126). Very rarely, a true myelopathy has been reported (47).

Less common complications. Infrequently, cisplatin produces encephalopathy, possibly associated with seizures and focal neurologic symptoms, including cortical blindness (47). The encephalopathy is associated with reversible abnormalities in white matter tracts of the occipital, parietal, and frontal lobes and clinically resembles the reversible posterior leukoencephalopathy syndrome. The encephalopathy tends to be more common after intraarterial administration of the drug (182). It needs to be distinguished from a metabolic encephalopathy secondary to water intoxication caused by excessive hydration, or from renal impairment, hypomagnesemia, hypocalcemia, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that may follow treatment with cisplatin. Cisplatin can also cause vascular toxicity, resulting in ischemic infarction (81; 119). One case of acute corpus callosum hemorrhages was reported following combination treatment with cisplatin, ifosfamide, and etoposide (54). Other rare complications include taste disturbance and a myasthenic syndrome (47). Interestingly, cisplatin may cause long-term adverse effects on cognitive function (267). The exact mechanisms on cognitive function are unclear. Cisplatin may be retained in tissues and plasma even for years after cessation of treatment (85; 24). Long-term toxicity and cognitive impairment may be related to damage to neural progenitor cell populations in the nervous system critically important in maintenance of brain plasticity, memory function, and subcortical network systems (53; 57).

Methotrexate. This is a dihydrofolate reductase inhibitor used in the treatment of a wide range of cancers, including leukemias, lymphomas, choriocarcinoma, breast cancer, lung cancer, sarcomas, central nervous system lymphoma, and leptomeningeal metastases. The degree of neurotoxicity is determined by the dosage, its route of administration, and the use of other concomitant therapeutic modalities with overlapping neurotoxicities, including other chemotherapeutic agents and irradiation.

Intrathecal methotrexate toxicity. Aseptic meningitis is the most common neurotoxicity associated with intrathecal methotrexate therapy (87; 162). This occurs in approximately 10% of patients, although some series have reported incidences as high as 50%. Symptoms usually start 2 to 4 hours after the drug is injected and can last for 12 to 72 hours. Neurotoxicity resulting in aseptic meningitis is characterized by headaches, nuchal rigidity, back pain, nausea, vomiting, fever, and lethargy and is indistinguishable from other types of chemical meningitis. The CSF shows a pleocytosis and an elevated protein. Although symptoms are self-limiting in most patients, there have been reports of delayed, disseminated, necrotizing leukoencephalopathy several months after treatment, especially in patients receiving high cumulative doses of intrathecal methotrexate combined with whole-brain radiotherapy (21). Aseptic meningitis can be prevented to some extent by injecting methotrexate together with hydrocortisone or by using oral corticosteroids (86). Some patients who developed aseptic meningitis have been subsequently retreated with methotrexate without problems.

Transverse myelopathy, a less common complication of intrathecal methotrexate, is characterized by back or leg pain followed by paraplegia, sensory loss, and sphincter dysfunction. Symptoms usually occur between 30 minutes and 48 hours after treatment but may be characterized by a delayed onset up to several weeks after treatment. Most affected patients will show clinical improvement, but the extent of recovery is variable (78). This complication is more common in patients receiving concurrent radiotherapy or frequent treatments of intrathecal methotrexate.

Acute and subacute neurotoxicity and leukoencephalopathy with stroke-like focal deficits may be associated with abnormal MRI findings, such as diffusion-weighted imaging hyperintensities that may not be confined to typical vascular territories (08). Diffusion-weighted imaging abnormalities can be seen in subcortical or deep periventricular white matter, corpus callosum, cortex, cerebellum, and thalamus (224; 71; 137; 103; 293; 11; 28). It has been suggested that DWI changes in methotrexate-associated neurotoxicity represent reversible cerebral dysfunction with associated cytotoxic edema and metabolic derangement rather than true ischemic structural injury (224; 103). Accidental overdosage of methotrexate (more than 500 mg) has resulted in myelopathy and encephalopathy with fatal outcome. The use of rapid CSF drainage, ventriculo-lumbar perfusion, high-dose leucovorin, and alkaline diuresis has allowed some patients to survive (253). Cases of irreversible cerebellar atrophy following intrathecal methotrexate have also been described (165).

Weekly low-dose methotrexate neurotoxicity. Up to 20% of patients receiving weekly low-dose methotrexate (eg, for rheumatological conditions) may experience headaches, dizziness, dysphoria, and subtle cognitive impairment (280). Both renal insufficiency and older age are associated risk factors for neurotoxicity. Oral methotrexate may also result in acute focal neurologic deficits (06) and abnormal imaging findings, consistent with reversible posterior leukoencephalopathy (213). Symptoms usually resolve when methotrexate is discontinued. Neurotoxicity characterized by dysarthria, gait dysfunction, dysmetria, and weakness has been described after low-dose subcutaneous methotrexate injection for rheumatoid arthritis. Symptoms were reversible, however, and resolved after discontinuation of treatment (165).

High-dose methotrexate neurotoxicity. High-dose methotrexate may cause acute, subacute, and chronic neurotoxicity.

Acute neurotoxicity following high-dose methotrexate is characterized by somnolence, confusion, and seizures within 24 hours of treatment. Symptoms usually resolve spontaneously without sequelae, and patients can often continue to receive this drug in the future (47). Weekly treatments with high-dose methotrexate may produce a subacute "stroke-like" syndrome characterized by transient focal neurologic deficits, confusion, and occasionally seizures (275). Typically, the disorder develops several days after high-dose methotrexate, lasts 15 minutes to 72 hours, and resolves spontaneously without sequelae. Neuroimaging and CSF studies are usually normal, but EEG may show diffuse slowing. Methotrexate may be subsequently administered without the encephalopathy recurring. The pathogenesis of this syndrome is unknown but may be related to impaired cerebral glucose metabolism.

Leukoencephalopathy. The major delayed complication of methotrexate therapy is leukoencephalopathy (52). Although this syndrome may be produced by intrathecal or high-dose systemic methotrexate alone, it is exacerbated by radiotherapy, especially if radiotherapy is administered before or during methotrexate therapy. The clinical features are characterized by the gradual development of cognitive impairment months or years after treatment with methotrexate. The clinical picture ranges from mild learning disabilities to severe progressive dementia associated with somnolence, seizures, ataxia, and hemiparesis (40). CT and MRI scans show cerebral atrophy and diffuse white matter lesions. Histopathologic evaluations of affected brain lesions range from loss of oligodendrocytes and gliosis to a picture of necrotizing leukoencephalopathy (107). The clinical course is variable.

Many patients stabilize or improve after discontinuation of methotrexate, but the course is progressive in some patients and may result in death. No effective treatment is available. The cause of leukoencephalopathy is poorly understood. Preclinical studies suggest that methotrexate activates microglia and astrocytes in white matter, which ultimately depletes myelin-forming cells, resulting in a persistent deficit in myelination (84). Studies also suggest that genetic polymorphisms for methionine metabolism, which is required for myelination, may constitute a risk factor for methotrexate-associated neurotoxicity (152; 177). It is likely that cranial irradiation either potentiates the toxic effects of methotrexate or disrupts the blood-brain barrier, allowing high concentrations of methotrexate to enter the brain parenchyma. It is also seen after high dose intravenous methotrexate chemotherapy.

Pemetrexed is an antifolate that is used alone or in combination with other chemotherapeutic agents such as in malignant mesothelioma and non-small cell lung cancer. It causes a neuropathy that can be prophylactically treated with vitamin B12 and folate supplementation (30; 140).

Oxaliplatin. Oxaliplatin is a third-generation platinum complex that has activity against cisplatin-resistant tumor cells. It is used to treat colorectal cancer. An acute transient neuropathy occurs in most patients and is characterized by cold sensitivity, throat discomfort, discomfort swallowing cold liquids, and muscle cramps (155). Symptoms can occur at the time of infusion but typically peak 2 to 3 days after infusion. This complication occurs more frequently at doses of 130 mg/m² (79). A sensory neuropathy remains the dose-limiting toxicity, which occurs in up to 50% to 90% of patients (136; 132; 143). Neuropathies tend to be associated with increased cumulative doses (197) but are rarely severe at conventional doses and tend to improve after therapy is discontinued (67; 82). In some patients, oxaliplatin-induced neuropathy can worsen for 2 to 3 months after cessation of therapy (so-called coasting phenomenon) before improving (155). Approaches used to prevent or minimize oxaliplatin neurotoxicity include stopping and reintroducing oxaliplatin, dose reduction, and lengthening the duration of infusion. Calcium and magnesium infusions (79; 111; 112) were initially reported to be beneficial for the prevention of oxaliplatin-induced peripheral neuropathy. However, a phase 3 randomized, placebo-controlled trial of intravenous Ca/Mg with oxaliplatin demonstrated no benefit in preventing or diminishing the severity of acute or chronic neurotoxicity from oxaliplatin (156).The 2020 American Society for Clinical Oncology Clinical Practice guideline on chemotherapy-induced peripheral neuropathy so far does not recommend any agents for the prevention of oxaliplatin-induced neuropathy, but it provides a recommendation for the treatment of neuropathy with duloxetine (155).

Taxanes: paclitaxel and docetaxel. Taxanes are used to treat a variety of cancers including ovary, breast, and non-small cell lung cancers. They contain a plant alkaloid that inhibits microtubule function, leading to mitotic arrest (227). Paclitaxel produces a dose-limiting peripheral neuropathy, which occurs in 60% of patients receiving 250 mg/m² (153; 173). Toxicity is predominantly characterized by a symmetric, sensory axonal neuropathy affecting both large and small fibers (07). Symptoms usually begin after 1 to 3 weeks of treatment. Patients develop burning paresthesias of the hands and feet and loss of reflexes. The neuropathy often does not progress despite continued treatment, and there have even been reports of patients improving with continuing therapy. Some patients develop a pain syndrome primarily involving the trunk and hips beginning 2 to 3 days after a course of paclitaxel lasting 2 to 4 days; although previously labeled as myalgias and arthralgias, newer data suggest that these symptoms represent an acute neuropathy (155). Less commonly, paclitaxel can result in motor neuropathies that predominantly affect proximal muscles (76), perioral numbness, and autonomic neuropathies (227). Rarely, paclitaxel causes visual scotomas, optic neuropathies, seizures, vocal cord palsies, transient encephalopathies (201; 41), or phantom limb pain in patients with prior amputation (130). Neuropathies are less common with docetaxel, but some patients develop sensory and motor neuropathies similar to paclitaxel (76; 181). Docetaxel can occasionally produce a Lhermitte sign (269). High-dose paclitaxel (greater than 600 mg/m2) can lead to an acute encephalopathy and subsequent death between 7 and 23 days after treatment (184; 93). The neurotoxic effects of paclitaxel and docetaxel are increased when combined with cisplatin (110; 109). Liposomal encapsulation of paclitaxel may reduce the incidence of neurotoxicity (266). Again, the 2020 American Society for Clinical Oncology Clinical Practice guideline on chemotherapy-induced peripheral neuropathy does not recommend any agents for the prevention of taxane-induced neuropathy but does provide moderate recommendation for treatment of established neuropathy with duloxetine (251; 155).

Vinca alkaloids: vincristine and vinorelbine. Vincristine is a vinca alkaloid used to treat many cancers, including leukemia, lymphomas, sarcomas, and brain tumors. Its main toxicity is an axonal neuropathy resulting from disruption of the microtubules within axons and interference with axonal transport (126). The neuropathy involves both sensory and motor fibers, although small sensory fibers are especially affected. Virtually all patients have some degree of neuropathy, which is the dose-limiting toxicity (44). The clinical features resemble those of other axonal neuropathies such as diabetic neuropathies. The earliest symptoms are usually paresthesias in the fingertips and feet and muscle cramps. These symptoms may occur after several weeks of treatment, or even after the drug has been discontinued, and progress for several months before improving. Children tend to recover more quickly than adults. Initially, objective sensory findings tend to be relatively minor compared to the symptoms, but loss of ankle reflexes is common. Occasionally there may be profound weakness, with bilateral foot and wrist drop and loss of all sensory modalities. Severe neuropathies are more likely to develop in older patients who are cachectic, patients who have received prior radiation to the peripheral nerves or concomitant hematopoietic colony-stimulating factors (279), and those who have preexisting neurologic conditions such as Charcot-Marie-Tooth (113; 278). The severity of vincristine-related peripheral neuropathy is cumulative, occurring in most patients after a total dose of more than 4 mg/m² (126).

Patients with mild neuropathies can receive full doses of vincristine, but when the neuropathies increase in severity and interfere with neurologic function, reduction in dose or discontinuation of the drug may be necessary. Although symptoms often improve over months after dose reduction or discontinuation of vincristine, the coasting phenomenon can be seen in up to 30% of patients. Vincristine may also cause focal neuropathies (74; 47). Although anecdotal reports indicate that glutamine may help some patients with vincristine neuropathy, there is generally no effective treatment (74). Rarely, vincristine can cause a fulminant neuropathy with severe quadriparesis that mimics Guillain-Barré syndrome (176; 90).

Autonomic neuropathy is common in patients receiving vincristine. Abdominal pain and constipation occur in almost 50% of patients. A paralytic ileus may occur. Because of the known adverse gastrointestinal effects, patients receiving vincristine should take prophylactic stool softeners and laxatives. Less commonly, patients may develop impotence, postural hypotension, and atonic bladders.

Cranial neuropathies may occasionally be seen with vincristine. The most common nerve to be involved is the oculomotor nerve, resulting in ptosis and ophthalmoplegia. Other nerves that may be involved include the recurrent laryngeal nerve, optic nerve, facial nerve, and the auditory vestibular system. Vincristine may also cause retinal damage and night blindness. Some patients may experience jaw and parotid pain.

CNS complications are rare, as vincristine poorly penetrates the blood-brain barrier. Rarely, vincristine may cause the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), resulting in hyponatremia, confusion, and seizures (220). CNS complications unrelated to the syndrome of inappropriate secretion of antidiuretic hormone may also occur. These include seizures, encephalopathy, reversible posterior leukoencephalopathy (193; 98), transient cortical blindness, ataxia, athetosis, and a Parkinson syndrome (101; 47).

The related vinca alkaloids vindesine, vinblastine, and vinorelbine tend to have less frequent neurotoxicity (258). This may be related to differences in lipid solubility, plasma clearance, terminal half-life, and sensitivities of axoplasmic transport (74; 47). Vinorelbine is a semisynthetic analogue of vinblastine that is being increasingly used for patients with breast and lung cancer. Like vincristine, vinorelbine inhibits microtubule assembly but has less affinity for neural tissue and, therefore, was predicted to be less neurotoxic. Vinorelbine use is associated with mild paresthesias in about 20% of patients (228). Severe neuropathy is rare but appears to be more common in patients treated previously with paclitaxel (68; 185).

Drugs that occasionally cause neurotoxicity

Asparaginase. L-asparaginase is used mainly to treat acute lymphocytic leukemia. Direct neurotoxicity with L-asparaginase at conventional doses is rare, as it does not readily cross the blood-brain barrier. However, it may affect coagulation, causing hemorrhagic and thrombotic complications, including sagittal sinus thrombosis and cerebral infarction (121; 69; 66). These complications typically occur after several weeks of treatment. Patients may present with headaches, seizures, and focal neurologic deficits. There may be papilledema as a result of increased intracranial pressure. MRI may show venous infarction, which is often hemorrhagic, and MR venography demonstrates decreased or absent flow in the affected sinus (239; 147). Treatment is controversial, but anticoagulation with heparin is generally recommended. At high doses, asparaginase may also produce a reversible encephalopathy (212). Seizures have been reported as the single manifestation of CNS toxicity (100). The related PEG-asparaginase has a similar neurotoxicity profile to L-asparaginase (92).

Cytosine arabinoside. Cytosine arabinoside (cytarabine, Ara-C) is a pyrimidine analogue used in the treatment of leukemias and lymphomas. Blood-brain barrier penetration is good after intravenous application, and about 50% of plasma Ara-C levels are detected in CSF. High doses (1 to 3 g/m2 every 12 to 24 hours) can cause an acute cerebellar syndrome in 10% to 25% of patients (284; 118; 108). Patients above the age of 40 with abnormal liver or renal function or underlying neurologic dysfunction or who are receiving more than 30 g of the drug are more likely to develop cerebellar toxicity. Typically, the patients develop somnolence and occasionally encephalopathy 2 to 5 days after treatment. Subsequently, patients develop cerebellar signs. These range from mild ataxia to severe truncal ataxia with inability to sit or walk unassisted (10). In addition to cerebellar syndromes, Ara-C may cause seizures.

Although it has been shown that Ara-C is preferentially toxic to cerebellar Purkinje cells and cerebellar granule neurons (284; 64; 45), Ara-C also targets both lineage-committed progenitor cell populations and nondividing oligodendrocytes, which are the myelin-forming cells of the central nervous system (53). Thus, some of the neurotoxic adverse reactions and symptoms seen in patients may, therefore, be a direct consequence of both oligodendrocyte toxicity and impairment of progenitor self-renewal in the CNS.

Neuroimaging studies may show T2/FLAIR hyperintensities, white matter abnormalities, and eventually cerebellar atrophy (52; 285). MR imaging in patients with acute toxicity may demonstrate multifocal T2/FLAIR hyperintensities involving both gray and white matter and may resemble a picture of reversible posterior leukoencephalopathy (233). No specific treatment of acute CNS toxicity is available, but the drug should be discontinued immediately. In some patients, the cerebellar syndrome resolves spontaneously but it is permanent in others. Avoidance of very high doses of the drug, especially in patients with renal impairment, has led to a decline in the incidence of this syndrome (252; 151).

Other neurotoxic adverse effects seen after high-dose cytosine arabinoside include peripheral neuropathies resembling Guillain-Barré syndrome, brachial plexopathy, encephalopathy, lateral rectus palsy, and extrapyramidal syndromes (202; 189; 205; 190; 232; 47).

Intrathecal administration of cytosine arabinoside is used to treat leptomeningeal metastases. It can cause a transverse myelopathy similar to what is seen with intrathecal methotrexate (63; 141). Other rare CNS toxicities include aseptic meningitis, encephalopathy, headaches, posterior leukoencephalopathy, and seizures (105; 47). The incidence of aseptic meningitis may significantly increase after use of a sustained-release preparation of cytosine arabinoside (124), but this formulation is no longer available for commercial use. CNS complications with intrathecal Ara-C may partially be prevented by prophylactic treatment with corticosteroids (87).

Eribulin. Eribulin is a non-taxane microtubule dynamics inhibitor used to treat metastatic breast cancer (91). In clinical trials, peripheral neuropathy has been reported in 30.6% of patients, with 6.6% experiencing severe neuropathy and 4.7% discontinuing eribulin due to this neurotoxicity. Eribulin-related neuropathy has a cumulative effect.

5-Fluorouracil. 5-Fluorouracil is a fluorinated pyrimidine that disrupts DNA synthesis by inhibiting thymidylate synthetase. It is used to treat many cancers, including colon and breast, as well as head and neck cancers.

An acute cerebellar syndrome occurs in approximately 5% of patients (217; 202). This usually begins weeks or months after treatment and is characterized by the acute onset of ataxia, dysmetria, dysarthria, and nystagmus. The drug should be discontinued in any patient who develops a cerebellar syndrome. With time, these symptoms usually resolve. The development of a cerebellar syndrome may be explained partly by the fact that 5-fluorouracil readily crosses the blood-brain barrier. Highest concentrations are found in the cerebellum.

In rare cases, 5-fluorouracil may cause acute and subacute encephalopathies, optic neuropathy, eye movement abnormalities, focal dystonia, cerebrovascular disorders, extrapyramidal syndromes (74; 23), peripheral neuropathy (254), or seizures (203). Patients with decreased dihydropyrimidine dehydrogenase activity are at an increased risk for developing severe neurologic toxicity following 5-fluorouracil (259).

The combination of 5-fluorouracil and levamisole used to treat colon cancer has been rarely associated with the development of an encephalopathy and ataxia resulting from multifocal demyelinating lesions in the periventricular white matter (114). The cause of these lesions is unknown, and they usually improve with steroids and discontinuation of the drugs. A similar syndrome of multifocal leukoencephalopathy has also been reported after capecitabine, a 5-fluorouracil prodrug (183; 273). MRI may show increased signals on FLAIR, T2, and diffusion-weighted imaging sequences in cerebral white matter tracts. The importance of recognizing this syndrome is that the cerebral lesions may be mistaken for brain metastases.

Experimental studies have shed further light on the cell-biological basis of 5-fluorouracil-related short-term and long-term toxicity. 5-fluorouracil appears to be particularly harmful to oligodendrocyte precursor cells, and long-term adverse effects may be explained by a disruption of the integrity of myelinated fiber tracts and delayed demyelination (102).

The administration of 5-fluorouracil with other drugs may increase the incidence of neurotoxicity. For example, the coadministration of 5-fluorouracil with allopurinol, N-phosphonoacetyl-L-aspartate, doxifluridine, carmofur, or tegafur can result in increased incidences of encephalopathies and cerebellar syndromes (74; 186).

Ifosfamide. This is an analog of cyclophosphamide, with similar systemic toxicities. Unlike cyclophosphamide, it is associated with encephalopathy in 20% of patients (169; 292; 207; 02; 29). The encephalopathy begins hours or days after administration of the drug and usually resolves completely after several days. This encephalopathy is thought to result from accumulation of chloroacetaldehyde, one of the breakdown products of ifosfamide. Patients at increased risk for the encephalopathy include those with renal dysfunction, low serum albumin, prior treatment with cisplatin, and previous encephalopathy with ifosfamide (169; 207; 216). There have been reports that methylene blue may be useful in preventing or treating ifosfamide encephalopathy by inhibiting monoamine oxidases (01; 200; 268; 198). For most patients, no specific treatment is necessary, and the encephalopathy usually improves with time. Rarely, ifosfamide can cause seizures, cerebellar ataxia, weakness, cranial nerve dysfunction, neuropathies, or extrapyramidal syndrome (72; 208; 46). Notably, toxicity can be of varying degrees, from mild to transient and even fatal (50).

Nitrosoureas. Nitrosoureas (BCNU, CCNU, PCNU, ACNU) are lipid soluble alkylating agents that rapidly cross the blood-brain barrier and are used to treat brain tumors, melanoma, and lymphoma. These drugs are considered to have little neurotoxicity when used intravenously or orally and at conventional doses, although confusion, lethargy, and ataxia may occur. In contrast, high-dose intravenous BCNU used in the setting of autologous bone marrow transplantation can cause encephalomyelopathy and seizures, which develop over a period of weeks to months after the administration of the drug.

Intraarterial BCNU produces ocular toxicity and neurotoxicity in 30% to 48% of patients (246; 247). It is uncommon to use intraarterial administration of this drug in contemporary times. Intravenous administration or direct intratumoral administration via polymer wafers impregnated with BCNU are far more common. Patients often complain of headache and eye and facial pain. Retinopathy and blindness may occur. The neurotoxicity further includes significant confusion, seizures, and progressive neurologic deficits. Imaging and pathologic studies show findings similar to radiation necrosis confined to the vascular territory perfused by the BCNU (47). Concurrent radiotherapy increases the neurotoxicity of intraarterial BCNU (226). Injection of the drug above the origin of the ophthalmic artery reduces the incidence of ocular toxicity but increases neurotoxicity. Although the detailed pathophysiology of nitrosourea-associated CNS toxicity is poorly understood, BCNU appears to be directly toxic to oligodendrocytes and neural progenitor cells. Even exposure to sublethal doses significantly impairs key progenitor cell functions of proliferation and differentiation. In animal models, repetitive exposure was associated with long-term impairment of proliferation in the germinal zones of the CNS (53). Consequently, it has been suggested that toxicity to progenitor cells and oligodendrocytes constitutes the main cellular basis for CNS toxicity, including leukoencephalopathy and cognitive impairment (53; 62).

Procarbazine. Procarbazine is a weak monoamine oxidase inhibitor that probably acts as an alkylating agent. It is used to treat lung carcinoma, lymphoma, and brain tumors. At normal oral doses it can cause a mild reversible encephalopathy and neuropathy, and rarely psychosis and stupor (74; 47). The incidence of encephalopathy may be increased in patients receiving “high-dose” procarbazine, CCNU, and vincristine chemotherapy for malignant gliomas (206). Procarbazine also potentiates the sedative effects of narcotics, phenothiazines, and barbiturates. Intravenous and intracarotid procarbazine can produce a severe form of encephalopathy.

Thalidomide. Thalidomide is a sedative and hypnotic agent, which was initially introduced in Europe in 1954, but was withdrawn in 1961 due to the high incidence of limb malformations in children of women exposed to the drug. Thalidomide also exhibits immunomodulatory and antiangiogenic mechanisms. The FDA approved thalidomide for the treatment of multiple myeloma in 2006. The most common side effect is a sensory (often painful) peripheral neuropathy, which develops in approximately 75% of patients who receive a prolonged course of thalidomide (35; 122; 265; 174; 204; 135). This may improve slightly with discontinuation of the medication, although recovery is often slow and incomplete. Another common side effect is somnolence, affecting 43% to 55% of patients. Many patients develop tachyphylaxis to this side effect with decreased somnolence after 2 or 3 weeks. Lenalidomide is an analog of thalidomide and is associated with a lower incidence of peripheral neuropathy (166).

Drugs that rarely cause neurotoxicity

Anthracycline antibiotics (doxorubicin, daunorubicin, idarubicin, mitoxantrone). Doxorubicin is an anthracycline antibiotic used to treat a variety of cancers including hematologic malignancies and breast cancer. It can cause arrhythmias and cardiomyopathies, which in turn can result in cerebrovascular complications (238). Doxorubicin in combination with cyclosporine can lead to coma and death (195). Apart from accidental intrathecal injection, which can cause severe myelopathy and encephalopathy, these agents have little overall neurotoxicity (47). Idarubicin and daunorubicin appear to be much less neurotoxic than doxorubicin, and nervous system toxicity may only be seen after high-dose applications or when administered in combination with other neurotoxic agents. Mitoxantrone has no known neurotoxicity when given intravenously but may produce a radiculopathy and myelopathy when given intrathecally (99).

Bleomycin sulfate. Bleomycin inhibits DNA synthesis by binding to guanosine and cytosine through intercalation mechanisms as well as by cleaving DNA strands via free radical production. It is used to treat lymphoma, Hodgkin disease, testicular cancer, and head and neck cancer. When used in combination with cisplatin, it can produce cerebral infarction (59; 54).

Busulfan. This is an alkylating agent used in patients with leukemia. It has little neurotoxicity at standard doses, but high-dose therapy can cause seizures (270; 142).

Capecitabine. This is metabolized to its cytotoxic form, 5-FU, by the enzyme thymidine phosphorylase and is used to treat breast and gastrointestinal malignancies. Neurologic complications are uncommon, but some patients experience paresthesias, headaches, and cerebellar symptoms. Several cases of neuropathies have been described (231). There have also been case reports of capecitabine-induced multifocal leukoencephalopathy (183; 273). Capecitabine leukoencephalopathy has an earlier onset than 5-FU leukoencephalopathy, and the MRI changes are nonenhancing (273). Delayed leukoencephalopathy with stroke-like presentation has been described following capecitabine exposure (08).

Carboplatin. Carboplatin is an alkylating agent used for ovarian, cervical, testicular, lung, and head and neck cancers. Unlike cisplatin, peripheral neuropathy and CNS toxicity occur only rarely at conventional doses. However, a severe neuropathy can develop after high-dose carboplatin (104). Intraarterial carboplatin may produce stroke-like syndromes (276) and retinal toxicity (256). Carboplatin may be associated with peripheral nervous system toxicity, including ototoxicity and neuropathy. Toxicity may present as a pure sensory and painful neuropathy, as also seen with cisplatin and oxaliplatin (210). Neurotoxicity depends on the total cumulative dose and other predisposing factors, such as diabetes mellitus, alcohol use, or inherited neuropathy. Overall, carboplatin-associated neuropathy is considered much less frequent than cisplatin-associated neuropathy.

2-chlordeoxyadenosine (cladribine). This drug inhibits DNA polymerase and ligase and ribonucleotide reductase, resulting in DNA strand breakage. It is used for hairy cell leukemia, low-grade non-Hodgkin lymphoma, chronic myelogenous leukemia, and Waldenstrom macroglobulinemia. It has little neurotoxicity at conventional doses but can produce headache, dizziness, and paraparesis at high doses (36).

Chlorambucil. Chlorambucil is an alkylating agent used to treat chronic lymphocytic leukemia, low-grade non-Hodgkin lymphomas, Hodgkin disease, ovarian cancer, Waldenstrom macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and nephrotic syndrome. It usually has little neurotoxicity at lower doses but can cause encephalopathy, myoclonus (289), and seizures when taken in very high doses (234).

Etoposide. This is a topoisomerase-II inhibitor used in the treatment of lung cancer, germ cell tumors, and refractory lymphoma. It is generally well tolerated, even at high doses. Rarely, it can cause a peripheral neuropathy, mild disorientation, seizures, transient cortical blindness, or optic neuritis (74).

Fludarabine. Fludarabine is an inhibitor of DNA polymerase and ribonucleotide reductase. It is used to treat chronic lymphatic leukemia, macroglobulinemia, and indolent lymphomas. It has been increasingly used in recent years as part of a lymphodepleting regimen prior to CAR-T cell therapy (159). Neurotoxicity is uncommon, but fludarabine can cause headaches, somnolence, confusion, and paresthesias at low doses (39; 47), and a delayed progressive encephalopathy with seizures, visual loss, paralysis, and coma at high doses (277). There have been some reports about severe leukoencephalopathy following fludarabine with lethal outcome (221; 172; 286). Fludarabine may increase the risk of JC virus associated multifocal leukoencephalopathy (236; 272; 133). Cladribine (2-chlordeoxyadenosine), a related drug used for Waldenstrom macroglobulinemia, can produce paraparesis at high doses (195).

Cyclophosphamide. Cyclophosphamide at standard doses has little neurotoxicity. High-dose cyclophosphamide may produce reversible visual blurring, dizziness, and confusion (47). Its metabolite, 4-hydroperoxy-cyclophosphamide, has been used experimentally as intrathecal therapy for leptomeningeal metastases. At high doses it can cause lethargy and seizures (202). Rarely, a reversible posterior leukoencephalopathy syndrome (98) or a necrotizing leukoencephalopathy syndrome, which can be fatal, have been reported following the cyclophosphamide-containing CHOP regimen for non-Hodgkin lymphoma (31; 19).

Dacarbazine. Dacarbazine mainly is used to treat melanoma. Neurotoxicity is very rare, but seizures, encephalopathy, and dementia have been reported (199).

Estramustine. Estramustine has estrogenic effects and causes dissociative effects on microtubules leading to metaphase arrest. It is used to treat advanced prostate carcinoma. It has been associated with headaches and stroke (36; 195). Another study estimates a relatively high rate of thromboembolic events, including strokes, in up to 25% of patients, which appears to be a dose-independent side effect (161).

Gemcitabine. This is a deoxycytidine analogue used for the treatment of pancreatic cancer, but it also has activity against other tumors, including breast cancer and small cell lung cancer. Neurotoxicity is uncommon, but up to 10% of patients experience mild paresthesias, and, rarely, more severe peripheral and autonomic neuropathies (60). Administration of gemcitabine after radiation therapy for brain metastases may increase the risk of neurotoxicity (125).

Hydroxyurea. This is an antimetabolite used to treat chronic myelogenous leukemia and certain solid tumors, including melanoma, ovarian carcinoma, trophoblastic neoplasms, and meningiomas as well as cervical, head and neck, and prostate cancers. Rarely, it causes headaches, drowsiness, hallucinations, confusion, and seizures (47).

Irinotecan. This is a topoisomerase inhibitor used to treat cancer of the colon, lung, and skin. It also has been used in combination with bevacizumab in patients with malignant glioma. Severe neurologic toxicity has not been observed, but some patients experience transient visual disturbances and symptoms suggestive of cholinergic overactivity (195). In combination with other chemotherapeutic agents, such as 5-fluorouracil, neurotoxicity has been reported and may present in these patients as posterior reversible leukoencephalopathy (04; 95; 194).

Levamisole. Levamisole is an immune-enhancer that is used in combination with 5-fluorouracil for patients with colon cancer. A metabolite, p-hydroxy-tetramisole, may enhance 5-fluorouracil activity by inhibiting tyrosine phosphatase. When used in combination with 5-fluorouracil, it can cause a multifocal leukoencephalopathy (114; 134; 237). Rarely, levamisole may cause headache, insomnia, dizziness, seizures, or aseptic meningitis when used as a single agent.

Mechlorethamine (nitrogen mustard). This alkylating agent is used to treat Hodgkin lymphoma and malignant pleural effusions. Rarely, it causes somnolence, headaches, vertigo, hearing loss, and weakness. When used at high doses for bone marrow transplantation, confusion may occur (47).

Mitomycin C. This is an alkylating agent used to treat carcinomas of the gastrointestinal tract, breast cancer, and head and neck malignancies. It has been associated with an encephalopathy caused by thrombotic microangiopathy (59).

Nelarabine. Nelarabine is a cytotoxic deoxyguanosine analogue prodrug approved for treatment of pediatric and adult patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Neurologic complications were observed in 76% of adult subjects treated on phase I and II clinical trials (180). Most were mild to moderate (grade 1 to 2), including headache, somnolence, neuropathy, and sensory deficits. However, grade 3, grade 4, and grade 5 (fatal) neurologic events were observed in 19% of patients, including cranial neuropathies (oculomotor and abducens nerve palsies), progressive multifocal leukoencephalopathy, peripheral demyelination similar to Guillain-Barré syndrome, cerebral and intracranial hemorrhage, coma, status epilepticus, demyelination, and metabolic encephalopathy (139; 219; 180). The median time to onset of the first neurologic event was 5 days from first infusion (180). Because of these uncommon but severe toxicities, the prescribing information insert on nelarabine contains a black box warning recommending discontinuation for grade 2 or higher neurologic adverse reaction (180).

Pentostatin. This adenosine deaminase inhibitor is used for the treatment of a variety of leukemias, including hairy cell leukemia. At low doses, lethargy is a common neurotoxic side effect, whereas higher doses can cause encephalopathy, seizures, and coma (39; 195).

Retinoic acid. All-transretinoic acid and 13-cis-retinoic acid are vitamin A derivatives that are so-called differentiation agents with activity against several solid tumors and hematologic malignancies. It has mostly been used to treat promyelocytic leukemia. Retinoic acid frequently causes headaches (09). Rarely, it can cause pseudotumor cerebri (243) and multiple mononeuropathies (290). It may also be associated with depression and increased risk of suicide.

Temozolomide. This oral alkylating agent plays a central role in the treatment of gliomas and melanoma and has been investigated for treatment of numerous other malignancies. Approximately 40% of patients receiving the drug experience headaches, although serious neurologic complications are rare (291). It is possible that these headaches are primarily due to the primary disease being treated (glioma) and less likely due to the temozolomide.

Teniposide. This is a topoisomerase inhibitor used for acute lymphoblastic leukemia, Kaposi sarcoma, and cutaneous T-cell lymphoma. It has rarely been associated with paresthesias, fatigue, somnolence, and seizures. It can, however, enhance vincristine-induced neuropathy when used in combination (264; 120).

Thioguanine. This purine antimetabolite is used to treat leukemia and brain tumors. Rarely, it causes loss of vibratory sense, encephalopathy, and ataxia, likely secondary to hepatic toxicity.

Thiotepa. This is an alkylating agent occasionally used to treat leptomeningeal metastases. Rarely, intrathecal thiotepa causes a myelopathy (97). High intravenous doses of thiotepa can produce encephalopathy that can be fatal (252; 195).

Topotecan. This is a topoisomerase inhibitor mostly used in the treatment of ovarian cancer. It can occasionally cause headaches and paresthesias (26).

Hormonal therapy

Aromatase inhibitors (anastrozole, exemestane, and letrozole). These selective aromatase inhibitors are used in the treatment in postmenopausal women with hormone receptor-positive breast cancer. Headaches occur in about 10% of patients treated with aromatase inhibitors. Anastrozole is also uncommonly associated with carpal tunnel syndrome, with most cases reported as mild to moderate in intensity and occurring within 18 months of treatment initiation (244).

Corticosteroids. Corticosteroids are frequently used in cancer patients for a variety of reasons. They reduce peritumoral edema in patients with primary and secondary brain tumors and spinal cord edema in patients with epidural spinal cord compression. Corticosteroids have a direct cytotoxic effect against neoplastic lymphocytes and are used in the treatment of leukemias and lymphomas. High-dose corticosteroids are frequently given with chemotherapy to reduce nausea and vomiting, whereas low doses are used to improve appetite and sense of well-being in some cancer patients.

The side effects of prolonged steroid therapy are well known (271; 56). The incidence of complications increases with higher doses and prolonged therapy, but individual susceptibility varies significantly.

Systemic side effects include a Cushingoid appearance, truncal obesity, hirsutism, acne, impaired wound healing, striae, easy bruising and capillary fragility, immunosuppression, hypertension, glucose intolerance, electrolyte disturbance, fluid retention, peripheral edema, increased appetite, gastrointestinal bleeding, osteoporosis, avascular necrosis, growth retardation, cataracts, glaucoma, and visual blurring.

The neurologic complications of corticosteroids are summarized in Table 2.

Table 2. Neurologic Complications of Corticosteroids

The most common complication is steroid myopathy (61; 65). Steroid-induced myopathy is characterized by weakness of the proximal muscles affecting primarily the hip girdle. Patients typically complain of difficulty getting up from a chair or climbing stairs. In severe cases, the pectoral girdle and neck muscles may also be involved. Steroid myopathy tends to occur after prolonged use of high doses of steroids, but there is significant variation in patient susceptibility, and some patients develop a myopathy after using low doses of steroids for only a short period. Creatine kinase levels are usually not elevated.

Corticosteroids often produce alterations in mood. An improved sense of well-being, anxiety, irritability, insomnia, difficulty concentrating, and depression are all relatively common. Occasionally, patients may develop steroid psychosis. This usually takes the form of acute delirium, but the psychosis may resemble mania, depression, or schizophrenia.

Other common neurologic complications of corticosteroids include tremors, visual blurring, reduced sense of taste and smell, and cerebral atrophy on neuroimaging studies. Rare complications include hiccups, dementia, seizures, and cord compression as a result of epidural lipomatosis (196).

Steroid withdrawal can also produce a variety of symptoms, which can be quite disabling. These include headaches, lethargy, nausea, vomiting, anorexia, myalgia and arthralgia (pseudo-rheumatism), fever, abdominal pain, postural hypotension, pseudotumor, and panniculitis.

Enzalutamide. Enzalutamide is an androgen receptor inhibitor used to treat metastatic castration-resistant prostate cancer. Clinical trials reported seizures in as many as 2% of patients treated with enzalutamide at doses greater than 360 mg/day and less than 1% at a dose of 160 mg/day (250). In a prospective, international, multicenter, post-approval study of 366 patients treated with enzalutamide 160 mg/day with at least one known risk factor for seizure at baseline (including use of a concomitant medication that lowered the seizure threshold, history of brain injury, or history of stroke or TIA), 1.1% had at least one confirmed seizure within 4 months of enzalutamide initiation (250).

Goserelin. This is an analogue of luteinizing hormone-releasing hormone used to treat prostate and breast cancer. When the drug is first used it can produce a tumor flare, resulting in bone pain and potentially exacerbating cord compression.

Leuprolide acetate. This is a gonadotropin-releasing hormone analogue used to treat prostate cancer and refractory breast cancer. Neurologic complications are uncommon, but it can cause headaches, dizziness, and paresthesias.

Mitotane (OP'-DDD). This drug, which suppresses adrenocorticosteroid production and is cytotoxic to adrenal cortical cells, is used to treat adrenocortical carcinoma. It produces lethargy, sedation, and dizziness in 40% of patients (144).

Octreotide. This is a long-acting analogue of somatostatin used to treat carcinoid tumors, vasoactive intestinal peptide-secreting tumors, and certain pituitary adenomas. It can cause headaches, dizziness, and rarely seizures.

Tamoxifen. This is a selective estrogen receptor modulator antiestrogen used to treat estrogen receptor-positive breast cancer. It can produce retinopathy, encephalopathy, and ataxia, especially when used in high doses (47). Tamoxifen-related toxicities include irritability, confusion, and ocular toxicities (14). Cognitive adverse effects have been reported (241).

Toremifene citrate. Toremifene citrate is an antiestrogen used to treat breast cancer. Neurologic complications are uncommon, but patients may experience dizziness, depression, tremor, blurred vision, and ataxia (83).

Biological response modifiers

Alpha interferon. This agent is occasionally used in hairy cell leukemia, Kaposi sarcoma, melanoma, and myeloma. Systemic toxicities include flu-like symptoms and myelosuppression. Flu-like symptoms tend to be worse at the onset of therapy and usually improve with time. Neurotoxicity tends to be dose dependent. It is generally mild when low doses of alpha-interferon are used as adjuvant therapy in patients with malignant melanoma (32). At higher doses, alpha-interferon can cause headaches, confusion, lethargy, hallucinations, and seizures (222; 170; 171). These are usually reversible, but occasionally a permanent dementia or a persistent vegetative state may result (170; 171). Rarely, alpha interferon has been associated with oculomotor palsy, sensorimotor neuropathy (230), myasthenia gravis (22), brachial plexopathy, and polyradiculopathy (48).

A high incidence of neuropsychiatric toxicity has been noted in patients treated with recombinant interferon alpha-2b. In a study of 91 patients with chronic myelogenous leukemia, one quarter experienced grade 3 or 4 neuropsychiatric toxicity that affected daily functioning. All patients recovered on withdrawal of interferon alpha-2b. Patients with a psychiatric history were more likely to develop severe neuropsychiatric toxicity than patients without a psychiatric history (106).

Interleukin-2 (IL-2). IL-2 has been used alone and in combination with lymphokine-activated killer cells and tumor-infiltrating lymphocytes in the treatment of a number of cancers, especially renal cell carcinoma and melanoma. Neuropsychiatric complications occur in 30% to 50% of patients (49). These include cognitive changes, delusions, hallucinations, and depression. In addition, there have been reports of transient focal neurologic deficits (15), acute leukoencephalopathy, carpal tunnel syndrome, and brachial neuritis (154). Administration of IL-2 directly into the tumor bed for the treatment of gliomas can cause significant cerebral edema (12).

One case of grade 5 neurotoxicity has been reported in a patient treated with IL-2 in combination with granulocyte-macrophage-colony stimulating factor. This patient experienced a fatal cerebral hemorrhage associated with thrombocytopenia, leading the authors to recommend extreme caution in using these agents together (116).

Growth factors

Colony-stimulating factors (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor). Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are used to increase the granulocyte and neutrophil cell counts and reduce the incidence of infections in patients with non-myeloid tumors receiving chemotherapy. Musculoskeletal symptoms such as cramps and bone pain occur commonly. Rarely, they cause fatigue and headaches. Other rare adverse reactions include confusion (218) and reversible posterior leukoencephalopathy (149).

Erythropoietin. This is used to stimulate red cell production. Some patients may experience fatigue, dizziness, and paresthesias, but serious neurologic complications have not been described. With long-term administration, erythropoietin has rarely been associated with hypertensive encephalopathy and seizures.

Oprelvekin. This is a recombinant platelet growth factor used to prevent severe chemotherapy-induced thrombocytopenia and for platelet transfusion following myelosuppressive chemotherapy. Neurologic complications are uncommon, but some patients complain of headaches, dizziness, insomnia, and paresthesias.

Monoclonal antibodies

Bevacizumab. This is a monoclonal antibody directed against vascular endothelial growth factor. It is used in patients with colorectal, breast, non-small cell lung cancer, and malignant glioma. There have been reports of syncope, hypertension, cerebral thrombosis and hemorrhage, and reversible posterior leukoencephalopathy (88; 192; 55; 225; 263). Rarely, severe optic neuropathy has been reported in patients with brain tumors after bevacizumab treatment (248). Patients with brain metastases were often excluded from clinical trials of VEGF/VEGFR inhibitors due to the concern for intratumoral hemorrhage. However, subsequent studies of anti-VEGF therapy found relatively low rates of intracranial hemorrhage, even in the presence of CNS metastases (33; 223). The incidence of arterial thromboembolic events including strokes is slightly elevated in patients treated with bevacizumab (38). Approximately 1.8% to 1.9% of patients with glioblastoma treated with bevacizumab will have an ischemic stroke (75; 242).

Blinatumomab. This is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia, and minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia. In a phase 2 clinical trial of 189 patients with Ph- ALL (255), 52% of patients experienced a neurologic adverse event, such as dizziness, tremor, confusional state, or encephalopathy. Most neurologic events occurred during the first cycle, were mild in severity, and resolved with treatment interruption and after use of dexamethasone.

Brentuximab vedotin. This is an antibody-drug conjugate targeting CD30 and is used in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Peripheral neuropathy (24% any grade, 6% grade 3 or 4) is the most common treatment-emergent, nonhematologic adverse event reported, sometimes requiring treatment discontinuation (294). Rarely, progressive multifocal leukoencephalopathy has been reported in patients who received brentuximab vendotin (34).

Cetuximab. This chimeric mouse-human antibody targeted against epidermal growth factor is FDA approved for head and neck cancer as well as colorectal cancer. Cases of aseptic meningitis (70) and chronic immune-mediated demyelinating polyneuropathy (16) have been reported in association with cetuximab. Patients may also develop decrease in magnesium levels, causing severe fatigue, cramps, and somnolence (261).

Gemtuzumab ozogamicin. Gemtuzumab ozogamicin is an antibody targeted chemotherapeutic agent used in patients with CD33+ acute myelogenous leukemia. It can cause headaches and dizziness. Severe thrombocytopenia is common and may result in intracranial hemorrhage.

Ibritumomab tiuxetan. This is a radiopharmaceutical that is used for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma. It is a combination of monoclonal antibody ibritumomab bound to tiuxetan (chelated to Y-90 and In-111) and directed against the CD20 antigen on lymphoma cells. Neurologic side effects include headaches (12%), dizziness (10%), back pain (8%), insomnia (5%), and encephalopathy (less than 1%) (288).

Iodine-131 tositumomab. This is a radiolabeled immunoglobulin G-2a murine monoclonal antibody directed against the CD20 antigen. In addition to the cytotoxic effects induced by the antibody, the presence of iodine-131 results in focused targeting of beta radiation to the tumor and surrounding tissue. To date, it has been primarily used to treat relapsed or refractory non-Hodgkin lymphoma. Iodine-131 tositumomab is well-tolerated. A minority of patients experience headache or myalgia, and a few develop hypothyroidism (127; 274).

Rituximab. Rituximab is a genetically engineered chimeric murine and human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. It is used for the treatment of low-grade or follicular B-cell lymphoma. Neurologic complications are uncommon, but some patients complain of headaches, myalgia, dizziness (164), or paresthesias (73). There may be an increased risk for patients treated with rituximab to develop progressive multifocal leukoencephalopathy, with a reported incidence of 1 per 32,000 in HIV-negative patients (20).

Trastuzumab and ado-trastuzumab emtansine. Trastuzumab is a humanized anti-p185(HER2) monoclonal antibody used alone or in combination with chemotherapeutic agents in patients with HER/neu-overexpressing metastatic breast cancer (245). Rarely, patients will experience headaches, dizziness, and insomnia after infusion of the antibody (42).

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate containing trastuzumab and the microtubule inhibitor DM1 and is also used in the treatment of advanced HER/neu-overexpressing breast cancer. In a randomized clinical trial, 2% of patients in the T-DM1 group experienced grade 3 peripheral neuropathy compared to 0.2% in the lapatinib plus capecitabine group (51). T-DM1 may increase the risk of clinically significant radiation necrosis and cerebral edema in brain metastases treated with stereotactic radiosurgery (257), although further data are needed from ongoing clinical trials of T-DM1 to support these findings.

Targeted molecular agents

Bortezomib. This is a proteosome inhibitor used in the treatment of patients with multiple myeloma. A subacute sensory, and often painful, axonal neuropathy occurs in approximately 35% of patients and results in dose reduction in 12% (214). Autonomic dysfunction may occur, but motor fibers are rarely affected (126). The risk of bortezomib-induced peripheral neuropathy is increased in patients with a preexisting neuropathy. Nerve conduction studies may be normal, as small fibers are preferentially affected. Treatment discontinuation or dose modification leads to improvement in most patients (214; 215). A dose adjusted algorithm is available for patients who develop bortezomib-related neuropathy (www.accessdata.fda.gov/drugsatfda_docs/label/2008/021602s015lbl.pdf).

Ibrutinib. Ibrutinib is a first-in-class oral irreversible inhibitor of Bruton tyrosine kinase (BTK) used in the treatment of a variety of B cell malignancies including mantel cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Although direct neurologic toxicities are uncommon, ibrutinib and other Bruton tyrosine kinase inhibitors can increase the risk of invasive fungal infections, including CNS aspergillosis (37; 148).

Imatinib mesylate. Imatinib is a protein tyrosine kinase inhibitor of the BCR-Abl oncogene and c-kit used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Neurologic side effects are usually mild and may include headache and fatigue (43). Rarely, cerebral edema and encephalopathy may occur.

Ivosidenib. This inhibitor of isocitrate dehydrogenase 1 (IDH1) is approved for use in adults with acute myeloid leukemia (AML). Based on a safety assessment of 258 patients treated with ivosidenib, two patients (less than 1%) developed Guillain-Barre syndrome (123).

Larotrectinib. This oral TRK inhibitor is used in the treatment of adult and pediatric solid tumors with neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a rare driver of cancers. Among 176 patients treated with larotrectinib on trial, 53% experienced neurologic adverse reactions of any grade, including 6% grade 3 and 0.6% grade 4 (146; 160). The most common neurologic toxicities included delirium, dysarthria, dizziness, gait disturbance, and paresthesias.

Lorlatinib. Lorlatinib is an inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 with blood-brain barrier penetration and is used in the treatment of ALK-positive metastatic non-small cell lung cancer. Peripheral neuropathy was reported in 47% of patients, but most cases were mild and reversible with dose modifications or standard medical therapy (157; 13). In clinical trials, a variety of CNS toxicities occurred in 54% of patients receiving lorlatinib, including changes in cognitive function, mood, and speech (157; 13). Of those patients who experienced such CNS side effects, 71.8% had CNS metastases at baseline. Most toxicities were mild, intermittent, and improved or resolved with dose modifications.

Sorafenib. This is a multikinase inhibitor, with activity against CRAF, BRAF and mutant BRAF receptors, and extracellular KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFR-B receptors. It has been approved for renal cancer, hepatocellular carcinoma, and thyroid cancer. Rarely has it been associated with peripheral neuropathies. Similar to bevacizumab, sorafenib is associated with a slightly increased incidence of arterial thromboembolic events including strokes (38).

Sunitinib. This molecularly targeted agent inhibits multiple tyrosine receptor kinases, including PDGFR, KIT, and VEGFR. It is approved for advanced renal cancer and gastrointestinal stromal tumor. Sunitinib has been reported to induce reversible cognitive disorder characterized by confusion, hallucinations, and extrapyramidal symptoms (240).

Tipifarnib. This is a methyl-quinolone, which is a selective inhibitor of farnesyl transferase. It is currently being evaluated in phase II and III trials in a variety of cancers. It can cause a peripheral neuropathy. CNS complications are uncommon, but some patients experience lethargy, confusion, ataxia, photophobia, and neuropathy (128; 211).

Immunotherapy

Chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy, a patient’s own T lymphocytes are genetically modified ex vivo to attack specific proteins, expanded in a production facility, and infused back into the patient (27). Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy approved for the treatment pediatric B-cell precursor acute lymphoblastic leukemia (ALL), whereas axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy approved for use in relapsed or refractory diffuse large B cell lymphoma. Several other CAR-T cell therapies are currently being evaluated in clinical trials, including for hematological malignancies and solid cancers. By the end of 2022, six CAR-T cell products targeting either CD19 or BCMA were FDA approved (Axicabtagene ciloleucel, Tisagenlecleucel, Brexucabtagene autoleucel, Ciltacabtagene autoleucel, Idecabtagene vicleucel and Lisocabtagene maraleucel).

A cytokine release syndrome (CRS) is the most common toxicity associated with CAR T cell therapies, which is characterized by a systemic inflammatory response and can lead to widespread reversible organ dysfunction. Treatment includes aggressive supportive care, including management of hypotension and any concurrent infections, as well as consideration of interleukin-6 receptor blockade with tocilizumab (27; 167).

Neurologic toxicities have been reported with anti-CD19 CAR T cells at high frequency in up to 80% of patients and with varying manifestations, including headache, confusion, somnolence, hallucinations, dysphasia, ataxia, apraxia, facial nerve palsy, tremor, dysmetria, and seizures (96; 235; 27; 129; 52). Deaths related to cerebral edema have been reported in a small number of patients. These neurologic symptoms mostly occur in the setting of CRS but have also been reported in patients without CRS, suggesting a differential pathogenesis (167). The manifestations can be severe, sometimes necessitating intubation and ventilation for airway protection. In patients treated with CAR-T cells for CNS malignancies, a distinct syndrome of “tumor inflammation-associated neurotoxicity” may occur and can be life-threatening as a result of increased intracranial pressure and brain herniation (163). Retrospective reviews suggest increased risk of neurotoxicity in young patients, patients with B-ALL, higher tumor burden, presence of CD19+ cells in the bone marrow, high CAR-T cell dose, pre-existing neurologic comorbidity, higher peak CAR-T cell expansion, and early and higher elevations of proinflammatory cytokines in blood (96; 235; 129; 80). Limited experience suggests that tocilizumab may not ameliorate neurologic toxicity. Instead, supportive care, symptomatic management (ie, seizure medications for patients experiencing seizures), and corticosteroids are recommended for severe neurologic toxicities (179; 167).

Ipilimumab. Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that inhibits the immune system, and is approved for use in unresectable or metastatic melanoma. The incidence of neurologic complications is low, less than 4% with ipilimumab alone and 12% with combination ipilimumab and anti-PD1 therapy (209). Common neurologic symptoms include headache, although most cases are mild (115). Immune-related neurologic complications have rarely been described, including inflammatory myopathy (117), aseptic meningitis, posterior reversible encephalopathy syndrome (260), Guillain-Barre syndrome (282), inflammatory enteric neuropathy (17), a myasthenia gravis-like syndrome, chronic inflammatory demyelinating polyneuropathy, transverse myelitis (150), and a meningo-radiculo-neuritis (115). Autoimmune encephalitis has also been reported in patients treated with combined ipilimumab and nivolumab (283). Immunotherapy-related neurologic complications are a diagnosis of exclusion (287). Therefore, diagnostic evaluation is often aimed at ruling out other causes (such as hypophysitis, infectious etiologies, metastatic disease, strokes, seizures, paraneoplastic disorders, and toxic-metabolic derangements) (145; 94). Management of neurologic toxicities involves prompt recognition and intervention. For moderate to severe toxicities, cessation of immunotherapy and corticosteroids may be indicated (145; 209). The National Comprehensive Cancer Network (NCCN) provides guidelines for management of immunotherapy-related toxicities (178).

PD-1 inhibitors (cemiplimab, nivolumab, and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab). Cemiplimab, nivolumab, and pembrolizumab are programmed death 1 (PD-1) immune checkpoint inhibitor antibodies, whereas atezolizumab, avelumab and durvalumab are anti-programmed death ligand 1 (PD-L-1) antibodies. These agents are collectively approved for use in non-small cell lung cancer, head and neck cancer, colorectal cancer, urothelial cancer, hepatocellular carcinoma, and melanoma. The incidence of neurologic complications is low, 6% with anti-PD1 therapy alone and 12% with combination ipilimumab and anti-PD1 therapy (209). Neurologic complications similar to ipilimumab have been described with anti-PD1 therapy, including cases of Guillain-Barre syndrome, myasthenia gravis, facial and abducens nerve paresis, demyelination, and acute encephalitis (115; 131; 145; 287; 229). Also similar to ipilimumab, management of neurologic toxicities may include diagnostic evaluation for other causes, cessation of immunotherapy, or corticosteroids (145; 209). The NCCN provides guidelines for management of immunotherapy-related toxicities (178).

Other agents

Amifostine. This is a thiophosphate cytoprotectant agent that is used to reduce renal toxicity associated with cisplatin. There is also evidence that it may reduce the neurotoxicity of many chemotherapeutic agents, including cisplatin (58), carboplatin, and paclitaxel (158), but there are conflicting reports (188). Neurologic complications are uncommon but amifostine may cause hypotension and lead to syncope. There have been rare reports of seizures.

Bisphosphonates: pamidronate and zoledronic acid. These are used to treat hypercalcemia and bony metastases. Approximately 2% of patients experience insomnia, sleepiness, or abnormal vision.

Denileukin diftitox. Denileukin diftitox is a fusion toxin used to treat cutaneous T-cell lymphoma expressing the CD25 component for the IL-2 receptor. The most common complication is a vascular leak syndrome, but some patients experience myalgias, dizziness, paresthesias, nervousness, confusion, and insomnia (187; 05).