Acute or subacute encephalopathy
Methotrexate
Cisplatin
Vinca alkaloids
Mechlorethamine
Procarbazine
Cytosine Arabinoside (Ara-C)
Fludarabine
Gemcitabine
Hydroxyurea
Pentostatin
Chlorambuicil
Thiotepa (high dose)
Ifosfamide
Hexamethylmelamine
Cyclophosphamide
Etoposide
Paclitaxel
Docetaxel
Doxorubicin (IT administration)
Mitotane
l-Asparaginase
Chronic encephalopathy
Methotrexate
Cytosine Arabinoside (Ara-C) (IT administration)
5-Fluorouracil
Carmustine (IA or high-dose IV administration)
Ifosfamide
Fludarabine
Cisplatin (IA administration)
–
–
Seizures
Methotrexate
Cisplatin
Vinca alkaloids
Mechlorethamine
Nitrosoureas (IA or intracavitary administration)
Chlorambuicil (overdose only)
Hexamethylmelamine
Cyclophosphamide
5-Fluorouracil
Cytosine arabinoside (Ara-C)
Fludarabine
Gemcitabine
Pentostatin
Dacarbazine
Temozolomide
Ifosfamide
Etoposide
Paclitaxel
Docetaxel
l-asparaginase
–
Headache
Methotrexate (IT administration)
5-Fluorouracil
Cytosine arabinoside (Ara-C) (IT administration)
Cladribine
Gemcitabine
Hydroxyurea
Dacarbazine
Temozolomide
Nitrosoureas (i.e., BCNU) (IA administration)
Mechlorethamine
Procarbazine
Thiotepa (IT administration)
Hexamethylmelamine
Retinoids
Etoposide
Topotecan
Mitomycin C
l-Asparaginase
Thalidomide
Lenalidomide
Pomalidomide
Octreotide
Mitotane
–
Cerebrovascular complications
Cisplatin
Doxorubicin (IA administration)
Mitomycin C
l-Asparaginase
–
–
Visual loss
Fludarabine
Cisplatin (IA and high-dose IV administration)
Carmustine (BCNU) (IA and high-dose administration)
Retinoids
Chlorambucil
Vinca alkaloids
Paclitaxel
Mitotane
–
Table 15.2
Chemotherapy drugs that can cause peripheral neurotoxicity
Sensory neuropathy | ||
Cisplatin | Carboplatin | Oxaliplatin |
Vinca alkaloids | Taxanes | Bortezomib |
Carfilzomib | Ixabepilone | Thalidomide |
Lenalidomide | Pomalidomide | – |
Motor neuropathy | ||
Oxaliplatin | Vinca alkaloids | Taxanes |
Bortezomib | Ixabepilone | Thalidomide |
Lenalidomide | Pomalidomide | – |
Autonomic neuropathy | ||
Vinca alkaloids | Bortezomib | Thalidomide |
Lenalidomide | Pomalidomide | – |
Alkylating Agents
Nitrogen Mustards
Mechlorethamine
Mechlorethamine is the original nitrogen mustard, which inhibits DNA and RNA syntheses by producing interstrand and intrastrand cross-links in DNA. It is used in lymphomas and malignant effusions. When used at conventional intravenous (IV) doses, mechlorethamine does not cause neurotoxicity. When used in high-dose IV regimens, such as preparation for bone marrow transplantation (BMT), the drug has been reported to cause encephalopathy , headache, and seizures [1, 2]. The symptom onset is usually within a few days of treatment; spontaneous recovery is typical. Mechlorethamine has also been administered during intra-arterial (IA) chemotherapy for treatment of recurrent gliomas in the 1950s and 1960s, but was associated with significant cerebral edema, seizure activity, focal neurological deficits, and encephalopathy [3].
Chlorambucil
Chlorambucil is an orally administered nitrogen mustard interfering with DNA replication and RNA transcription by cross-linking DNA strands, used in the treatment of chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma, and non-Hodgkin’s lymphomas. Rarely, seizures may occur. A history of nephrotic syndrome and high-dose chlorambucil pulses are risk factors for chlorambucil-induced seizures [4, 5]. Ocular toxicities including retinal edema and hemorrhage, as well as keratitis, have been described [6]. Uncommon central neurotoxicities include agitation, ataxia, confusion, drug fever, hallucinations, encephalopathy, and myoclonus [7, 8]. PNS toxicity of chlorambucil includes neuropathy, tremor, and myoclonia [9, 10].
Cyclophosphamide
Cyclophosphamide is a prodrug that requires activation in the liver. Antineoplastic properties are derived from cross-linking DNA strands and decreasing DNA synthesis. It is frequently used in combination chemotherapy regimens for many solid and hematologic tumors. Neurotoxicity is uncommon, especially compared to ifosfamide, but may present during high-dose IV infusions used for hematopoietic stem cell transplant. Toxicity at these doses includes a mild, reversible encephalopathy with dizziness, blurred vision, and confusion. Posterior reversible encephalopathy has also been described [11].
Ifosfamide
Ifosfamide is an alkylating agent structurally similar to cyclophosphamide that is used for treatment of many solid and hematopoietic tumors, known to frequently cause CNS toxicity. Central neurotoxicity occurs in 10–30% of all patients that receive high-dose IV ifosfamide treatment [12–15]. The toxicity is more likely to occur when IV therapy is continuous over several days or given in a large bolus dose, as opposed to fractionated schedules. Other risk factors include low serum albumin [12, 13], renal dysfunction [12, 13], use of the antiemetic aprepitant [16–19], underlying brain disease [20], concurrent phenobarbital treatment [21], previous neurotoxicity with ifosfamide [12], and prior cisplatin therapy [12, 13]. Accumulation of chloroacetaldehyde, a metabolite of ifosfamide, is thought to cause the encephalopathy. Neurotoxicity can occur hours to days into the treatment and the majority of patients do not require treatment; the encephalopathy resolves completely within days [22]. Small studies have used dexmedetomidine, thiamine, and/or methylene blue as treatment of prevention of ifosfamide-induced encephalopathy [23–26]. The most common symptoms include delirium, mutism, visual hallucinations, seizures, focal motor deficits, facial nerve palsy, and aphasia. Cases of death [27, 28] and irreversible neurologic deficits have been reported [22]. Electroencephalography (EEG) generally reveals diffuse, slow-wave activity, without epileptiform discharges. Other neurotoxicity with ifosfamide is typically described in the setting of encephalopathy but includes seizures [29, 30], ataxia [29], neuropathy [31], extrapyramidal symptoms [32, 33], and cranial nerve dysfunction [13].
Melphalan
Melphalan inhibits DNA and RNA syntheses by creating cross-links in DNA. It is used in multiple myeloma, ovarian cancer, and as a conditioning regimen for autologous hematopoietic stem cell transplantation. Neurotoxicity is uncommon, although cases of encephalopathy and seizures have been reported [34–36].
Bendamustine
Bendamustine is a nitrogen mustard derivative that causes single- and double-strand breaks leading to cell death. It is used in the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Neurotoxicity is uncommon with fatigue, headache, vertigo, anxiety, and depression described [37, 38].
Estramustine
Estramustine , a nitrogen mustard linked to estradiol, has both antiandrogen and anti-microtubular effects. It is mainly used for refractory prostate cancer and is not associated with significant CNS toxicity. Trials report uncommon neurotoxicity such as lethargy, insomnia, emotional lability, anxiety, and headache [39]. Approximately 25% of patients experienced a thromboembolic event [40]. Rare cases of thrombotic microangiopathy with cerebral infarction have been described [41].
Nitrosoureas
The nitrosoureas are a class of drugs that alkylate DNA and RNA, and include carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), nimustine (ACNU), fotemustine, and streptozotocin. They are all very lipid soluble and have excellent penetration of the BBB, with CSF drug levels approximately 15–30% of simultaneous plasma levels. Nitrosoureas are used predominantly for the treatment of high-grade gliomas, melanoma, lymphoma, and in conditioning regimens for allogeneic hematopoietic stem cell transplantation. When used at conventional IV doses, the incidence of CNS toxicity is minimal. High-dose BCNU has been associated with optic neuropathy and leukoencephalopathy in rare cases [42].
CNS toxicity is more likely to occur when nitrosoureas are administered to the brain via the IA route [3]. IA BCNU and ACNU have been used for the treatment of high-grade gliomas, with a high incidence of cerebral and ocular toxicity. Ocular toxicity included acute orbital pain during drug infusion, along with optic neuropathy and retinal injury. These symptoms could be mitigated with supra-ophthalmic delivery of the drug. Cerebral symptoms could include focal or generalized seizures, encephalopathy, coma, focal weakness, and stroke. In some patients this constellation of symptoms and signs can be caused by necrotizing leukoencephalopathy, a relatively uncommon and occasionally fatal complication of IA BCNU [43]. Concurrent irradiation increases the risk for development of the syndrome [43]. The onset of symptoms is often delayed after drug administration, up to 6 months in some cases. Neuroimaging usually demonstrates prominent edema in the ipsilateral hemisphere; gyral enhancement may be present. Pathological evaluation reveals focal necrosis and mineralizing axonopathy in the affected hemisphere. The mechanism of injury remains unknown but, similar to methotrexate, may be related to a combination of a direct neurotoxic effect of the drug and endothelial damage.
BCNU is also administered to brain tumor patients in wafer form, implanted directly into the resection cavity [44]. In general, there is only a mild risk of neurotoxicity in this setting, with the potential for increased cerebral edema, seizure activity, and new focal neurological deficits after BCNU wafer placement.
Alkyl Sulfonates
Busulfan
Busulfan is a non-cell-cycle-specific alkylating agent that interferes with DNA replication and transcription of RNA. It is used as an oral treatment for chronic myelogenous leukemia (CML) and IV in hematopoietic stem cell transplant conditioning regimens. Busulfan is known to cross the BBB easily with a CSF-to-plasma ration of 1:1. Seizures have been reported with IV busulfan and with high-dose oral busulfan [45–47]. The seizures usually appear within 48 h of drug administration. Seizures are more common in adults compared to children [48]. When busulfan is used as a conditioning regimen for transplant, prophylactic anticonvulsant therapy should be initiated (e.g., phenytoin, levetiracetam, benzodiazepines, or valproic acid) prior to treatment. It should be noted that phenytoin increases busulfan clearance by greater than 15% and doses should be adjusted accordingly. Busulfan should be used with caution in patients predisposed to seizures, history of seizures, head trauma, or with other medications associated with inducing seizures. Dimethylacetamide is the solvent in IV busulfan and has been associated with hallucinations, somnolence, lethargy, and confusion. Other neurotoxic side effects of busulfan include insomnia, fever, anxiety, headache, chills, vertigo, depression, confusion, delirium, encephalopathy, and cerebral hemorrhage [49].
Triazines
Dacarbazine
Dacarbazine causes DNA double-strand breaks leading to cell apoptosis. It is commonly used in Hodgkin’s lymphoma, melanoma, and many sarcoma histologies. Seizures, encephalopathy, and dementia have rarely been reported [50]. Mild neurotoxicy, such as headache and fatigue, are more common and self-limiting.
Temozolomide
Temozolomide is a prodrug that is converted to the active alkylating metabolite MTIC. It is used in the treatment of Ewing’s sarcoma, melanoma, and many types of brain tumors including astrocytoma and glioblastoma. Central neurotoxicity appears to be very uncommon, with reports of seizures and exacerbation of focal neurological deficits [51]. However, it is difficult to differentiate if these symptoms might be related to the underlying brain tumor, the medication, or a combination of both. Transient neurological deterioration may occur in the early stages of therapy in glioma patients and has been referred to as “tumor flare” syndrome, “treatment effect,” and tumor “pseudoprogression” [52, 53]. The incidence of tumor “pseudoprogression” ranges from 28 to 66% in glioblastoma patients and typically occurs within 3 months post-completion of temozolomide and concurrent radiation [53]. Neuroimaging shows an increased area of contrast enhancement and enlargement of noncontrast T2/FLAIR hyperintensities surrounding the enhancement. Treatment of “pseudoprogression” may include corticosteroids, bevacizumab, or watchful waiting with short-interval brain MRI depending on the extent radiological changes and neurological symptoms.
Ethylenimines
Thiotepa
Thiotepa is an alkylating agent that produces DNA cross-links leading to inhibition of DNA, RNA, and protein syntheses. It is used for ovarian cancer, intracavitary effusions, intrathecally for leptomeningeal metastases, intravesically for bladder cancer, and at high doses for hematopoietic stem cell transplant in patients with active CNS malignancy. It readily crosses the BBB [54]. Thiotepa may cause chills, vertigo, fatigue, fever, and headache. Intrathecal use can cause similar toxicity to that of MTX and Ara-C including a mild, reversible aseptic meningitis and, in rare cases, a transient or persistent myelopathy [55–57]. Neurotoxicity from thiotepa is significantly increased in patients with previous CNS radiation [58]. CNS toxicity is rare at conventional IV doses. High doses of thiotepa IV have been associated with neurotoxicity in the form of encephalopathy, including fatal encephalopathy [59].
Hexamethylmelamine (Altretamine)
Hexamethylmelamine structurally resembles an alkylating agent but has demonstrated activity in tumors resistant to classic alkylating agents. Its mechanism is not fully understood, but it is thought to bind and damage DNA. It is used for recurrent ovarian cancer [60]. The parent drug does not readily cross the BBB, but the metabolites readily enter the CNS. Peripheral neuropathy with hexamethylmelamine can occur, but the drug has been administered safely to patients with pre-existing neuropathy due to cisplatin [61, 62]. It is recommended that a neurological examination be done routinely before each cycle and throughout treatment. The most common neurotoxic side effects include headache and mild encephalopathy. Less frequent CNS toxicities include seizures, ataxia, tremor, and Parkinsonism. These usually occur in patients receiving high-dose daily treatment, and in most cases are reversible after drug discontinuation [59].
Platinum Compounds
Cisplatin (Cis-Diamminedichloroplatinum (II), CDDP, DDP)
Cisplatin inhibits DNA synthesis by the formation of DNA cross-links. It is utilized in a variety of oncologic and hematologic malignancies. Cisplatin has a wide range of neurotoxicity including peripheral neuropathy, ototoxicity, vestibulopathy, and encephalopathy.
The peripheral neuropathy associated with cisplatin is a sensory peripheral neuropathy. This typically begins developing at a cumulative dose of 300 mg/m2. Once a cumulative dose of 500–600 mg/m2 has been achieved, almost all patients have evidence ofperipheral neuropathy [63–65]. Increasing the dose intensity of cisplatin therapy has been shown not to increase the severity of the peripheral neuropathy [66]. There is significant variance among patients in the susceptibility of peripheral neuropathy [64, 67, 68], thought to be due to genetic polymorphisms in the enzymes responsible for cisplatin metabolism [69, 70].
Cisplatin-induced peripheral neuropathy is an axonal neuropathy that affects large myelinated sensory fibers [63, 67, 71, 72]. The major site of damage is the dorsal root ganglion [73], where cisplatin promotes alterations in cell-cycle kinetics leading to induction of apoptosis [74]. Oxidative stress and mitochondrial dysfunction may also trigger neuronal apoptosis and could also play a role in cisplatin-induced peripheral neuropathy [75–77].
Symptomatology of cisplatin-induced peripheral neuropathy includes numbness, paresthesias, and pain. Normally these symptoms begin bilaterally in the toes and fingers, spreading proximally to the arms and legs. Pinprick, temperature sensation, and motor strength are usually intact or less severely affected compared to proprioception and reflexes [63]. Nerve conduction studies exhibit sensory axonal damage, with decreased amplitude of sensory nerve action potentials and prolonged sensory latencies [78].
After discontinuation, cisplatin-induced peripheral neuropathy worsens in 30% of patients [71, 72], and symptoms may even begin after therapy is discontinued. A large study in patients with testicular cancer found that peripheral neuropathy remained detectable on long-term follow-up (i.e., greater than 5 years) in approximately 20% of patients, and caused significant symptoms in 10% of patients [65]. Once developed, there is no effective therapy to reverse the neuropathy and treatment is aimed at controlling symptoms. Over time, the peripheral neuropathy improves but full recovery is often not observed.
High-frequency sensorineural hearing loss with tinnitus is a dose-dependent toxicity of cisplatin [79]. This has been reported with both intravenous and rarely with intraperitoneal use [80]. Cisplatin-induced ototoxicity occurs from damage to the outer hair cells in the organ of Corti and the vascularized epithelium in the lateral wall of the cochlea [81, 82]. Ototoxicity occurs in approximately 15–20% of patients receiving cisplatin, and early detection with audiometry is vital to prevention as there is no consensus on pharmacologic agents to prevent or treat this toxicity.
The most frequent neurotoxic side effects of cisplatin involve the peripheral nervous system . However, central nervous system toxicity can also be very significant in selected patients, and will depend on the dose and route of administration (i.e., IV vs. IA). Seizures and diffuse encephalopathy are the most common forms of CNS toxicity associated with cisplatin [83–85], yet still rarely occur (Fig. 15.1a, b). This occurs due to acute injury to neural tissues, metabolic abnormalities, or a combination of both. Hypomagnesaemia is common in patients receiving cisplatin, noted in 55–60% of patients. It is caused by impaired magnesium reabsorption in the proximal renal tubules [86]. Both seizure activity and encephalopathy can occur in the setting of hypomagnesaemia, along with diffuse muscle weakness, depending on the severity of the magnesium deficit. Patients are also at risk for hyponatremia, which can result from the syndrome of inappropriate antidiuretic hormone (SIADH) , excessive hydration with hypotonic fluids during cisplatin infusion, or severe cisplatin-induced emesis [87]. In rare cases, especially those with intracranial space-occupying lesions, excessive hydration during cisplatin therapy can result in cerebral edema, somnolence, seizure activity, and tonsillar herniation [88]. Lhermitte’s phenomenon , manifesting as paresthesias in the back and extremities with neck flexion can be seen in patients receiving cisplatin. This is most likely caused from transient demyelination of the posterior columns [89]. Lhermitte’s phenomenon is self-limiting after drug discontinuation [90, 91]. Encephalopathy may occur as a direct toxic effect during IV treatment, but is even more common during IA infusion [3, 92]. Other symptoms that can arise during or within hours to days of IV cisplatin include stroke, seizures, cortical blindness, retinal toxicity, dysphasia, and focal motor deficits. The neurological injury usually resolves without specific intervention and may not recur with subsequent cycles of cisplatin. In patients with stroke, angiography may reveal branch occlusion or, in some cases, be completely normal. The cause of cisplatin-induced stroke remains unclear; possible mechanisms include vasospasm in the setting of hypomagnesaemia, coagulopathy, and drug-induced endothelial injury.
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Fig. 15.1
a, b Acute cisplatin toxicity. The MRI with sagittal (a) and axial (b) T1-weighted and gadolinium enhanced sequences shows multiple small hemorrhages and small necrotic cysts with minor focal contrast enhancement and small edema restricted to the corpus callosum. The 38-year-old developed significant lethargy and confusion after the second cycle of cisplatin chemotherapy (cisplatin, ifosfamide, and etoposide) for testicular cancer (Generously provided by Dr. Patrick Wen, Dana-Farber Cancer Institute, Boston, MA.)
Intra-arterial cisplatin is associated with a broad range of CNS neurological complications, including encephalopathy, confusional states, seizures, stroke, chronic leukoencephalopathy, and ocular toxicity [3, 92]. The ocular injury can manifest as optic neuropathy and/or retinopathy, and may include retinal infarcts. The risk for ocular toxicity is reduced if the catheter is advanced beyond the origin of the ophthalmic artery. However, supra-ophthalmic delivery of cisplatin has been associated with more frequent and severe neurological toxicity.
Carboplatin
Carboplatin is a platinum alkylating agent that covalently binds to DNA-producing interstrand DNA cross-links. It is used in many different solid and hematologic malignancies, as well as in high doses for hematopoietic stem cell transplant. Peripheral neuropathy and CNS toxicity are uncommon when carboplatin is given at conventional dosing. A severe neuropathy can develop with higher than standard dose carboplatin, in the setting of hematopoietic cell transplantation [93]. Reversible posterior leukoencephalopathy has been described with carboplatin [94] and retinal toxicity after IA administration [95], along with stroke-like symptoms [96] and cortical blindness [97]. The incidence of neuropathy is lower than with cisplatin [98]. Carboplatin, via the IA route, has been used for the treatment of primary or metastatic brain tumors and appears to have less neurotoxicity compared to cisplatin [3].
Oxaliplatin
Oxaliplatin forms cross-links in DNA leading to inhibition of DNA replication and transcription. It is commonly used in colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, and types of lymphomas. Peripheral neuropathy is common with oxaliplatin and comprises two distinct syndromes. The first is an acute peripheral neurotoxicity that can appear during or shortly after the first couple of infusions. The second is a cumulative sensory neuropathy, with distal loss of sensation and dysesthesias. Oxaliplatin-induced peripheral neuropathy is extremely common with greater than 85% of patients affected [99].
Acute symptoms are more frequently observed at single doses ≥130 mg/m2 than with doses ≤85 mg/m2 [100]. Typical symptoms include cold intolerance with discomfort swallowing cold beverages, throat discomfort, sensitivity to touching cold items, paresthesias and dysesthesias of the hands, feet, and perioral region, and muscle cramps. Prolonging the infusion time from 2 to 6 h decreases the incidence of acute neuropathy including pseudolaryngospasm [101].
General consensus has been that oxaliplatin-induced acute neuropathy resolves after two to three days; a more recent report suggests that it may not completely resolve between oxaliplatin doses with every two-week dosing [102]. Symptoms are typically most severe with the first cycle but recur with each cycle. In subsequent cycles, the severity of the acute neuropathy is approximately half as severe compared to the first cycle and maintains that severity throughout treatment [102].
The mechanism of oxaliplatin-induced acute peripheral neuropathy has been postulated to be a result of chelation of calcium by oxalate, a metabolite of oxaliplatin. This causes a transient activation of disinhibited peripheral nerve voltage-gated calcium-dependent sodium channels, causing hyperexcitability of peripheral nerves [103, 104]. As patients progress through therapy, acute changes in axonal excitability seem to become less pronounced. This is likely due to chronic nerve dysfunction and sensory loss that mask the acute effects at higher cumulative doses [105]. Calcium and magnesium supplementations for treatment and prevention are controversial. Several studies have shown benefit [106–108] while others, including a prospective phase III study, were not able to show benefit [109, 110].
The second distinct oxaliplatin-induced peripheral neuropathy is a cumulative sensory neuropathy. It is dose-limiting with a late onset comparable to that of cisplatin. It presents as a symmetric distal axonal neuropathy without motor involvement, and with rare autonomic involvement. The mechanism of this neuropathy is similar to cisplatin. Oxaliplatin forms fewer platinum-DNA adducts compared to cisplatin, and thus is slightly less neurotoxic [111]. Other rare manifestations of neurotoxicity include urinary retention and Lhermitte’s phenomenon in patients receiving high cumulative oxaliplatin doses [112, 113]. Reversible posterior leukoencephalopathy has also been reported [114–116].
Other Alkylating Agents
Procarbazine-HCL ( N-Methylhydrazine)
Procarbazine is a prodrug that is activated in the liver. It inhibits transmethylation of methionine into transfer RNA and thus inhibits DNA, RNA, and protein syntheses. It penetrates the BBB and is used for the treatment of lymphomas and brain tumors. Procarbazine can cause a mild reversible encephalopathy at normal doses (100 mg/m2 for 14 days every 28 days). At this dose it may also rarely cause psychosis and stupor [117]. The incidence of encephalopathy may be higher in patients receiving higher doses for gliomas [118]. In addition, due to its weak activity as an MAO inhibitor, procarbazine can cause hypertensive encephalopathy, headache, and delirium when administered in combination with sympathomimetic agents or after consumption of tyramine-containing foods.
Antimetabolites
5-Fluorouracil (5-FU)
5-FU is a pyrimidine analog metabolite that interferes with DNA and RNA syntheses. It is a prodrug that inhibits thymidylate synthetase, depleting thymidine triphosphate, which is a necessary component of DNA synthesis. It is used in many oncologic settings including breast cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, and others.
5-FU rarely causes an acute cerebellar syndrome manifesting as acute onset of ataxia, dysmetria, dysarthria, and nystagmus [119, 120]. It can develop weeks to months after the initiation of therapy. 5-FU is known to readily cross the BBB and has been found to have the highest concentration in the cerebellum, potentially explaining the acute cerebellar syndrome. Clinical investigations with CT, MRI, and CSF evaluation are generally unremarkable. 5-FU should be discontinued if patients experience cerebellar toxicity and over time signs and symptoms usually resolve completely. Encephalopathy has also been described with 5-FU chemotherapy [121–124]. In these cases, elevated serum ammonia levels without evidence of decompensated liver have been observed. Risk factors associated with encephalopathy include renal dysfunction, weight loss, and constipation.
Other rare neurologic side effects of 5-FU include seizure [125], peripheral neuropathy [126], a parkinsonian syndrome [127], cerebrovascular disorders [128], focal dystonia [129], eye movement abnormalities [130], and optic neuropathy [131]. Approximately 3–5% of the general population has a deficiency in the enzyme responsible for 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD) [132, 133]. Patients with a DPD deficiency are at increased risk of developing severe neurologic toxicity, including cerebellar toxicity [134].
The biochemical basis of 5-FU neurotoxicity remains unknown [125, 135]. Pathological examination of the brains of patients with 5-FU neurotoxicity is usually benign, with minimal if any abnormality. Numerous theories have been proposed, including blockade of the Kreb’s cycle by fluoroacetate, a by-product of 5-FU catabolism that is able to inhibit the Kreb’s cycle enzyme aconitase. Another proposal suggests that the drug may induce neurological toxicity via an acute deficiency of thiamine, since 5-FU is able to block the production of thiamine phosphate, the active form of the vitamin [136].
The differential diagnosis of 5-FU neurotoxicity is broad, and covers a wide range of disease processes, including cerebellar metastases, paraneoplastic cerebellar syndromes, vertebrobasilar ischemia, and intoxication by other medications.
Capecitabine
Capecitabine is an oral prodrug that is converted to fluorouracil in the liver and tissue. It is commonly used in breast cancer, colorectal cancer, and many other malignancies. Neurotoxicity includes fatigue, paresthesia, lethargy, neuropathy, headache, insomnia, vertigo, depression, and mood changes [137–139]. A subacute encephalopathy is rare with symptoms of confusion, memory loss, and white matter changes on MRI [140, 141]. Symptoms resolve within days following discontinuation of therapy. Cranial MRI showed some nonspecific white matter changes [140], while other reports detail more pronounced white matter changes on MRI in patients with capcitabine-induced encephalopathy [140, 141]. Pure syndromes causing only encephalopathy or a cerebellar syndrome have also been described [142, 143].
Mercaptopurine
Mercaptopurine is used in the maintenance phase for acute lymphoblastic leukemia. It is a purine antagonist that inhibits DNA and RNA syntheses. Neurotoxicity is rare and mainly includes fatigue. Cases of drug fever have been reported [144].
Cytosine Arabinoside (Ara-C, Cytarabine)
Cytosine arabinoside (Ara-C) is a pyrimidine analog that is phosphorylated within tumor cells into aracytidine triphosphate (Ara-CTP), the active moiety that inhibits DNA polymerase. It is commonly used in multi-agent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for carcinomatous meningitis. Central neurotoxicity from Ara-C is usually noted in the context of high-dose IV therapy (≥3 g/m2 every 12 h × 4–6 days), and typically presents with a subacute, pancerebellar syndrome [145–147]. In most cases, the onset of symptoms is within hours to days of completion of the infusion but can rarely occur during the infusion. The size of an individual dose may be more important than the cumulative dose of the drug. Patients with renal failure are at increased risk of developing the syndrome. The decrease in use of high-dose Ara-C in patients with renal dysfunction has led to a decrease in the incidence of cerebellar syndrome [148]. Symptoms include dysarthria, dysmetria, ataxia, nystagmus, and dysdiadochokinesia. Signs of cerebral dysfunction, such as somnolence, altered mentation, headache, and seizures [149], can also be noted in some patients. Symptoms usually resolve after complete discontinuation of Ara-C.
MRI shows T2/FLAIR hyperintensities, with white matter abnormalities and cerebellar atrophy almost resembling reversible posterior leukoencephalopathy [150] (Fig. 15.2). CSF analysis is usually unremarkable and EEG may show slowing. On neuropathological examination, the most common findings are cerebellar cortical atrophy and Purkinje cell loss.
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Fig. 15.2
Leukoencephalopathy after high-dose Ara-C and idarubicin. The axial MRI reveals extensive and diffuse T2/FLAIR air hyperintensities affecting bilateral subcortical white matter consistent with diffuse leukoencephalopathy. Two years earlier, this 44-year-old patient received chemotherapy with cytosine arabinoside/idarubicin and bone marrow transplant for AML. The patient became increasingly symptomatic with progressive cognitive impairment and recurrent falls (Generously provided by Dr. Patrick Wen, Dana-Farber Cancer Institute, Boston, MA.)
Other central neurotoxic effects of IV Ara-C include Horner’s syndrome, parkinsonism [151], and anosmia [152, 153]. Peripheral neurotoxicy is rare. Neuropathies have been described with high doses [154–156] but are most commonly described in the setting of other neurotoxic agents [157, 158]. Demyelinating [152, 159], axonal [160], and fatal cases of neuropathy [158, 160] have been reported.
Intrathecal use of Ara-C can produce a mild chemical meningitis, similar to methotrexate [161]. Myelopathy [162, 163], seizure [149], papilledema [164], and locked-in syndrome [165] have been associated with intrathecal use. Neurotoxicity is more common with the liposomal, sustained-release preparation of Ara-C (i.e., DepoCyt®, Sigma-Tau Pharmaceuticals, Gaithersburg, MD), and can recur with subsequent doses of the drug. Dexamethasone prophylaxis should be used in all patients receiving IT liposomal Ara-C to decrease the incidence and severity of chemical meningitis. Rarely, seizures, and confusional syndromes occur with IT usage.
Floxuridine
Floxuridine is catabolized to fluorouracil after IA administration, inhibiting thymidylate synthetase and interrupting DNA and RNA synthesis. It is administered intra-arterially for hepatic metastases from colorectal cancer. Due to the local administration, neurotoxicity is rare.
Fludarabine
Fludarabine inhibits DNA synthesis by blocking DNA polymerase and ribonucleotide reductase, leading to cell apoptosis. It is mainly used in chronic lymphocytic leukemia (CLL) . Serious neurotoxicity has been observed at higher than recommended doses (up to 96 mg/m2/day for 5–7 days) including delayed blindness, coma, and death [166]. After high-dose fludarabine, neurotoxicity generally appeared from 21 to 60 days following the last dose of fludarabine, and has been reported as early as 7 days and as late as 225 days after treatment. At the standard dose of 40 mg/m2, severe neurotoxicity is observed in less than 1% of patients [167]. Other neurotoxicity including agitation, coma, confusion, and seizure has been reported with standard CLL doses [167].
Reports of fludarabine neurotoxicity have relied on brain CT or have described MRI abnormalities without detail [166–171]. One series of three patients describes variable, ill-defined, mildly hyperintense lesions on the periventricular and periarterial cerebral white matter on T2 and FLAIR sequences with restricted diffusion but no enhancement. The MRI abnormalities were minimal compared to the profound clinical deficits of the patients. Abnormalities reportedly increased in intensity and size over time, further emphasizing the point that fludarabine neurotoxicity appears to be delayed with progressive lesions many weeks after drug cessation [172].
Progressive multifocal leukoencephalopathy (PML) has been reported with the use of fludarabine [173–180] (Fig. 15.3a–d). The majority of these patients had received previous chemotherapy and/or other concurrent chemotherapy. The onset of PML may be within a few weeks or can be delayed up to one year [167, 170]. PML may be confused with fludarabine neurotoxicity as described above; however, imaging should differentiate the two. PML lesions involve the subcortical white matter and do not show restricted diffusion with lesion size correlating with clinical symptoms. Both PML and fludarabine neurotoxicity generally lack enhancement and mass effect.
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Fig. 15.3
a–d This 78-year-old woman with an 8-year history of CLL developed slowly progressive right hemiparesis and hand twitching over several months. She had received rituximab and fludarabine within one year of onset of these symptoms. FLAIR MR sequences demonstrated multiple hyperintense lesions (a, b). Brain biopsy revealed prominent gliosis with scattered cells with enlarged nuclei and stippled, rim-like chromatin patter suggestive of viral inclusions (c). Immunohistochemistry for JC virus showed positive staining of these cells (d) (Generously provided by Dr. David Schiff, University of Virginia, Charlottessville, VA.)
Gemcitabine
Gemcitabine , a pyrimidine antimetabolite, inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase. It is used in breast, lung, ovarian, pancreatic, cervical, bladder, sarcoma, and head and neck cancer. Posterior reversible encephalopathy syndrome (PRES) has been reported both with single-agent and with combination chemotherapy [181–184]. PRES may manifest with blindness, confusion, headache, hypertension, lethargy, seizure, and other visual and neurologic disturbances. Therapy should be discontinued if PRES is confirmed. Other neurotoxicity includes drowsiness and paresthesias. Peripheral neurotoxicity can occur, with studies showing that approximately 20% of patients treated with gemcitabine experience sensory neuropathy; however, it should be noted that in these studies gemcitabine was administered with oxaliplatin [185, 186].
Hydroxyurea
Hydroxyurea is an antimetabolite that inhibits ribonucleotide reductase thus halting the cell cycle at the G1/S phase. For sickle cell anemia, hydroxyurea increased red blood cell (RBC) hemoglobin F levels, RBC water content, deformability of sickled cells, and alters the adhesion of RBCs to endothelium. It is used for chronic myelocytic leukemia, in solid tumors in conjunction with radiation, and sickle cell anemia. Significant neurotoxicity is rare with only scattered reports of mild encephalopathy and headaches [187].
Methotrexate (Amethopterin , MTX)
Methotrexate (MTX) is an antimetabolite drug that inhibits the enzyme dihydrofolate reductase. This inhibition prevents the conversion of folic acid into tetrahydrofolate, and inhibits DNA synthesis in the S phase of the cell cycle. MTX is often used for systemic malignancies such as leukemia, lymphoma, and sarcoma, and is also the most effective chemotherapeutic agent for primary CNS lymphoma [188]. The drug does not cross the BBB very well, as it is highly ionized and somewhat hydrophobic. Therefore, CNS toxicity is uncommon unless MTX is administered IV at high doses or via the IT route. MTX-induced neurotoxicity can be divided into acute (during or within hours of administration), subacute (days to weeks after administration), and chronic (months to years after administration) effects.
Acute/Subacute Effects
After IT administration, MTX induces a chemical meningitis in approximately 10% of patients [189, 190]. Symptoms include headache, stiff neck, photophobia, and low-grade fever, arising within hours of drug administration and potentially lasting for days. CSF analysis will typically demonstrate a mild pleocytosis, with no evidence of a viral and/or bacterial process. The reaction appears to be idiosyncratic, does not usually recur with subsequent cycles of IT treatment, and does not seem to be dose-related. Oral corticosteroids or hydrocortisone along with the MTX may decrease the severity and incidence of chemical meningitis. The symptoms are usually self-limiting and require no treatment. Patients that have had an acute reaction to IT MTX do not appear to be predisposed to developing a late or chronic effect of the drug.
Less common acute and subacute side effects of IT and systemic MTX include seizures, encephalopathy, transient focal neurologic deficits, and transverse myelopathy [189, 190]. Seizures rarely occur as an acute toxicity after IT administration and are self-limiting. The most extensive experience with this complication has been in pediatric patients receiving IT MTX for treatment of acute leukemia [191]. Acute and subacute encephalopathy can occur in the setting of high-dose IV MTX (3–12.5 g/m2; 2.5–15% of patients), most often administered in combination with other chemotherapy agents for CNS lymphoma [188]. The clinical presentation typically includes somnolence, the acute onset of focal signs such as hemiparesis, dysphasia, dysarthria, and occasional seizure activity. Brain CT and MRI may demonstrate transient white matter abnormalities, or can be normal in some cases (Fig. 15.4). One report discussed the use of MRI within 1 h of onset of the syndrome. This revealed bilateral, symmetrical restricted diffusion involving white matter of the cerebral hemispheres, without evidence of vasospasm or perfusion defect [192]. The authors suggested that transient cytotoxic edema in the white matter was the likely mechanism of MTX-induced neurotoxicity. EEG evaluation usually reveals an abnormal study, with diffuse slowing of the background. The syndrome is not likely to correlate with serum or CSF MTX concentrations, and symptoms can occasionally recur with subsequent courses of treatment. In most cases, there is complete resolution of the clinical and imaging abnormalities but, rarely, a chronic leukoencephalopathy can be noted. Transverse myelopathy can occur after IT MTX, often within hours to weeks of administration of the drug [190, 193]. In most cases, the toxicity develops after the patient has received multiple doses of MTX. The clinical examination reveals bilateral leg weakness, pain, spasticity, sensory loss, bladder dysfunction, and gait difficulty. MRI of the spinal cord may be normal or show T2 high signal abnormalities with patchy enhancement [194]. Pathological examination is often unrevealing, although one case has been reported with vacuolar degeneration and necrosis, without inflammation [195]. The symptoms improve after drug discontinuation but the extent of improvement is variable [196]. Accidental overdosage of IT MTX is extremely uncommon, with cases describing no neurologic injury [197] and others reporting severe reactions to overdosage, with rapidly progressive encephalopathy and death [198]. Potential treatment options for patients with an overdose of IT MTX include CSF drainage, ventriculo-lumbar perfusion, and administration of IT carboxypeptidase-G2, an enzyme that hydrolyzes MTX into inactive metabolites [199, 200].
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Fig. 15.4
Acute methotrexate toxicity. The axial MRI shows bihemispheric T2/FLAIR hyperintensities with frontal and occipital accentuation after intrathecal methotrexate injection in a 19-year old with AML. The patient developed mental status changes and confusion 1–2 h after methotrexate injection (Generously provided by Dr. Patrick Wen, Dana-Farber Cancer Institute, Boston, MA.)
Chronic Effects
Chronic and/or late side effects of IT and IV MTX occur at least six months after initial drug administration [189, 190]. The most common chronic effect is a leukoencephalopathy, which is well described in children with acute leukemia, but can also occur in adults [201]. In children, the clinical presentation includes progressive learning disorders, developmental delay, memory loss, gait difficulty, and urinary incontinence. These symptoms are similar in adults, with confusion and memory loss that often progresses to dementia, as well as somnolence, irritability, impaired vision, dysphasia, seizures, and ataxia. Imaging with CT and MR reveals diffuse white matter damage, cortical atrophy, ventricular enlargement, and punctate areas of calcification within the basal ganglia and deep white matter (Fig. 15.5). In addition, asymptomatic patients who have only received high-dose IV or IT MTX may demonstrate similar, but much milder, damage to the white matter on imaging studies.
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Fig. 15.5
Leukoencephalopathy. A 75-year-old woman with primary central nervous system lymphoma was treated with CHOP, ten doses of intraventricular methotrexate, and fractionated whole brain radiotherapy (5040 cGy in 28 fractions). Her tumor responded and never recurred. Three years later, she noted moderate short-term memory deficits and gait unsteadiness. MRI (axial T2-weighted image) demonstrated extensive periventricular white matter changes. The patient’s dementia progressed, and she developed rigidity and mutism prior to her death one year later (Generously provided by Dr. Patrick Wen, Dana-Farber Cancer Institute, Boston, MA.)
The leukoencephalopathy is most likely to occur after combination treatment with high-dose IV MTX, IT MTX, and cranial irradiation (45%), with a much lower incidence following high-dose MTX and/or IT MTX alone (2% or less) [190, 202]. Neurotoxicity is especially enhanced when the patient receives irradiation before the administration of MTX (Fig. 15.6). The mechanisms underlying this synergistic toxicity remain unclear. It may be due to a radiation-induced increase in the permeability of the BBB, reduced clearance of MTX from the CSF, increased passage of MTX into the white matter through the ependymal–brain barrier, and potential direct cellular toxicity caused by irradiation [190]. Neuropathological changes are most notable around the periventricular white matter and deep centrum semiovale, and include demyelination, multifocal white matter necrosis, astrocytosis, dystrophic calcification of deep cerebral vessels, and axonal damage. Inflammatory cellular infiltration is typically not present.
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Fig. 15.6
Disseminated necrotizing leukoencephalopathy. This 44-year-old man with Burkitt’s lymphoma developed progressive lethargy and subsequent coma weeks after receiving fractionated radiotherapy to the skull base and eight doses of intraventricular methotrexate for lymphomatous involvement of the right cavernous sinus. Multiple CSF exams demonstrated no leptomeningeal lymphoma despite his neurologic deterioration. Persistent vegetative state ensued, and he died 2 months later from systemic relapse. MRI (coronal, T1 with gadolinium) demonstrated multiple scattered punctate foci and abnormal signal, particularly in the deep gray nuclei, with contrast enhancement. Postmortem analysis revealed multiple discrete, microscopic foci of demyelination, axonal loss, and necrosis distributed in a random manner throughout the white matter and gray/white interface. The foci contained a moderate to large number of CD68-immunoreactive foamy macrophages and a scant number of perivascular lymphocytes. Although there was no evidence of dural lymphoma, there was no leptomeningeal tumor identified (Generously provided by Dr. Patrick Wen, Dana-Farber Cancer Institute, Boston, MA.)
Pemetrexed
Pemetrexed acts as an antifolate by disrupting folate-dependent metabolic processes essential for cell replication. It is indicated in the treatment of pleural mesothelioma and non-small cell lung cancer. It has little associated neurotoxicity. Fatigue is a dose-limiting toxicity and depression has been rarely reported [203].
Pralatrexate
Nelarabine
Nelarabine is a prodrug that incorporates into DNA of leukemic blasts and inhibits DNA synthesis inducing cell apoptosis. It is used in the treatment of T-cell acute lymphoblastic leukemia (ALL) . When first studied, a higher dose was utilized that produced significant neurotoxicity. In phase II trials, 40–72% of patients have had neurotoxicity of any grade attributed to nelarabine, and 15–20% had severe neurotoxicity [206–208]. CNS toxicity can manifest in numerous ways including somnolence, vertigo, headache, hypoesthesia, ataxia, confusion, depressed level of consciousness, seizure, motor dysfunction, amnesia, gait disorders, sensory loss, aphasia, encephalopathy, etc. One series described three patients post-stem-cell transplant that developed irreversible paresthesias and muscle weakness in both lower extremities after neutrophil engraftment [209].
Dosing should occur on alternate days to decrease neurotoxicity, as early studies found that daily administration can result in 72% of patients experiencing some form of neurotoxicity [210]. A demyelination syndrome similar to Guillain-Barre syndrome, with an ascending peripheral neuropathy, has also been reported [206]. Neurologic toxicity may not fully resolve even after treatment cessation. Studies have shown that concurrent or previous intrathecal chemotherapy or crainospinal irradiation increase the risk of nelarabine-induced neurotoxicity [211].
Many antimetobolite chemotherapy agents cause neurotoxicity, and the mechanism for nelarabine-induced neurotoxicity remains unknown. CNS consequences of abnormal purine metabolism can occur in patients with a purine nucleoside phophorylase deficiency that is associated with spasticity and other neurologic abnormalities [212, 213]. Cytotoxic ara-GTP, the prodrug of nelarabine, has been postulated to be in high concentrations in brain and nerve tissue due to the high levels of deoyguanosine kinase activity. Further studies are needed to determine the risk factors and pathogenesis of nelarabine-induced neurotoxicity.
Clofarabine
Clofarabine is a purine nucleoside analog used for acute lymphoblastic leukemia (ALL). Hemorrhage, including intracranial hemorrhage, has been seen due to the profound thrombocytopenia that is associated with therapy. CNS toxicity includes headache, chills, fatigue, anxiety, irritability, lethargy, agitation, mental status changes, and confusion [214, 215].
Thioguanine (6-TG)
Thioguanine is a purine analog that incorporates into DNA and RNA blocking the synthesis of purine nucleotides. It is used in the treatment of pediatric patients with ALL. No central or peripheral neurotoxicity has been reported.
Cladribine (2-Chlorodeoxyadenosine)
Cladribine is a purine nucleoside analog that incorporates into DNA and results in DNA strand breaks, shutting down DNA synthesis and repair. It is utilized in the treatment of hairy cell leukemia. Cladribine is associated with dose-related neurologic toxicity including irreversible paraparesis and quadriparesis. This was reported with continuous infusion or higher doses (4–9 times conventional dosing), but may still rarely occur at the normal dose. This neurotoxicity may be delayed and present as progressive, irreversible weakness. Diagnostics with electromyography and nerve conduction studies are consistent with demyelinating disease. Treatment with cladribine is also associated with fever with or without neutropenia. Other central neurotoxicity includes fatigue, headache, dizziness, insomnia, and anxiety. Cases of confusion and progressive multifocal leukoencephalopathy have also been reported [216].
Pentostatin (2′-Deoxycoformycin)
Pentostatin is a purine antimetabolite that inhibits adenosine deaminase. The anti-tumor effects occur due to a reduction in purine metabolism which blocks DNA synthase and ultimately leads to cell death. It is used in hairy cell leukemia. Phase I dose findings studies showed increased neurotoxicity at higher doses (5–30 mg/m2/day for 1–5 days) [217]. Toxicity included somnolence, lethargy, and one case of fatal coma. CNS toxicity was described as delayed onset and prolonged lasting as long as three weeks. Neurotoxicity is infrequent when used within the typical dose range. Ocular toxicity has also been reported as blurred vision, photophobia, and retinopathy [217, 218].
Anti-Tumor Antibiotics
Anthracyclines
Doxorubicin, Daunorubicin, Epirubicin, Idarubicin
Doxorubicin and daunorubicin are anthracycline antibiotics that bind nucleic acids, disrupting the structural integrity of DNA, and are used for the treatment of numerous hematologic and solid malignancies. Following IV infusion, neither drug penetrates the BBB to any significant degree; central neurotoxicity has not been reported. Doxorubicin when administered with cyclosporine has resulted in neurological symptoms and coma [219]. However, when administered IA for brain tumors, doxorubicin has been linked to cerebral infarcts and hemorrhagic necrosis [220]. Inadvertent IT injection of either drug can lead to an acute or subacute ascending myelopathy and encephalopathy, which can be fatal [221].
Epirubicin is an anthracycline known to inhibit DNA and RNA syntheses by intercalating between DNA base pairs used in breast cancer, gastric cancer, and types of sarcoma. Neurotoxicity is rare though studies have reported lethargy and fever.
Idarubicin is mainly used in the treatment of acute myeloid leukemia (AML) . Like other anthracyclines, it inhibits DNA and RNA syntheses by intercalation between DNA base pairs. Neurotoxicity is rare with headache and seizure described. All anthracyclines can cause arrhythmias and cardiomyopathies that can lead to cerebrovascular complications.
Other Anti-Tumor Antibiotics
Dactinomycin
Bleomycin Sulfate
Bleomycin acts by directly binding to DNA, leading to both single- and double-strand breaks, as well as inhibiting RNA and protein synthesis. Bleomycin is utilized in the treatment of testicular cancer, and Hodgkin’s lymphoma. Generally, neurotoxicity is uncommon. An idiosyncratic reaction has been reported in 1% of lymphoma patients treated with bleomycin that is similar to anaphylaxis, but can include symptoms of confusion, fever, and chills along with other non-CNS toxicity. Cerebral infarction has been described following the combination of bleomycin and cisplatin [224].
Mitomycin C
Mitomycin acts as an alkylating agent by producing DNA cross-links and therefore inhibiting DNA and RNA syntheses. It is used for gastric and pancreatic cancer. It is only known to cause central neurotoxicity in the context of mitomycin-induced disseminated intravascular coagulation and thrombotic microangiopathy, which can lead to headaches and other CNS complications [225].
Mitoxantrone
Mitoxantrone has a mechanism similar to anthracyclines by intercalating into DNA, resulting in cross-links and strand breaks. It is utilized in the treatment of acute myeloid leukemia (AML) and multiple sclerosis. Like anthracyclines, neurotoxicity is uncommon with headache, anxiety, depression, and seizures reported [226]. Radiculopathy and myelopathy have been reported following intrathecal administration [227].
Topoisomerase Inhibitors
Topoisomerase I Inhibitors
Topotecan
Topotecan is a topoisomerase I inhibitor and derives its activity from binding to topoisomerase I and stabilizing the cleavable complex so that relegation of the cleaved DNA strand cannot occur. It is used in cervical, ovarian, small cell lung cancer, and sarcoma. Neurotoxicity is rare with fatigue and headache reported [228, 229].
Irinotecan (CPT-11)
Irinotecan is a topoisomerase I inhibitor resulting in the prevention of re-ligation of single-strand breaks in DNA during DNA synthesis. It is used in colon, lung, cervical, ovarian, pancreatic, glioblastoma, and skin cancer. Irinotecan has been associated with nonspecific dizziness and insomnia, as well as occasional episodes of dysarthria, either alone or in combination with other drugs. The dysarthria resolves after discontinuation of the drug.
Topoisomerase II Inhibitors
Etoposide (VP-16)
Etoposide, a topoisomerase II inhibitor, delays transit of cells through the S phase and arrests cells in late S or early G2 phase, halting the cell cycle and leading to apoptosis. Etoposide is commonly used in lung cancer, testicular cancer, hematopoietic stem cell transplant, and mobilization. Neurotoxicity is uncommon, with rare reports of peripheral neuropathy, transient cortical blindness, and optic neuritis. Hypersensitivity reactions can occur during the infusion that can manifest with chills, fever, and loss of consciousness. It is important to note that the injectable formulation contains ethanol (approximately 33% v/v) and may contribute to neurotoxicity due to ethanol toxicity, especially at higher doses used for stem cell mobilization. Rarely, confusion, papilledema, somnolence, worsening motor deficits, and seizures have been described [230].
Teniposide (VM-26)
Teniposide (VM-26) is a topoisomerase II inhibitor that induces single- and double-strand breaks in DNA and DNA–protein cross-links. Teniposide is used in refractory acute lymphoblastic leukemia (ALL). It is highly protein bound and poorly penetrates the BBB. Hypersensitivity reactions can occur and include chills and fever. Acute CNS depression has been reported with high IV dosing [231]. Like in etoposide, there is an ethanol component to the diluent used in the medication, which can cause acute ethanol toxicity leading to CNS depression.
Mitotic Inhibitors
Paclitaxel
Paclitaxel is a semisynthetic derivative of the Western yew tree. It is a microtubule-inhibiting compound that is widely used in solid tumors, including breast and ovarian cancer. Paclitaxel stabilizes microtubules leading to mitotic arrest and apoptosis in dividing cells. The neurotoxicity of paclitaxel is manifested by a motor and sensory polyneuropathy [232]. The major manifestations are burning paresthesias of the hands and feet, as well as loss of reflexes. The main risk factor that contributes to the peripheral neuropathy is cumulative dose of approximately 1000 mg/m2 [233]. Paclitaxel may induce peripheral neuropathy after the first cycle of treatment with higher doses (>250 mg/m2) [234]. Paclitaxel also causes a motor neuropathy affecting proximal muscles [234].
There are conflicting data regarding the impact of the dosing schedule on paclitaxel-induced peripheral neuropathy. Studies have reported less neuropathy with weekly paclitaxel [235, 236], while others have found no difference [237]. The length of infusion has also been studied with conflicting results. Studies have found that increasing the infusion from 3 to 24 h decreases the incidence of neuropathy [238], while others did not find a difference in rates of severe neuropathy [239].
Less common paclitaxel neurotoxicity includes perioral numbness, autonomic neuropathies [232], seizure [240], transient encephalopathy [240, 241], and phantom limb pain [242]. There are reports of transient scintillating scotomas and occasional visual loss [243]. An acute pain syndrome associated with paclitaxel has been described. It is characterized by severe arthralgias and myalgias with numbness and tingling, beginning one to two days after treatment and lasting four to five days. Recent data suggest that this is a form of an acute neuropathy rather than a joint and/or muscle disorder [244–246].
Protein-Bound Paclitaxel
Protein-bound paclitaxel is an albumin-bound paclitaxel that promotes microtubule assembly and stabilizes the microtubules interfering with the mitotic phase and inhibiting cell replication. It is used in metastatic breast cancer, non-small cell lung cancer, and pancreatic adenocarcinoma. Like paclitaxel, this formulation commonly produces a sensory neuropathy. Rarely, autonomic neuropathy and cranial nerve palsy have been described [247]. Other neurotoxicity includes fatigue, headache, decreased visual acuity, optic nerve damage, and depression [248, 249].
Docetaxel
Docetaxel is derived from the needles of the European yew tree. Like paclitaxel, docetaxel promotes the assembly of microtubules and inhibits the depolymerization of tubulin which stabilizes the mircotubules, inhibiting DNA, RNA, and protein synthesis. It is commonly used in breast, non-small cell lung, prostate cancer, and sarcomas. Docetaxel, like paclitaxel, causes both sensory and motor neuropathies, although both occur less frequently in comparison to paclitaxel [236]. Peripheral neurotoxicity is directly related to the cumulative docetaxel dose with the threshold being approximately 400 mg/m2 [233]. A phase III trial in women with breast cancer patients used a dose of docetaxel of 100 mg/m2 every three weeks. The onset of moderate to severe neuropathy occurred at a median cumulative dose of 371 mg/m2 [250].
There are conflicting data as to the effect of the administration schedule on docetaxel-induced peripheral neuropathy. A trial in breast cancer patients compared docetaxel 75 mg/m2 every three weeks to 35 mg/m2 weekly and rates of severe peripheral neuropathy were higher with every three-week docetaxel administration (10% vs. 5%) [251]. Conversely, a meta-analysis of randomized trials in non-small cell lung cancer comparing the two dosing regimens found similar rates of moderate to severe peripheral neuropathy with both schedules (2.5% with every three-week administration versus 3% with weekly administration) [252]. Docetaxel has also been associated with Lhermitte’s phenomenon [253].
Cabazitaxel
Cabazitaxel is a taxane derivative that acts as a microtubule inhibitor by stabilizing microtubules and thus inhibiting tumor proliferation. It is used in castration-resistant prostate cancer. Central nervous system toxicity includes fatigue, vertigo, and headache [254]. Peripherally, cabazitaxel can cause peripheral neuropathy but a recent report indicated that there is significantly less peripheral neuropathy compared to docetaxel [255].
Eribulin
Eribulin is a non-taxane microtubule inhibitor used for metastatic breast cancer. It inhibits the growth phase of the microtubule by inhibiting the formation of mitotic spindles, thus arresting the cell cycle. Centrally, eribulin can cause fatigue, headache, depression, dizziness, insomnia, and myasthenia. 35% of patients report peripheral neuropathy, with 8% reporting severe neuropathy symptoms. The peripheral neuropathy associated with eribulin may be prolonged and lasts greater than one year in approximately 5% of patients [256–258].
Ixabepilone
Ixabepilone is a microtubuluar stabilizing agent that promotes tubulin polymerization and stabilizing the microtubular function, arresting the cell cycle, and inducing apoptosis. It is approved for metastatic breast cancer. The diluent of ixabepilone contains ethanol and patients should be cautioned about performing tasks that require alertness after treatment. Headache, vertigo, and insomnia have also been reported.
Peripheral sensory neuropathy is common (up to 63% of patients) and dose-limiting. The peripheral neuropathy typically occurs during the first three cycles of therapy. A peripheral motor neuropathy can also occur in approximately 10% of patients. Small studies have shown that ixabepilone exposure induces a dose-dependent toxicity on small sensory fibers and progression axonal loss where mitochondria appear to bear the cumulative toxic effect [259]. Cases of autonomic neuropathy have also been reported [260, 261].
Vincristine, Vinblastine, Vinorelbine
Vincristine binds to tubulin and inhibits microtubule formation arresting the cell at metaphase causing cell apoptosis. It is widely used in both solid and hematologic malignancies. Vincristine has poor penetration of the BBB and therefore is not commonly associated with central neurotoxicity. Mental status changes, depression, confusion, and insomnia rarely occur. These neurotoxicities occur more frequently in the presence of other neurotoxic agents and spinal cord irradiation. Ataxia, coma, dizziness, headache, seizures, and vertigo may also occur. Cranial nerve dysfunction manifesting as auditory damage, extraocular muscle impairment, laryngeal muscle impairment, paralysis, paresis, vestibular damage, and vocal cord paralysis can also occur.
The dose-limiting toxicity of vincristine is an axonal neuropathy. Vincristine disrupts the microtubules within the axons and interferes with axonal transport [262, 263]. These neuropathies include both sensory and motor fibers, with small sensory fibers being especially affected. Almost all patients treated with vincristine with have signs and symptoms of neuropathy. Early neuropathy manifests as paresthesias in the fingers and feet with or without pain. These symptoms develop at a cumulative dose of approximately 30–50 mg [264] but may occur after the first dose. Symptoms may also appear after the medication has been discontinued. Like other chemotherapy-induced peripheral neuropathy, the neuropathy improves over time but may not completely resolve. Risk factors for severe vincristine neuropathies include age, nutritional status, prior irradiation to peripheral nerves, concomitant hematopoietic colony-stimulating factors [265], use of azole antifungal agents or other CYP3A4 inhibitors [266, 267], and those with pre-existing neurologic conditions such as Charcot–Marie–Tooth syndrome [268, 269], and high-dose liposomal vincristine [270].
Autonomic neuropathies are common in patients who are treated with vincristine and may precede paresthesias or loss of deep tendon reflexes. Abdominal pain and constipation occur in almost 50% of patients; paralytic ileus can occur rarely [262]. Vincristine may also cause focal mononeuropathies, at times involving the cranial nerves [271], with the oculomotor nerve most commonly affected. Other nerves may be involved include recurrent laryngeal nerve, optic nerve, facial nerve, and the auditory nerve. Vincristine may also cause retinal damage and night blindness, and patients may experience jaw and/or parotid pain.
Vincristine can rarely cause inappropriate secretion of antidiuretic hormone (SIADH), resulting in hyponatremia, confusion, and seizures [272]. Other rare neurotoxicities include seizures [273], reversible posterior leukoencephalopathy [274, 275], transient cortical blindness [276], ataxia, athetosis, and parkinsonism.
Liposomal vincristine is approved for acute lymphoblastic leukemia and can also cause significant peripheral neuropathy [277–279]. Vincristine and liposomal vincristine are not interchangeable. With both agents intrathecal administration is associated with ascending myelopathy, coma, and death [280–282]. Pathological analysis after IT administration demonstrates diffuse necrosis in the brain and spinal cord in regions exposed to the CSF.
Vinblastine is used in many lymphomas, mycosis fungoides, testicular cancer, and Kaposi sarcoma. Vinblastine-induced peripheral neuropathy is less severe than that of vincristine, but occurs in the majority of patients. Vinorelbine is utilized in the treatment of lung and breast cancer. It is associated with mild distal neuropathy, mainly paresthesias in approximately 20% of patients. Severe neuropathies are rare and most often manifest in patients with prior paclitaxel exposure [283, 284].
Proteasome Inhibitors
Bortezomib
Bortezomib reversibly inhibits the 26S proteasome activating signaling cascades leading to cell-cycle arrest and apoptosis. It is used in multiple myeloma as well as many lymphomas and amyloidosis. Peripheral neuropathy is the major dose-limiting toxicity associated with bortezomib [285–287]. Peripheral neuropathy manifests early, normally within the first course of therapy, and generally worsens through the fifth cycle. After five cycles of therapy the peripheral neuropathy does not seem to worsen [288]. It is typically reversible within months of discontinuation, but can persist for years or even indefinitely [287, 289, 290].
Many mechanisms of bortezomib-induced peripheral neuropathy have been proposed but the precise mechanism is unclear [288]. It has been shown to cause direct toxicity to the dorsal root ganglion [291]. Bortezomib is able to activate the mitochondrial apoptotic pathway that leads to mitochondrial and endoplasmic reticulum damage potentially playing a role in the peripheral neuropathy [292]. Dysregulation of intracellular calcium and/or neurotrophins has also been shown to be a potential determinant of bortezomib-induced peripheral neuropathy [293, 294].
Bortezomib-induced neurotoxicity manifests as painful sensory neuropathy with dysesthesias of the fingers and toes. On exam, there is distal sensory loss to all modalities and changes in proprioception, with absent or suppressed deep tendon reflexes [286, 295]. Motor neuropathy is less common and manifests as distal weakness in the lower extremities. Autonomic neuropathies have also been described, leading to diarrhea, constipation, and orthostatic hypotension [294, 296, 297]. Demyelinating neuropathies have also been reported [286, 298].
Studies have examined strategies to prevent the incidence and severity of bortezomib peripheral neuropathy. When compared to twice weekly administration, weekly administration of bortezomib resulted in significantly less severe neuropathy and fewer patients discontinued therapy due to neuropathy [299]. Studies have also shown that subcutaneous administration significantly reduces the overall occurrence and severity of peripheral neuropathy compared to intravenous administration [300, 301]. This is thought to be due to the decrease in peak concentrations with subcutaneous dosing compared to intravenous administration. Dose reductions at the onset of peripheral neuropathy have been associated with an improvement or reversal in many patients [285, 289, 294, 302].
Carfilzomib
Carfilzomib is a second-generation proteasome inhibitor that binds the 20S proteasome, leading to cell-cycle arrest and apoptosis. It is used in refractory multiple myeloma. Peripheral neuropathy can still occur but the incidence and severity seems less than that of bortezomib [306–308]. Centrally, carfilzomib causes fatigue, headache, insomnia, and dizziness.
Histone Deacetylase (HDAC) Inhibitors
Belinostat , Panobinostat , Romidepsin , Vorinostat
Histone deacetylase inhibitors increase acetylation of histone proteins causing cell-cycle arrest and apoptosis. They are used for peripheral and cutaneous T-cell lymphoma as well as multiple myeloma. CNS toxicity is uncommon with fatigue, headache, and dizziness reported [309–312]. Ischemic stroke has been reported with vorinostat [313].
DNA Methylation Inhibitors
Decitabine
Azacitidine (5-Azacytidine)
Azacitidine, like decitabine, is a hypomethylating agent, incorporating into DNA, inhibiting DNA methylation, leading to cell death. Azacitidine is used for MDS and AML. Central nervous system toxicities include fatigue, rigors, headache, vertigo, anxiety, depression, insomnia, malaise, and hypoesthesia. Rare reports of hepatic coma [316] and seizure have been described [317, 318].
Miscellaneous Chemotherapy Agents
Thalidomide
Thalidomide is a drug with anti-angiogenesis and immunomodulatory properties, mainly used for the treatment of myeloma and Kaposi’s sarcoma. Peripheral neuropathy is a dose-limiting toxicity of thalidomide. Clinically, patients present with symmetric paresthesias and or dysesthesias, with or without sensory loss. Motor neuropathy is also common [319–325]. Neuropathy was more common and severe when high doses were given (greater than 200 mg per day) [326]. With newer dosing regimens peripheral neuropathy is present in about half of patients treated with thalidomide, but the severity of the neuropathy is significantly decreased [322, 327, 328]. Mechanistically, toxic axonopathy and dysregulation of neurotrophin activity may play a role with the pathogenesis of the neuropathy [321, 329].
Central neurotoxicity is generally mild, with varying degrees of somnolence as the most common manifestation. At high doses (i.e., 400 mg/day or above), the somnolence can be quite severe in some patients. Headache can also be noted on occasion. Seizures have been reported, but generally occur in patients with an underlying epileptogenic brain disorder (i.e., brain tumor) [330]. Dizziness [320], tremor [322, 324], and unresponsiveness leading to coma [331] have also been reported.
Lenalidomide
Lenalidomide , a second-generation agent, has immunomodulatory, antiangiogenic, and antineoplastic properties due to multiple mechanisms. It is used in mantle cell lymphoma, multiple myeloma, and myelodysplastic syndromes. Like thalidomide, it can cause peripheral neuropathy but the incidence and severity is significantly less compared to thalidomide [332]. It has been used in patients with pre-existing peripheral neuropathies [333]. Cognitive decline and expressive aphasia have been described with resolution after drug discontinuation [331]. A case of short-term memory loss is also described [331].
Pomalidomide
Pomalidomide is a second-generation agent used to treat refractory multiple myeloma. It has a similar mechanism to that of thalidomide and lenalidomide causing antiangiogenic, immunomodulatory, and antineoplastic effects. In the large phase III trials, peripheral neuropathy was seen in 9% of patients but severe peripheral neuropathy was not observed [334, 335]. A case of dysarthria has been described [331].
Arsenic Trioxide
Arsenic trioxide induces apoptosis and damages and degrades the fusion protein PML–RAR alpha. It is used for acute promyelocytic leukemia. Common CNS toxicity includes fatigue, fever, headache, insomnia, anxiety, tremor, and vertigo. Less common side effects include seizures that occur in 8% of patients. Agitation, coma, and confusion have also been described [336].
Bexarotene
Bexarotene binds and activates the retinoid X receptors, which function as the regulation pathway to express genes which control cell proliferation. It is used in cutaneous T-cell lymphoma. It can cause headache, fever, and insomnia [337].
l-Asparaginase
l-asparagine is an amino acid required for the synthesis of many cellular proteins in normal human cells. Many tumors lack the enzyme l-asparagine synthetase and are unable to synthesize cellular proteins, and therefore require an exogenous supply of the amino acid. l-asparaginase is a bacterial-derived enzyme that hydrolyzes l-asparagine into aspartic acid and ammonia. It is capable of depleting the extracellular supply of l-asparagine, thereby depleting tumor cells of the amino acid and inhibiting protein synthesis [338]. l-asparaginase is a large molecule with poor BBB penetration as negligible CSF levels are noted after an IV infusion. However, even though the drug does not readily cross the BBB it is associated with several forms of central neurotoxicity, including diffuse encephalopathy, cerebral venous thrombosis with venous infarction, and cerebral hemorrhage [339] (Fig. 15.7). The encephalopathy can be acute or subacute and appears to be dose-related. Although the mechanism remains unclear, it may be due to hepatic toxicity and hyperammonemia [340, 341]. Symptoms are variable, and can range from mild lethargy and personality changes to coma. Focal neurological deficits and seizures may also be noted [342]. EEGs usually demonstrate diffuse slowing with triphasic waves. The majority of patients with encephalopathy have elevated levels of ammonia. Improvement in symptoms usually occurs within a few days of discontinuing l-asparaginase. More modern protocols use lower doses of l-asparaginase and are much less likely to induce encephalopathy.
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