Neurologic complications of chemotherapy - Alzheimer's ...

Neurologic complications of chemotherapy

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

  The neurologic complications of the more commonly used chemotherapeutic agents, hormones, biological response modifiers, and targeted molecular agents in cancer patients will be discussed. This topic is reviewed in greater detail in a number of reviews (Forsyth and Cascino 1995; Posner 1995; Gilbert 1998; Hammack and Cascino 1998; Keime-Guibert et al 1998; Paleologos 1998; Postma et al 1998; Windebank 1999; Wen 2001; Collins and Amato 2002; Briemberg and Amato 2003; Plotkin and Wen 2003; Verstappen et al 2003).


Dietrich J, Wen PY. Neurologic complications of chemotherapy.

Former author(s)
Santosh Kesari and Jeanine Grier
 
Last reviewed
May 25, 2009
 
ICD codes
ICD-9:
Leukoencephalopathy: 323.9
Myelopathy: 336.9
Epilepsy: 345
Inflammatory and toxic neuropathy: 357
Alteration of consciousness: 780.0
Headache: 784.0
 
ICD-10:
Encephalitis, myelitis and encephalomyelitis, unspecified: G04.9
Myelopathy NOS: G95.9
Generalized idiopathic epilepsy and epileptic syndromes: G40.3
Inflammatory polyneuropathy: G61
Unconsciousness NOS: R40.2
Headache: R51
 

INTRODUCTION


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

  The neurologic complications of the more commonly used chemotherapeutic agents, hormones, biological response modifiers, and targeted molecular agents in cancer patients will be discussed. This topic is reviewed in greater detail in a number of reviews (Forsyth and Cascino 1995; Posner 1995; Gilbert 1998; Hammack and Cascino 1998; Keime-Guibert et al 1998; Paleologos 1998; Postma et al 1998; Windebank 1999; Wen 2001; Collins and Amato 2002; Briemberg and Amato 2003; Plotkin and Wen 2003; Verstappen et al 2003).

  The neurologic complications of the most common chemotherapeutic drugs are summarized in Table 1.
 
Table 1. Neurologic Complications of Chemotherapy
 
Acute encephalopathy
• Asparaginase
• 5-Azacytidine
• BCNU
• Chlorambucil
• Cisplatin
• Corticosteroids
• Cyclophosphamide
• Cytosine arabinoside
• Dacarbazine
• Doxorubicin
• Etoposide
• Fludarabine
• 5-Fluorouracil
• Gemcitabine
• Hexamethylmelamine
• Hydroxyurea
• Ibritumomab
• Ifosfamide
• Imatinib
• Interferons
• Interleukins 1 and 2
• Mechlorethamine
• Methotrexate
• Misonidazole
• Mitomycin C
• Nelarabine
• Paclitaxel
• Pentostatin
• Procarbazine
• Suramin
• Tamoxifen
• Thalidomide
• Thiotepa
• Tumor necrosis factor
• Vinca alkaloids
• Zarnestra
 
Dementia
• BCNU
• Carmofur
• Cisplatin
• Corticosteroids
• Cytosine arabinoside
• Dacarbazine
• Fludarabine
• 5-Fluorouracil
• Interferon
• Levamisole
• Methotrexate
 
Cranial neuropathy
• BCNU
• Cisplatin
• Cytosine arabinoside
• Ifosfamide
• Methotrexate
• Nelarabine
• Vincristine
 
Acute cerebellar syndrome
• Cytosine arabinoside
• 5-Fluorouracil
• Hexamethylmelamine
• Ifosfamide
• Interleukin-2
• Procarbazine
• Tamoxifen
• Thalidomide
• Vinca alkaloids
• Zarnestra
 
Leukoencephalopathy
• Bevacizumab
• Capecitabine
• Cisplatin
• Cytosine arabinoside
• Cyclosporin-A
• 5-Fluorouracil
• G-CSF/GM-CSF
• Methotrexate
• Nelarabine
• Oxaliplatin
• Sorafenib
• Sunitinib malate
• Vinca alkaloids
Headache
• Asparaginase
• BCNU
• Capecitabine
• Cetuximab
• Cisplatin
• Corticosteroids
• Cytosine arabinoside
• Danazol
• Estramustine
• Etoposide
• Fludarabine
• Gefitinib
• Gemcitabine
• Hexamethylmelamine
• Hydroxyurea
• Ibritumomab
• Imatinib
• Interferons
• Interleukins
• Leuprolide
• Levamisole
• Mechlorethamine
• Methotrexate
• Mitomycin
• Mitotane
• Nelarabine
• Octreotide
• Oprelvekin
• Plicamycin
• Procarbazine
• Rituximab
• Retinoic acid
• SU-5416
• Tamoxifen
• Temozolomide
• Thalidomide
• Thiotepa
• Tumor necrosis factor
• Topotecan
• Tositumomab
• Trastuzumab
• ZD-1839
 
Aseptic meningitis
• Cytosine arabinoside
• Levamisole
• Methotrexate
• Thiotepa
 
Myelopathy
• Cisplatin
• Cladaribine
• Corticosteroids
• Cytosine arabinoside
• Docetaxel
• Doxorubicin
• DFMO
• Fludarabine
• Interferon alpha
• Methotrexate
• Mitoxantrone
• Taxotere
• Thiotepa
• Vincristine
 
Vasculopathy and stroke
• Asparaginase
• BCNU
• Bevacizumab
• Bleomycin
• Carboplatin
• Cisplatin
• Danazol
• Doxorubicin
• Erlotinib
• Erythropoietin
• Estramustine
• 5-Fluorouracil
• Interleukin
• Imatinib mesylate
• Methotrexate
• Mitomycin
• Nelarabine
• Tamoxifen
Seizures
• Amifostine
• Asparaginase
• BCNU
• Busulfan
• Chlorambucil
• Cisplatin
• Corticosteroids
• Cyclophosphamide
• Cytosine arabinoside
• Dacarbazine
• Docetaxel
• Erythropoietin
• Etanercept
• Etoposide
• 5-Fluorouracil
• Gemcitabine
• Hexamethylamine
• Hydroxyurea
• Ifosfamide
• Interferon
• Interleukin-2
• Letrozole
• Leuprolide
• Levamisole
• Mechlorethamine
• Methotrexate
• Octreotide
• Paclitaxel
• Pentostatin
• Suramin
• Temozolomide
• Teniposide
• Thalidomide
• Vinca alkaloids
 
Visual loss
• BCNU
• Carboplatin
• Chlorambucil
• Cisplatin
• Cytosine arabinoside
• Etanercept
• Etoposide
• Fludarabine
• 5-Fluorouracil
• Methotrexate
• Paclitaxel
• Pentostatin
• Retinoic acid
• Tamoxifen
• Suramin
• Vinca alkaloids
 
Neuropathy
• 5-Azacytidine
• Bortezomib
• Capecitabine
• Carboplatin
• Cisplatin
• Cytosine arabinoside
• Docetaxel
• Etoposide
• 5-FU
• Gemcitabine
• Hexamethylmelamine
• Ifosfamide
• Interferon-alpha
• Misonidazole
• Nelarabine
• Oprelvekin
• Oxaliplatin
• Paclitaxel
• Pemetrexed
• Procarbazine
• Purine analogs (fludarabine, cladribine, pentostatin)
• Sorafenib
• Sunitinib malate
• Suramin
• Taxanes
• Teniposide (VM-26)
• Thalidomide
• Tumor necrosis factor
• Vinca alkaloids
• Zarnestra
 
Syncope
• Bevacizumab
• Erlotinib
• Nelarabine
 


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 an axonal neuropathy affecting predominantly large myelinated sensory fibers (Roelofs et al 1984; Thompson et al 1984; Allen 1991;  Postma and Heimans 1998;Collins and Amato 2002; Pietrangeli et al 2006). 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 numbness, paresthesias, and occasionally pain 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 Sjögren syndrome. Paraneoplastic neuropathies tend to involve all sensory fibers and 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 the serum.

  There is marked individual susceptibility to the development of cisplatin-induced neuropathies (McWhinney et al 2009). Typically, neuropathies develop in patients following cumulative doses of cisplatin greater than 400 mg/m2 (Roelofs et al 1984; van der Hoop et al 1990a; 1990b; Brouwers et al 2009). Increased dose intensity of cisplatin administration does not appear to enhance the severity of the neuropathy (Hilkens et al 1997; Hilkens and ven den Bent 1997). 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 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 (Siegal and Haim 1990). Most patients eventually improve, although recovery is often incomplete (Brouwers et al 2009).

  As of yet, there is no treatment for cisplatin neurotoxicity. Amifostine (Kemp et al 1996), Ethiofos (WR-2721) (Mollman et al 1988), and the ACTH (4-9) analogue Org 2766 (van der Hoop et al 1990a; 1990b) partially protect peripheral nerves from cisplatin neurotoxicity. However, in a recently released official statement by the American Society of Clinical Oncology, the use of amifostine was not recommended for prevention of platinum-associated neuropathies (Hensley et al 2009). There is evidence that vitamin E levels are low in cancer patients with chemotherapy-induced neuropathies. There have been studies suggesting that vitamin E supplementation may be protective against cisplatin-induced neurotoxicity (Peltier and Russell 2002; Pace et al 2003; Argyriou et al 2006a). There is also limited evidence that interleukin-6 (Callizot et al 2008), valproic acid (Rodriguez-Menendez et al 2008), and acetyl-L-carnitine may be of benefit (Pisano et al 2003; Bianchi et al 2005; De Grandis 2007). In addition, alpha-lipoic acid may prove to be useful in preventing chemotherapy-related neuropathy. Alpha lipoic acid has powerful antioxidant and mitochondrial protective properties. In a recent experimental study, alpha-lipoic acid has been shown to protect dorsal root ganglion sensory neurons from cisplatin-induced neurotoxicity (Melli et al 2008).

  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 dose (Moroso and Blair 1983). 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. The hearing loss tends to be worse in children, although they have a slightly greater ability to improve after the drug has been stopped. Neurotrophin-4/5 enhances the survival of cultured spiral ganglion cells in vitro and may have therapeutic value in preventing cisplatin-induced ototoxicity (Zheng et al 1995). Cisplatin may also cause a vestibulopathy, resulting in ataxia and vertigo. It may or may not be associated with hearing loss. Previous use of aminoglycosides may exacerbate the vestibulopathy (Black et al 1982; Moroso and Blair 1983). Intra-arterial infusion of cisplatin for head and neck cancer produces cranial palsies in approximately 6% of patients (Frustaci et al 1987). Intracarotid infusion of cisplatin may also cause ocular toxicity, although these complications may also rarely occur after intravenous administration of the drug (Kupersmith et al 1988). They include retinopathy, papilledema (Ostrow et al 1978), optic neuritis (Ostrow et al 1978), and disturbed color perception due to dysfunction of retinal cones (Wilding et al 1985). Other complications of intra-arterial cisplatin include headaches, confusion, and seizures (Tfayli et al 1999).

  Myelotoxicity (Lhermitte sign). This symptom, characterized by paresthesias in 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 usually resolves spontaneously several months after the drug has been discontinued. It is thought to result from transient demyelination of the posterior columns. Very rarely, a true myelopathy has been reported (Forsyth and Cascino 1995; Posner 1995).

  Less common complications. Autonomic neuropathies have also been rarely observed (Posner 1995). Infrequently, cisplatin produces encephalopathy, possibly associated with seizures and focal neurologic symptoms, including cortical blindness (Berman and Mann 1980; Posner 1995; Ito et al 1998; Lyass et al 1998; Steeghs et al 2003). The encephalopathy is associated with reversible abnormalities in the white matter of the occipital, parietal, and frontal lobes and clinically resembles the reversible posterior leukoencephalopathy syndrome. The encephalopathy tends to be more common after intra-arterial administration of the drug (Newton et al 1989). It has to be distinguished from a metabolic encephalopathy that may result from water intoxication caused by prehydration, or from renal impairment, hypomagnesemia, hypocalcemia, and syndrome of inappropriate secretion of antidiuretic hormone that may follow treatment with cisplatin. Cisplatin can also cause vascular toxicity, resulting in strokes (Gerl et al 1993; Icli et al 1993). One case of acute corpus callosum hemorrhages was associated with combination treatment with cisplatin, ifosfamide, and etoposide (Dietrich et al 2004). Other rare complications include taste disturbance and a myasthenic syndrome (Posner 1995). Interestingly, cisplatin may cause long-term adverse effects on cognitive function (Troy et al 2000). The exact mechanisms on cognitive function are unclear. Cisplatin may be retained in tissues and plasma even for years after cessation of treatment (Gietema et al 2000; Brouwers et al 2008). Long-term toxicity and cognitive impairment may be related to damage to progenitor cell populations in the nervous system critically important in maintenance of brain plasticity, memory function, and subcortical network systems (Dietrich et al 2006; Dietrich and Wen 2008).

  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 (Geiser et al 1975; Phillips 1991; Glantz et al 1999b). 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 may 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 (Boogerd et al 1988). Aseptic meningitis can be prevented to some extent by injecting methotrexate together with hydrocortisone or by using oral corticosteroids (Glantz et al 1999a). 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. The 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. The majority of cases show clinical improvement, but the extent of recovery is variable (Gagliano and Costanzi 1976). This complication is more common in patients receiving concurrent radiotherapy or frequent treatments of intrathecal methotrexate.

  Rarely, intrathecal methotrexate produces acute encephalopathy, seizures, subacute focal neurologic deficits, posterior leukoencephalopathy, lumbosacral radiculopathy, neurogenic pulmonary edema, and sudden death (Yim et al 1991; Winick et al 1992; Hammack and Cascino 1998; Koh et al 1999; Kinirons et al 2005; Kuker et al 2005).

  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 (Baehring and Fulbright 2008). Diffusion-weighted imaging abnormalities can be seen in subcortical or deep periventricular white matter, corpus callosum, cortex, cerebellum, and thalamus (Rollins et al 2004; Fisher et al 2005; Kuker et al 2005; Haykin et al 2006; Ziereisen et al 2006; Balin et al 2008; Brugnoletti et al 2009). It has been suggested that DWI changes in methotrexate-associated neurotoxicity represent reversible cerebral dysfunction with associated cytotoxic edema and metabolic derangement rather than ischemic structural injury (Rollins et al 2004; Haykin et al 2006). Accidental overdosage of methotrexate (more than 500 mg) usually results in myelopathy and encephalopathy with fatal outcome. The use of rapid CSF drainage, ventriculolumbar perfusion, high-dose leucovorin, and alkaline diuresis has allowed few patients to survive (Spiegel et al 1984). Cases of irreversible cerebellar atrophy following intrathecal methotrexate have been described (Masterson et al 2008).

  Weekly low-dose methotrexate neurotoxicity. Up to 20% of patients receiving weekly low-dose methotrexate may experience headaches, dizziness, dysphoria, and subtle cognitive impairment (Wernick and Smith 1989). Both renal insufficiency and older age have been reported as associated risk factors for neurotoxicity. Oral methotrexate may also result in acute focal neurologic deficits (Aplin and Russell-Jones 1999) and abnormal imaging findings, consistent with reversible posterior leukoencephalopathy (Renard et al 2004). Symptoms usually resolve when the methotrexate is discontinued. Neurotoxicity characterized by dysarthria, gait dysfunction, dysmetria, and weakness has also been described after low-dose subcutaneous methotrexate injection for rheumatoid arthritis. Symptoms were reversible, however, and resolved after discontinuation of treatment (Masterson et al 2008).

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

  Acute, high-dose methotrexate neurotoxicity 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 (Phillips 1991; Posner 1995; Rubnitz et al 1998). Weekly treatments with high-dose methotrexate may produce a subacute "strokelike" syndrome characterized by transient focal neurologic deficits, confusion, and occasionally seizures (Walker et al 1986). Typically, the disorder develops several days after high-dose methotrexate, lasts 15 minutes to 72 hours, and resolves spontaneously without sequelae. Neuroimaging studies and CSF 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 intrathecal methotrexate therapy is a leukoencephalopathy (Rubinstein et al 1975a; 1975b; Pizzo et al 1979; Phillips 1991). Although this syndrome may be produced by intrathecal 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 (Ch'ien et al 1981). CT and MRI scans show cerebral atrophy and diffuse white matter lesions (Laxmi et al 1996; Oka et al 2003). Pathologic lesions range from loss of oligodendrocytes and gliosis to a necrotizing leukoencephalopathy (Hertzberg et al 1997). 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. It has been suggested that disruption of myelin metabolism (Davidson et al 2000), depletion of reduced folates in the brain (Vezmar et al 2003; Quinn et al 2004), injury to cerebral vascular endothelium, possibly mediated through elevated homocysteine levels (Quinn et al 1997) with increasing blood-brain barrier permeability, inhibition of cerebral glucose or protein metabolism (Miyatake et al 1992), or inhibition of catecholamine synthesis (Phillips et al 1987) may underlie this syndrome. Recent studies suggest that genetic polymorphisms for methionine metabolism, which is required for myelination, may constitute a risk factor for methotrexate-associated neurotoxicity (Linnebank et al 2005; Muller et al 2008). 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 a new antifolate that is used alone or in combination with other chemotherapeutic agents for malignant mesothelioma and non-small cell lung cancer. It causes a neuropathy that can be prophylactically treated with vitamin B12 and folate supplementation (Budde and Hanna 2004; Kut et al 2004).
 
Oxaliplatin.

Oxaliplatin is a third-generation platinum complex that has activity against cisplatin-resistant tumor cells. It is used to treat colon and ovarian cancer. An acute transient neuropathy occurs in the majority of patients and is characterized by transient paresthesias of the extremities and perioral region, and rarely in the pharynx that is thought to be due to peripheral nerve hyperexcitability (Lehky et al 2004). This complication occurs more frequently at doses of 130 mg/m2 (Gamelin et al 2004). A sensory neuropathy remains the dose-limiting toxicity, which may occur in up to 50% to 90% of patients (Krishnan et al 2005; Kiernan and Krishnan 2006; Land et al 2007). Neuropathies tend to be associated with increased cumulative doses (Pasetto et al 2006), but are rarely severe at conventional doses and tend to improve after therapy is discontinued (Extra et al 1998; Giacchetti et al 2000). Glutathione administration may prevent oxaliplatin-induced neuropathy without reducing the clinical activity of the agent (Cascinu et al 2002). Amifostine, carbamazepine, oxcarbazepine, and alpha-lipoic acid have also been reported to be beneficial (Penz et al 2001; Lersch et al 2002; Cersosimo 2005; Argyriou et al 2006b; Grothey 2006).

  Suramin.

Suramin inhibits the binding of a number of growth factors to their receptors, including platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor beta. It also inhibits DNA polymerases and glycosaminoglycan catabolism. Suramin is used mainly for the treatment of refractory prostate cancer. It causes a severe peripheral neuropathy in approximately 10% of patients (La Rocca et al 1990; Kaur et al 2002). Two patterns of neuropathy have been described: an inflammatory demyelinating neuropathy clinically resembling Guillain-Barré syndrome, which may improve after the drug is discontinued, and a distal, length-, dose-, and time-dependent axonal sensorimotor polyneuropathy (Chaudhry et al 1996; Peltier and Russell 2002). In addition, visual changes have been reported in 7% to 9% of patients (Hussain et al 2000). Initially, it was thought that the development of neuropathy correlated with blood levels of suramin. Subsequently, monitoring of blood levels was recommended as serious complications were uncommon at plasma levels less than 350 µg/mL (Posner 1995). However, other studies did not confirm any correlation between the degree of neurotoxicity and peak or trough levels (Hussain et al 2000).

  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 (Rowinsky et al 1990). Paclitaxel produces a dose-limiting peripheral neuropathy, which occurs in 60% of patients receiving 250 mg/m2 (Lipton et al 1989; Mielke et al 2006). Toxicity is predominantly characterized by a symmetric, sensory axonal neuropathy affecting both large and small fibers (Argyriou et al 2008). 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 arthralgias and myalgias beginning 2 to 3 days after a course of paclitaxel lasting 2 to 4 days. Less commonly, paclitaxel can result in motor neuropathies that predominantly affect proximal muscles (Freilich et al 1996), perioral numbness, and autonomic neuropathies (Rowinsky et al 1990). Rarely, paclitaxel causes visual scotomas, optic neuropathies, seizures, vocal cord palsies, transient encephalopathies (Perry and Warner 1996; Plotkin and Wen 2003; Choi and Robins 2008), or phantom limb pain in patients with prior amputation (Khattab et al 2000). Neuropathies are less common with docetaxel but some patients develop sensory and motor neuropathies similar to paclitaxel (Freilich et al 1996; New et al 1996). Docetaxel can occasionally produce Lhermitte sign (van den Bent et al 1998). High-dose paclitaxel (greater than 600 mg/m2) can lead to an acute encephalopathy and death between 7 and 23 days after treatment (Nieto et al 1999; Guglani et al 2003). The neurotoxic effects of paclitaxel and docetaxel are increased when combined with cisplatin (Hilkens and ven den Bent 1997; Hilkens et al 1997). Liposomal encapsulation of paclitaxel may reduce the incidence of neurotoxicity (Treat et al 2001). There is some evidence that vitamin E (Argyriou et al 2006a) and N-acetyl carnitine (Pisano et al 2003; Bianchi et al 2005) may reduce the severity of the neuropathy. Studies of neurotrophic agents such as human leukemia inhibitory factor have so far been unsuccessful (Davis et al 2005).

  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 (Legha 1986; Postma et al 1998). 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 (Collins and Amato 2002). 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 jerks is common. Occasionally there may be profound weakness, with bilateral foot and wrist drop and loss of all sensory modalities. Severe neuropathies are particularly likely to develop in older patients who are cachectic, patients who have received prior radiation to the peripheral nerves or concomitant hemopoietic colony-stimulating factors (Weintraub et al 1996), and those who have pre-existing neurologic conditions such as Charcot-Marie-Tooth (Hogan-Dann et al 1984; Weimer and Podwall 2006). 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. Vincristine may also cause focal neuropathies (Forsyth and Cascino 1995; Posner 1995). Although anecdotal reports indicate that glutamine may help some patients with vincristine neuropathy, there is generally no effective treatment (Forsyth and Cascino 1995). Rarely, vincristine can cause a fulminant neuropathy with severe quadriparesis that mimics Guillain-Barré syndrome (Moudgil and Riggs 2000; Gonzalez Perez et al 2007).
 
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, resulting in hyponatremia, confusion, and seizures (Robertson et al 1973). CNS complications unrelated to the syndrome of inappropriate secretion of antidiuretic hormone may also occur. These include seizures, encephalopathy, reversible posterior leukoencephalopathy (Ozyurek et al 2005; Haefner et al 2007), transient cortical blindness, ataxia, athetosis, and a Parkinson syndrome (Posner 1995; Hammack and Cascino 1998; Wen 2001).

  The related vinca alkaloids vindesine, vinblastine, and vinorelbine tend to have less neurotoxicity (Swain and Arezzo 2008). This may be related to differences in lipid solubility, plasma clearance, terminal half life, and sensitivities of axoplasmic transport (Forsyth and Cascino 1995; Posner 1995). 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 (Rowinsky et al 1994). Severe neuropathy is rare but appears to be more common in patients treated previously with paclitaxel (Fazeny et al 1996; Norris et al 2000).
 

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 (Ishii et al 1992; Feinberg and Swenson 1988; Erbetta et al 2008). 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 (Schick et al 1989; Lee and Levine 1999). Treatment is controversial, but anticoagulation with heparin is generally recommended. At high doses, asparaginase may also produce a reversible encephalopathy (Rathi et al 2002). Seizures have been reported as the single manifestation of CNS toxicity (Hamdan et al 2000). The related PEG-asparaginase has a similar neurotoxicity profile to L-asparaginase (Graham 2003).

  Cytosine arabinoside.

This is a pyrimidine analogue used in the treatment of leukemias, lymphomas, and neoplastic meningitis. Although its oral absorption is poor, Ara-C distributes well in CSF after intrathecal application with high CSF levels for at least 24 hours. The half-life is much prolonged with use of liposomal Ara-C, and cytotoxic CSF levels are maintained for up to 2 weeks (Glantz et al 1999b). 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 (Winkleman and Hines 1983; Hwang et al 1985; Herzig et al 1987). 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 especially likely to develop cerebellar involvement. Typically, the patients develop somnolence and occasionally encephalopathy 2 to 5 days after completing treatment. Subsequently, patients develop cerebellar signs. These range from mild ataxia to severe truncal ataxia with inability to sit or walk unassisted (Baker et al 1991). 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 (Winkelman and Hines 1983;(Dworkin et al 1985; Courtney and Coffey 1999), more recent data suggest that Ara-C targets both lineage-committed progenitor cell populations and nondividing oligodendrocytes, which are the myelin-forming cells in the central nervous system (Dietrich et al 2006). 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 germinal zones of the CNS.

  Neuroimaging studies may show T2/FLAIR hyperintensities, white matter abnormalities, and eventually cerebellar atrophy. 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 (Saito et al 2006). 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 (Smith et al 1997; Lindner et al 2008).

  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 (Phillips and Reinhard 1991; Posner 1995; Openshaw et al 1996; Plotkin and Wen 2003; Osborne et al 2004; Saito et al 2007).

  Intrathecal administration of cytosine arabinoside is used to treat leptomeningeal metastases. It can cause a transverse myelopathy similar to that seen with intrathecal methotrexate (Dunton et al 1986; Kwong et al 2009). Other rare CNS toxicities include aseptic meningitis, encephalopathy, headaches, posterior leukoencephalopathy, and seizures (Posner 1995; Henderson et al 2003). The incidence of aseptic meningitis may significantly increase to 25% to 40% after use of a sustained-release preparation of cytosine arabinoside (Jabbour et al 2007), especially when combined with intrathecal methotrexate. Significant neurotoxicity has been reported after liposomal Ara-C in patients after allogeneic hematopoietic stem cell transplantation and should be used with caution in this patient population (Hilgendorf et al 2008). CNS complications may partially be prevented by prophylactic treatment with corticosteroids (Glantz et al 1999b).

  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 (Riehl and Brown 1964; Phillips and Reinhard 1991). 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 completely. 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 (Forsyth and Cascino 1995; Brashear and Siemers 1997), peripheral neuropathy (Stein et al 1998), or seizures (Pirzada et al 2000). Patients with decreased dihydropyrimidine dehydrogenase activity are at an increased risk for developing severe neurologic toxicity following 5-fluorouracil chemotherapy (Takimoto et al 1996).

  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 (Hook et al 1992). 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-FU prodrug (Niemann et al 2004; Videnovic et al 2005). 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.

  Recent 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 in the mammalian nervous system (Han et al 2008).

  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 has been reported to cause increased incidences of encephalopathies and cerebellar syndromes (Forsyth and Cascino 1995; Ohara et al 1998).

  Ifosfamide.

This is an analog of cyclophosphamide, with similar systemic toxicities. Unlike cyclophosphamide, it associated with encephalopathy in 20% of patients (Meanwell et al 1986; Zalupski and Baker 1988; Pratt et al 1990; Ajithkumar et al 2007; Brunello et al 2007). 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 (Meanwell et al 1986; Pratt et al 1990; Rieger et al 2004). There have been reports that methylene blue may be useful in preventing or treating ifosfamide encephalopathy by inhibiting monoamine oxidases (Aeschlimann et al 1996; Pelgrims et al 2000; Turner et al 2003; Patel 2006). For most patients, no specific treatment is necessary, and the encephalopathy usually improves with time. Rarely, ifosfamide also causes seizures, cerebellar ataxia, weakness, cranial nerve dysfunction, neuropathies, or extrapyramidal syndrome (Fleming 1997; Postma et al 1998; Primavera et al 2002; Plotkin and Wen 2003; David and Picus 2005). Notably, toxicity can be of differing degree, varying from mild to transient and even fatal (Di Cataldo et al 2009).

  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 and at conventional doses, although confusion, lethargy, and ataxia may occur at conventional doses. In contrast, high-dose intravenous BCNU used in the setting of autologous bone marrow transplantation can cause an encephalomyelopathy and seizures, which develop over a period of weeks to months after the administration of the drug.

  Intra-arterial BCNU produces ocular toxicity and neurotoxicity in 30% to 48% of patients (Shapiro and Green 1987; Shapiro et al 1992). 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 (Posner 1995). Concurrent radiotherapy increases the neurotoxicity of intra-arterial BCNU (Rosenblum et al 1989). 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 central nervous system toxicity is poorly understood, one study has shed light on the cellular basis of BCNU toxicity. 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 (Dietrich et al 2006). 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 (Dietrich et al 2006; Duffner 2006).

  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 (Forsyth and Cascino 1995; Posner 1995). The incidence of encephalopathy may be increased in patients receiving “high-dose” procarbazine, CCNU, and vincristine chemotherapy for malignant gliomas (Postma et al 1998). Procarbazine also potentiates the sedative effects of narcotics, phenothiazines, and barbiturates. Intravenous and intracarotid procarbazine produces a severe 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. In 1998, the FDA approved thalidomide for the treatment of erythema nodosum leprosum. In preclinical studies, thalidomide has shown potent antiangiogenic effects. Based on this property, it has been used in clinical trials for multiple myeloma (Singhal et al 1999), gliomas (Fine et al 2000), Kaposi sarcoma (Little et al 2000), and breast cancer (Baidas et al 2000). The most 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. A predominantly sensory axonal neuropathy occurs in 3% to 32% of patients with prolonged use (Chaudhry et al 2002). This may improve slightly with discontinuation of the medication. Seizures have occurred in a minority of patients with gliomas.

 
Drugs that rarely cause neurotoxicity

  Anthracycline antibiotics (doxorubicin, daunorubicin, idarubicin, mitoxantrone).

Doxorubicin is an anthracycline antibiotic used to treat a variety of cancers including hematogenic malignancies and breast cancer. It can cause arrhythmias and cardiomyopathies, which in turn can result in cerebrovascular complications (Schachter and Freeman 1982). Doxorubicin in combination with cyclosporine can lead to coma and death (Paleologos 1998). Apart from accidental intrathecal injection, which can cause severe myelopathy and encephalopathy, these agents have little overall neurotoxicity (Posner 1995). Idarubicin and daunorubicin appear to be much less neurotoxic than doxorubicin, and nervous system toxicity may only be seen in high-dose applications or in combination with other neurotoxic agents. Mitoxantrone has no known neurotoxicity when given intravenously but may produce a radiculopathy and myelopathy when given intrathecally (Hall et al 1989).

  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 (Doll and Yarbro 1992; Dietrich et al 2004).

  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 (Vassal et al 1990; La Morgia et al 2004).

  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 (Saif et al 2004). There have also been case reports of capecitabine-induced multifocal leukoencephalopathy (Niemann et al 2004; Videnovic et al 2005). Capecitabine leukoencephalopathy has an earlier onset than 5-FU leukoencephalopathy and the MRI changes are nonenhancing and centralized within the white matter (Videnovic et al 2005). Delayed leukoencephalopathy with stroke-like presentation has been described following capecitabine exposure (Baehring and Fulbright 2008).

  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 (Heinzlef et al 1998). Intra-arterial carboplatin may produce stroke-like syndromes (Walker et al 1989) and retinal toxicity (Stewart et al 1992). 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 (Quasthoff and Hartung 2002). 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 (Chabner and Longo 1996).

  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 (Wyllie et al 1997), and seizures when taken in very high doses (Salloum et al 1997).

  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 (Forsyth and Cascino 1995).

  Fludarabine.

Fludarabine is an inhibitor of DNA polymerase and ribonucleotide reductase. It is used to treat chronic lymphatic leukemia, macroglobulinemia, and indolent lymphomas. Neurotoxicity is uncommon, but fludarabine can cause headaches, somnolence, confusion, and paresthesias at low doses (Cheson et al 1994; Posner 1995), and a delayed progressive encephalopathy with seizures, visual loss, paralysis, and coma at high doses (Warrell and Berman 1986). There have been some reports about severe leukoencephalopathy following fludarabine with lethal outcome (Rodriguez et al 2002; Mielke et al 2007). Fludarabine may increase the risk of JC virus associated multifocal leukoencephalopathy (Saumoy et al 2002; Vidarsson et al 2002; Kiewe et al 2003).Cladribine (2-chlordeoxyadenosine), a related drug used for Waldenstrom macroglobulinemia, can produce paraparesis at high doses (Paleologos 1998).

  Cyclophosphamide.

Cyclophosphamide at standard doses has little neurotoxicity. High-dose cyclophosphamide may produce reversible visual blurring, dizziness, and confusion (Posner 1995). Its metabolite, 4-hydroperoxyxyclophosphamide, has been used experimentally as intrathecal therapy for leptomeningeal metastases. At high doses it can cause lethargy and seizures (Phillips and Reinhard 1991). Rarely, a reversible posterior leukoencephalopathy syndrome (Haefner et al 2007) or a necrotizing leukoencephalopathy syndrome, which can be fatal, have been reported following the cyclophosphamide-containing CHOP regimen for non-Hodgkin lymphoma (Cain et al 1998; Blaes et al 2008).

  Dacarbazine.

Dacarbazine mainly is used to treat melanoma. Neurotoxicity is very rare, but seizures, encephalopathy, and dementia have been reported (Paterson and McPherson 1977).

  Alpha-difluoromethyl ornithine.

This is an irreversible inhibitor of ornithine decarboxylase used in gliomas and other tumors and can cause ototoxicity and myelotoxicity (Love et al 1998).

  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 (Chabner and Longo 1996; Paleologos 1998). 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 (Lubiniecki et al 2004).

  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 (Dormann et al 1998). Administration of gemcitabine after radiation therapy for brain metastases may increase the risk of neurotoxicity (Jeter et al 2002).

  Hexamethylmelamine, altretamine.

This is an alkylating agent with activity against ovarian cancer, lymphoma, and lung cancer. It can produce peripheral neuropathy, headaches, encephalopathy, seizures, tremor, ataxia, and a Parkinson syndrome. These neurologic complications appear to be dose related and are usually reversible (Posner 1995).

  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 (Posner 1995).

  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 (Paleologos 1998). In combination with other chemotherapeutic agents, such as 5-fluorouracil, neurotoxicity has been reported and may present in these patients as posterior reversible leukoencephalopathy (Allen et al 2006; Guiu et al 2008; Packer et al 2009).

  Levamisole.

Levamisole is an immune-enhancer that is used in combination with 5-FU for patients with colon cancer. A metabolite, p-hydroxy-tetramisole, may enhance 5-FU activity by inhibiting tyrosine phosphatase. When used in combination with 5-FU, it can cause a multifocal leukoencephalopathy (Hook et al 1992; Kimmel and Schutt 1993; Savarese et al 1996). 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 in high doses for bone marrow transplantation, confusion and seizures have been reported (Posner 1995).

  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 (Doll and Yarbro 1992).

  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 64% of subjects. Most were mild to moderate (grade 1 to 2), including headache, somnolence, neuropathy, and sensory deficits. Grade 4 and grade 5 (fatal) neurologic events were also observed, including cranial neuropathies (oculomotor and abducens nerve palsies), progressive multifocal leukoencephalopathy, peripheral demyelination similar to Guillain-Barré syndrome, cerebral and intracranial hemorrhage, coma, and metabolic encephalopathy (Kurtzberg et al 2005; Robak et al 2005).

  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 (Cheson et al 1994; Paleologos 1998).

  Plicamycin.

This is used to treat refractory hypercalcemia and may cause headaches, lethargy, and irritability. These side effects tend to be dose dependent.

  Pyrazoloacridine.

This is a DNA intercalating agent with activity against a variety of solid tumor cells lines. In phase I studies, neurotoxicity was dose-limiting. The complications seen included neuropsychiatric symptoms (restlessness, agitation, anxiety, personality changes, nightmares), motor symptoms, myoclonus, and dizziness (Rowinsky et al 1995).

  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. It has mostly been used to treat promyelocytic leukemia. Retinoic acid frequently causes headaches (Bailey et al 1995). Rarely, it can cause pseudotumor cerebri (Selleri et al 1996) and multiple mononeuropathies (Yamaji et al 1999).

  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 (Yung et al 1999).

  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 (Tirelli et al 1984; Ignoffo et al 1998).

  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 (Gutin et al 1977). High intravenous doses of thiotepa can produce encephalopathy that can be fatal (Smith et al 1997; Paleologos 1998).

  Topotecan.

This is a topoisomerase inhibitor mostly used in the treatment of ovarian cancer. It can occasionally cause headaches and paresthesias (Brown et al 2000).
 

Hormonal therapy

  Aminoglutethimide.

Aminoglutethimide inhibits the synthesis of steroid hormones and is used to treat breast carcinoma, adrenocortical carcinoma, and ectopic Cushing disease. It frequently causes mild lethargy and rarely causes vertigo and ataxia (Nemoto et al 1989).

  Anastrozole and letrozole.

These selective aromatase inhibitors have largely replaced aminoglutethimide for second-line hormone treatment in women with advanced breast cancer. Headaches and fatigue occur in about 10% of patients treated with letrozole, whereas other neurologic toxicities (insomnia, confusion, dizziness, somnolence, anxiety, and vertigo) are less common and affect approximately 5% of patients receiving either drug.

  Anastrozole is an aromatase inhibitor (inhibitor of estrogen) used for postmenopausal women with hormone receptor-positive advanced breast cancer. It can cause weakness and back pain (Wiseman and Adkins 1998).

  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 (Vecht and Verbiest 1995). 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
 
Common


Myopathy

Visual blurring

Tremor

Behavioral changes

Insomnia

Reduced taste and smell

Cerebral atrophy

 


Uncommon


Psychosis

Hallucinations

Hiccups

Dementia

Seizures

Dependency

Epidural lipomatosis
 
Neuropathy
 

   The most common complication is steroid myopathy (Dropcho and Soong 1991; Eidelberg 1991). 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