Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section G – Complications of Therapy

Chapter 61 – Neurologic Complications

Mark R. Gilbert

SUMMARY OF KEY POINTS

Incidence of Chemotherapy- and Radiation Therapy-Induced Neurotoxicity

  

   

The actual incidence of treatment-related neurotoxicity is unknown, but the frequency is increasing.

  

   

Improvements in supportive care, but not neuroprotective regimens, have allowed dose escalation for many drugs, so neurotoxicity often is the dose-limiting factor.

  

   

Increased survival from cancer has resulted in an increasing prevalence of late-onset neurotoxicity.

  

   

Newer treatments directed at tumors in the central nervous system often result in neurotoxicity, particularly with therapies administered directly into the brain.

Etiology of Neurotoxicity

  

   

Direct effects on neurons, myelin, and supporting glial cells have been implicated.

  

   

Effects on neuronal cytoskeleton and axonal transport, neuronal metabolism, and neurotransmitter function are the most commonly hypothesized mechanisms of toxicity. Alterations in specific ion channels have been reported in some cases of chemotherapy-induced peripheral neuropathy.

Evaluation of the Patient

  

   

In general, chemotherapy or radiation toxicity should be considered a diagnosis of exclusion.

  

   

Specific diagnostic tests do not exist for treatment-induced toxicity from most agents and regimens in use.

  

   

The diagnosis often is made by recognition of a neurotoxic syndrome temporally related to treatment and by exclusion of other causes of neurologic dysfunction.

Grading of the Complication

  

   

Grading scales are of limited value for monitoring individual patients and are used only for study populations.

  

   

More refined grading for management is a component of neurologic and neuropsychologic testing.

Treatment

  

   

With most neurotoxic syndromes, specific treatment is not available.

  

   

Prevention or reduction of risk often is possible with proper monitoring or treatment planning.

  

   

New agents are under development for management or prevention of neurotoxicity, but careful testing is required to ensure that the antineoplastic effect is not compromised.

INTRODUCTION

The neurotoxic effects of cancer chemotherapeutic agents and radiation therapy are of increasing importance in the management of patients with cancer. Although the exact incidence of treatment-related neurotoxicity is unknown, the frequency is certainly increasing. Several factors are known to be responsible for this increase in incidence of treatment-related neurotoxicity.

First, recent advances in supportive care allow the use of much higher doses of chemotherapeutic agents. For example, administration of granulocyte or granulocyte-macrophage colony-stimulating factors allows use of drug doses that previously would have caused severe bone marrow suppression. Unfortunately, similar factors for prevention of development of neurotoxicity do not exist. In initial studies of paclitaxel, a novel antitubulin agent, myelosuppression was dose-limiting. Use of colony stimulating factors has allowed dose escalation, but the development of severe peripheral neuropathy has been described in many patients receiving these higher doses. [1] [2] Similarly, nephrotoxicity and myelosuppression limited dose escalation of cisplatin in the past. Innovative hydration schemes and the availability of colony stimulating factors have reduced the risk of these toxicities. Dose escalation has resulted in severe neurotoxicity and ototoxicity, now considered the dose-limiting toxic effects.[3]

Second, improvements in cancer treatment have increased the duration of survival from many malignant diseases. As a consequence, treatment-related neurotoxicity with a long latency between treatment and onset of symptoms is being recognized with increasing frequency. Childhood acute lymphoid leukemia often was fatal until recognition of the central nervous system (CNS) as a sanctuary for leukemia cells. Treatment of cerebrospinal fluid (CSF) with direct administration of methotrexate and use of cranial irradiation resulted in a marked increase in long-term remission and cure. This treatment of the CNS, however, also caused delayed neurotoxicity. Severe dementia developed in some patients, and many others experienced a decline in cognitive function years after completion of treatment. [4] [5] [6] [7] [8] Similarly, combined-modality treatment using both whole-brain irradiation and chemotherapy with high-dose methotrexate has markedly improved survival over that achieved with radiation therapy alone. A marked increase in leukoencephalopathy, however, has been observed with this combination regimen, particularly in the elderly.[9]

Third, newer agents, including biologic response modifiers, and novel routes of administration designed specifically to target the nervous system for management of brain metastases or primary brain tumors are very likely to result in an increase in neurotoxicity. Likewise, chemical disruption of the blood-brain barrier to improve drug delivery to brain tumors has led to a marked increase in neurotoxicity compared with that with standard systemic administration. Results of animal studies have demonstrated that chemical opening of the blood-brain barrier results in a marked increase in exposure of normal brain parenchyma to chemotherapy with a much smaller increase in delivery to the tumor.[10] Implantation of carmustine (BCNU)-impregnated polymer wafers into the resection cavity has shown a survival benefit for patients with glioblastoma but with an increase in the incidence of brain necrosis and infection.[11]

Continued improvement in cancer treatment will result in prolonged survival and an increased rate of cure. Therefore long-term morbidity, particularly development of irreversible neurotoxicity, is a critical concern. This chapter discusses the agents most commonly responsible for neurotoxicity, describes the differential diagnosis for and evaluation of patients with neurologic dysfunction, and addresses management and prevention of chemotherapy- and radiation therapy-induced neurotoxicity.

SPECIFIC AGENTS

Cytosine Arabinoside

Cytosine arabinoside (ara-C), or cytarabine, can cause a wide range of neurotoxic effects. The toxicity that develops depends on the route of administration and the dose used.

Cerebellar Toxicity

Systemic administration of high-dose (greater than 1 g/m2) intravenous ara-C can cause acute cerebellar toxicity. [12] [13] [14] [15] Onset of neurologic symptoms generally is acute and often is noticed during administration of a multiday regimen. [12] [13] [16] Patients exhibit evidence of global cerebellar dysfunction, which manifests as truncal, limb, and gait ataxia; dysarthria; and nystagmus. In some cases, permanent cerebellar dysfunction results; in others, a mild cerebellar syndrome develops that resolves promptly after completion of the chemotherapy. [12] [13]

Patients with irreversible cerebellar damage have a characteristic and selective loss of Purkinje cells in the cerebellum.[15] The pathogenesis of the specific cellular damage is unknown, and no pathologic findings have been described in the cerebella of patients who have recovered from transient cerebellar dysfunction.

The incidence of irreversible cerebellar toxicity with high-dose ara-C regimens has been reported to be 8% to 20%. Factors reported to affect the likelihood of development of cerebellar toxicity include size of current dose, cumulative dose, age (persons older than 50 years are at higher risk), and renal status (renal dysfunction with impaired drug clearance is associated with increased risk). [13] [14] [17] [18]Whether patients in whom reversible cerebellar dysfunction develops with previous treatment are at higher risk for permanent dysfunction is unknown.

Encephalopathy

Acute encephalopathy, often accompanied by seizures, occurs less frequently than cerebellar dysfunction in patients receiving high-dose intravenous ara-C.[13] In most cases, somnolence and lethargy completely resolve soon after completion of chemotherapy. Patients with persistent encephalopathy usually have had additional medical problems, such as severe infection.[18] In addition, leukoencephalopathy that is clinically and pathologically indistinguishable from the leukoencephalopathy associated with methotrexate has been reported as a late complication of high-dose intravenous ara-C administration and with administration of ara-C directly into the CSF.[13]

Spinal Cord Toxicity

Direct administration of ara-C into the lumbar thecal space has been reported to cause myeloradiculopathy. [19] [20] [21] [22] [23] Patients exhibit evidence of both spinal cord and nerve root dysfunction. This complication is uncommon, usually being found only after an extensive course of intrathecal chemotherapy. In many instances, patients have received both intrathecal ara-C and methotrexate. [24] [25]Neurologic signs typically are noticed days to weeks after treatment, although myelopathy may develop within minutes of administration. In most cases, loss of neurologic function progresses slowly over days, and only one half of patients demonstrate improvement or achieve full recovery.

Several hypotheses have been proposed for the mechanism of chemotherapy-induced myelopathy. Focal damage from injection of hyperosmolar solution,[26] barbotage from injection,[27] and direct toxic effects of chemotherapy on the spinal cord parenchyma[20] are the most common proposed mechanisms of subacute myelopathy. Histologic examination of the spinal cord shows focal areas of necrosis, most marked along the periphery of the spinal cord. [20] [21] [24] Microscopic examination shows axonal swelling with accompanying demyelination. [20] [21] [24] A newer formulation of ara-C uses a liposomal preparation. Although the pharmacokinetics of drug delivery in the CSF is improving, an increase in the incidence of arachnoiditis has been observed, and isolated cranial nerve palsies may be more frequent. With chemotherapy-induced spinal cord injury, myelin basic protein levels in the CSF may be elevated before marked neurologic damage occurs. [24] [25] For patients with early symptoms, such as paresthesia, back pain, or Lhermitte's sign, the level of myelin basic protein in the CSF should be measured. If the level is elevated, further lumbar administration of chemotherapy should be avoided.[25]

Other Neurotoxicity Associated with Cytosine Arabinoside

Peripheral neuropathy has been reported after administration of high-dose ara-C.[28] In this report, symmetrical sensorimotor polyneuropathy developed 2 weeks after completion of treatment. Nerve biopsy demonstrated axonal damage with patchy regions of demyelination. In addition, a case of reversible parkinsonism has been reported after administration of high-dose ara-C.[13] Onset of tremor, bradykinesia, and mask-like facies were observed 3 weeks after completion of treatment. Treatment with carbidopa-levodopa provided only transient improvement. All parkinsonian features, however, resolved over 12 weeks.

L-Asparaginase

Cerebrovascular Events

Cerebrovascular events caused by L-asparaginase-induced coagulopathy constitute the most common form of neurotoxicity associated with L-asparaginase treatment. Both thrombotic and hemorrhagic strokes have been reported in patients receiving L-asparaginase. [29] [30] [31] Thrombosis of cerebral venous sinuses also has occurred in patients receiving this agent. The clinical manifestations of sinus thrombosis usually are acute and severe headache, nausea, and vomiting caused by the rapid increase in intracranial pressure. Changes in level of consciousness occur most frequently with sagittal sinus thrombosis with bilateral cerebral hemisphere involvement. Although most patients with sinus thrombosis demonstrate acute and rapidly progressive changes in neurologic function, some patients experience only headache and mild neurologic dysfunction.[29]

Patients in whom neurologic symptoms develop during L-asparaginase therapy should be evaluated with either head computed tomography (CT) or magnetic resonance imaging (MRI). MRI usually is preferred because it often depicts sinus thrombosis by absence of a flow void in the venous sinus. MRI also depicts early signs of ischemic brain injury, particularly on diffusion-weighted imaging, and punctate hemorrhages also may be seen.

Neuropsychiatric Effects

Less frequently, L-asparaginase treatment has been associated with development of neuropsychiatric symptoms,[32] most notably depression, delusions, hallucinations, disorientation, and altered level of consciousness. In the series described by Holland and colleagues,[32] 5 of 19 patients with acute leukemia experienced psychiatric symptoms. The onset of symptoms occurred 2 to 19 days after treatment, and the symptoms resolved completely in three patients who lived longer than 6 weeks. Neuropathologic analysis of the brains in two cases revealed leukemic infiltration. The combination of leukemic involvement of the CNS and treatment-induced depletion of L-asparagine and L-glutamine in the brain has been proposed as a possible factor contributing to development of psychiatric symptoms.

Busulfan

Busulfan administration has been reported to cause generalized tonic-clonic seizures.[33] This reaction has been reported with high-dose treatment as a preparative regimen for bone marrow transplantation. Prophylactic treatment with anticonvulsants, particularly phenytoin, has been shown to reduce the risk of seizures.[34]

Methotrexate

Methotrexate can cause acute, subacute, or chronic neurotoxicity.

Acute Neurotoxicity

Administration of high-dose intravenous methotrexate (dosage greater than 3 g/m2) has been associated with development of acute encephalopathy characterized primarily by somnolence, confusion, and seizures. [5] [35] Although the pathogenesis of this syndrome is unknown, laboratory studies with rats have shown profound metabolic alteration in the brain after intravenous administration of high-dose methotrexate.[36] In these experiments, a widespread decrease in glucose utilization and protein synthesis was found. In similar studies, folinic acid (leucovorin) markedly diminished these metabolic effects,[37] a finding that suggested a possible role for leucovorin in decreasing the severity of methotrexate-induced somnolence syndrome. Although the somnolence and confusion that occur with acute methotrexate toxicity resolve completely, evidence shows that patients in whom this syndrome develops are at greater risk for chronic methotrexate-induced neurotoxicity.[38] Cases have been reported in which, despite resolution of the clinical symptoms, white matter changes persist on MR images.[39]

Subacute Toxicity

Subacute methotrexate-induced neurotoxicity generally develops weeks after methotrexate administration and occurs most frequently in patients who also have received cranial radiation.[5] Transient inhibition of myelin formation is thought to be the mechanism of toxicity. The syndrome is completely reversible over weeks, and corticosteroid treatment may accelerate recovery.

Chronic Neurotoxicity

Chronic methotrexate neurotoxicity is known as leukoencephalopathy. This syndrome develops months to years after methotrexate administration and has been seen after both intravenous and intrathecal administration of methotrexate. [4] [5] [6] [7] [8] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] Cranial radiation therapy, particularly when it precedes methotrexate administration, greatly increases the risk of leukoencephalopathy. [5] [51] In addition, elevated CSF methotrexate concentration has been associated with an increased risk of neurotoxicity.[42] Younger patients are at higher risk for leukoencephalopathy. [52] [54] Clinically, patients show progressive loss of cognitive function and focal neurologic signs, which may progress to profound dementia, coma, or death. [4] [5] [6] [8] [43] Some patients experience seizures as a consequence of widespread neuronal injury. No treatment is known, and the neurologic deficits generally are irreversible. Brain imaging with MRI or CT often shows large areas of abnormalities in cerebral white matter ( Fig. 61-1 ). Elevated levels of myelin basic protein in CSF have been reported in patients with progressive neurologic dysfunction from methotrexate-induced leukoencephalopathy.[44]

 
 

Figure 61-1  Methotrexate-induced leukoencephalopathy. The patient was a 63-year-old man with meningeal lymphoma who underwent whole-brain radiation therapy. Several months later, his meningeal lymphoma recurred and was treated with intrathecal methotrexate. Progressive dementia developed. A and B, CT scans obtained 6 months after completion of intrathecal chemotherapy. Widespread destruction of white matter and diffuse atrophy are evident.

 

 

Neuropathologic examination shows wide areas of coagulative necrosis with swollen axonal cylinders and demyelination. [4] [40] [45] Regions with vascular changes, particularly microangiopathic calcifications, are characteristic. [46] [49] [54] The pathogenesis of leukoencephalopathy is unknown, but results of laboratory studies with brain explant cultures suggest that the primary injury may be neuronal (axonal), and the characteristic demyelination may be a secondary phenomenon.[55]

Spinal Cord Toxicity

Chemotherapy-induced myelopathy is an uncommon toxicity of intrathecal treatment with methotrexate. [56] [57] [58] [59] [60] Myelopathy generally develops only after extensive intrathecal treatment. Both methotrexate and ara-C have been associated with myelopathy. The clinical syndrome of methotrexate-induced myelopathy is identical to that with ara-C (see earlier under “Cytosine Arabinoside”). Loss of neurologic function may be progressive; only approximately one half of patients experience either complete or partial recovery. The onset of symptoms generally is subacute. Symptoms develop over days to weeks, usually beginning days to weeks after administration of chemotherapy. The histologic findings are identical to those with ara-C-induced myelopathy.

Vinca Alkaloids

Treatment with vinca alkaloids, particularly vincristine, commonly is associated with neurotoxicity.

Peripheral Neuropathy

Peripheral neuropathy is the toxicity associated most frequently with vincristine and correlates with the cumulative dose of the drug. [61] [62] [63] [64] [65] [66] Loss of deep tendon reflexes occurs in nearly all patients who receive several vincristine treatments. Distal sensorimotor polyneuropathy develops with continued treatment. [62] [64] [66] The predominant neurologic finding is loss of pain and temperature sensation in a stocking-and-glove distribution. Motor and vibration or proprioceptive loss usually is milder and occurs later with continued treatment.

The mechanism of toxicity is unknown but probably is related to the effects of the vinca alkaloids on microtubules. Vinca-induced disruption of axonal microtubules causes marked disarray of the axonal cytoskeleton and formation of neurofilamentous masses [65] [67] [68] [69] [70] [71] and reversible neurofilament-containing crystalloid inclusions.[72] These effects are very likely to influence axonal transport, which depends on microtubules as the transport mechanism.[73] In patients with underlying neuropathy, such as diabetic neuropathy or Charcot-Marie-Tooth disease, vinca-induced neuropathy may be severe even with low cumulative doses.[74] Severe, even life-threatening neuropathy has been reported after administration of as little as 2 mg to patients with Charcot-Marie-Tooth disease (hereditary motor sensory neuropathy type 1), and evidence suggests that patients should be screened for this disorder before administration of vincristine. [74] [75] [76] Previous radiation treatment of peripheral nerves also increases the neurotoxic effects of vincristine.[77]

In addition to peripheral neuropathy, autonomic neuropathy and cranial nerve palsy have been reported. Autonomic neuropathy most commonly manifests as gastrointestinal dysmotility (obstipation or constipation). In severe cases, paralytic ileus and intestinal perforation have resulted. [66] [78] Less frequently, orthostatic hypotension develops as a consequence of autonomic involvement. Vincristine-induced mononeuropathy involving the femoral nerve has been reported. Vincristine can cause cranial nerve palsies, affecting the optic (II), oculomotor (III), trigeminal, abducens, facial, acoustic, and vagus nerves. [62] [66] [79] [80] In addition, patients occasionally report facial pain with vincristine treatment, possibly due to a transient effect on the trigeminal nerve or ganglion.[66]

Central Nervous System Effects

Vincristine has been reported to cause encephalopathy, coma, and seizures. [81] [82] [83] [84] [85] These effects are rare and reversible. The underlying mechanism is unknown in most cases, although in some reports these neurologic effects have been attributed to vincristine-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia. [84] [86] [87] [88] [89] The mechanism of SIADH is unknown, but serum antidiuretic hormone levels are elevated.

Other Toxicity Associated with Vinca Alkaloids

Quadriplegia with vincristine treatment has been reported, in one case in association with Guillain-Barré syndrome. [90] [91] [92] The time of onset of has been variable. In some patients, quadriparesis develops soon after vincristine treatment, whereas in others, it occurs several weeks after treatment. In most instances, the weakness is partially reversible.[90]

Myopathy has occurred with vincristine therapy. [61] [93] No clinical correlate has been found in cases in which histopathologic examination of muscle tissue has revealed spheromembranous degeneration.

Cisplatin

Peripheral Neuropathy

The most common neurotoxicity associated with cisplatin is peripheral neuropathy. The neuropathy predominantly involves the large sensory fibers, which mediate vibration and proprioceptive function. Deep tendon reflexes are lost because of toxic effects on the large myelinated sensory fibers, which provide the afferent arm of the reflex arc. Involvement of motor function generally is mild and is seen only in patients with severe sensory neuropathy. Development of neuropathy is dose-related. The earliest signs are detected when the cumulative dose exceeds 300 mg/m2.[94] Schedule of administration may be a significant factor, because the reported incidence of neuropathy has been higher in patients receiving treatment on 5 consecutive days than in patients on a regimen with a shorter dosing schedule but the same cumulative dose. [95] [96] [97] Continued treatment with cisplatin in patients with neuropathy can result in severe sensory ataxia, which often impairs ambulation. The neuropathy is partially reversible, and patients with mild impairment generally are more likely to experience full recovery.[96] A longitudinal study confirmed there is often a delay in the onset of neuropathy. Eleven percent of the patients had neuropathy at the end of treatment, but the incidence had increased to 65% 3 months later. One year later, most of the patients had recovered, only 17% having persistent symptoms.[98]

The pathogenesis of cisplatin-induced neuropathy is unknown. Neuropathologic studies have shown involvement of the large sensory fibers with regions of axonal swelling and myelin breakdown and, in more severe cases, axonal loss.[99] The spinal cord shows almost exclusive involvement of myelinated axons in the dorsal columns—a finding consistent with the clinical features of vibratory and proprioceptive loss.[100] Platinum concentration in peripheral nerve and spinal ganglia was 20 times greater than in brain from patients at autopsy.[98] This finding may explain the predilection of cisplatin for sensory fibers and sparing of the CNS.

Spinal Cord Toxicity

Cisplatin treatment has been associated with the development of Lhermitte's sign, which is an electric shock-like sensation down the spine or into the extremities with neck flexion. [101] [102] The phenomenon most commonly is associated with spinal cord demyelinating lesions in multiple sclerosis. A similar mechanism, cisplatin-induced demyelination, may be the cause in patients with this syndrome. Most patients achieve full recovery, although, as with recovery from cisplatin-induced neuropathy, improvement may take several months.

Other Neurotoxicity Associated with Cisplatin

Other neurotoxic effects reported with cisplatin include optic neuropathy, seizures, encephalopathy, and cortical blindness.[103] These complications of treatment are rare. Patients with optic neuropathy may have prolonged vision loss and demonstrate pallor of the optic disk. [104] [105] The reported cases of seizures and cortical blindness have been self-limited, all patients recovering fully. [106] [107] [108] The cause of the seizures and cortical blindness from cisplatin treatment is unknown but may be similar to that in toxicity from other heavy metals (lead, thallium), although endovascular injury has been proposed as a possible mechanism. [103] [107] Many of these patients have white matter abnormalities on brain MRI, consistent with posterior reversible encephalopathy syndrome (PRES; see later under “Dementia and Encephalopathy”). A syndrome also has been described in which patients experience focal neurologic deficits and seizures after intravenous administration of cisplatin. In these patients, findings on brain MRI were normal. One patient experienced recurrence of encephalopathy with cisplatin rechallenge, and a second patient died of status epilepticus. At autopsy, the brain of the latter patient showed only focal gliosis.[109]

Toxicity Associated with Intra-arterial Administration

Intra-arterial administration of cisplatin causes focal toxicity. Administration into the internal carotid artery can cause severe retinal toxicity. [110] [111] Supraophthalmic administration can cause focal areas of brain parenchymal necrosis with resulting seizures and neurologic impairment.[111]

Ototoxicity

Ototoxicity is a dose-related effect of cisplatin. Patients receiving more than 200 mg/m2 are at high risk for the development of hearing loss.[112] Hearing loss, particularly when it is moderate to severe, often is permanent. [112] [113] Results of most studies suggest that patients with underlying hearing loss are at greater risk for functional hearing loss, although a small series found no relation to previous hearing loss. [112] [114] [115] Additional risk factors include age older than 46 years and previous cranial radiation therapy involving the ears or temporal lobes. [113] [114] Patients with normal hearing lose high-frequency hearing first, but with continued treatment, hearing may be lost in all frequency ranges.[112] A rapid screening audiogram technique has been developed to monitor patients undergoing cisplatin treatment.[115] Postmortem pathologic examination of cochleae from patients with cisplatin-induced ototoxicity reveals extensive loss of the outer hair cells and less effect on the inner hair cells.[112]

Oxaliplatin

Oxaliplatin has been shown to cause two distinct types of neuropathy: acute and chronic.[116] The acute neuropathy syndrome may begin during oxaliplatin infusion or up to 1 to 2 days after completion of treatment. Patients experience paresthesia and dysesthesia of the hands and feet, jaw tightness, and a sensation of loss of breathing without respiratory distress. The last syndrome has been called pharyngolaryngodysesthesia.[117] Dysesthesias constitute the most prominent symptom, although many patients describe pain that is more like muscle spasms of the jaw, tongue, and extremities. Some patients are unable to relax a tensed muscle, such as a grasp, during these episodes. The incidence of acute neuropathy increases with continued dosing, and an increased incidence also has been noted with higher dosing regimens. Overall, acute, severe (grade 3 or 4) neurotoxicity has been estimated to occur in 10% of patients with the initial dose, but that increases to 50% by the ninth cycle of treatment.[118]Most patients experience some resolution of symptoms, but most have residual neuropathic symptoms up to 6 months after treatment cessation. The pathogenesis of acute oxaliplatin neuropathy is thought to be related to drug-induced alterations in voltage-gated Na+ channels.[119]

The development of chronic neuropathy from oxaliplatin is related to cumulative dose, with most studies reporting early neuropathy noted after a total dose of greater than 540 mg/m2. As with cisplatin, chronic oxaliplatin peripheral neuropathy affects large caliber sensory nerves, with the resultant loss of proprioceptive function as the predominent clinical manifestation. Additionally, the Lhermitte's-like phenomenon described with cisplatin also has been reported with oxaliplatin.[120] The chronic neuropathy may abate over several months after the cessation of treatment, although some reports suggest that symptoms may persist in a small percentage of patients for longer than 5 years.[121]

Cyclophosphamide

Cyclophosphamide can indirectly cause metabolic encephalopathy and seizures. High-dose cyclophosphamide can result in SIADH. [122] [123] [124] [125] Unrecognized, this syndrome can lead to severe hyponatremia, coma, and seizures. Although not reported in the literature in association with cyclophosphamide-induced SIADH, rapid correction of hyponatremia can result in central pontine myelinolysis, which is irreversible loss of the central pontine pathways.[126] A locked-in syndrome may develop, or a chronic vegetative state can result from central pontine myelinolysis.

Ifosfamide

The most common manifestation of neurotoxicity associated with ifosfamide is encephalopathy. Severe ifosfamide-induced encephalopathy has been reported in children and adults. [127] [128] [129] [130] [131]Neurologic deterioration usually begins within hours of administration of ifosfamide. [127] [129] [131] Confusion, hallucinations, and aphasia are the most common initial signs. Progression to coma generally is rapid. Some patients also exhibit clinical evidence of seizure activity or myoclonus with intermittent twitching of the extremities. [127] [130] Electroencephalography (EEG) shows severe slowing with delta wave activity and can display evidence of seizure activity. [127] [130] In most cases, encephalopathy completely resolves over several days after cessation of therapy, although in one study, investigators found persistent mental status changes in some patients 10 weeks after treatment.[132] A recent study of 60 patients reported the incidence of ifosfamide neurotoxicity to be 26%.[133] Several risk factors have been reported to predispose patients to development of neurotoxicity from ifosfamide. These factors include low serum albumin concentration,[131] high serum creatinine concentration, pelvic cancer,[134] and previous treatment with cisplatin.[135] A recent report, however, could not confirm any risk factor except age, with an increased incidence of encephalopathy in younger patients.[133] Ifosfamide treatment has been associated with an extrapyramidal syndrome characterized by choreoathetosis, blepharospasm, and opisthotonic posturing.[136] These abnormalities resolved over several days.

5-Fluorouracil

Cerebellar Toxicity

5-Fluorouracil (5-FU) causes acute cerebellar dysfunction. Patients experience moderate to severe gait ataxia, scanning speech, appendicular ataxia marked by severe dysmetria, and often nystagmus. [137] [138] [139] [140] These neurologic abnormalities resolve completely within several days after completion of therapy. The incidence of cerebellar toxicity has been reported to be 3% to 7% and correlates with dose and the interval between treatments.[141]

Neuropsychiatric Symptoms

Organic brain syndrome has been reported with 5-FU treatment.[142] Confusion and disorientation develop without evidence of cerebellar dysfunction. In one patient, retreatment with 5-FU resulted in a similar episode of mental deterioration. Oculomotor disturbances, specifically vergence disturbances characterized by diplopia on viewing distant objects, were reported in two patients.[143] A possible association of 5-FU treatment with recurrent acute toxic neuropathy also has been reported.[144]

Other Neurotoxicity Associated with 5-Fluorouracil Treatment

Several cases have been reported of multifocal inflammatory leukoencephalopathy associated with use of 5-FU and levamisole in adjuvant therapy for colon carcinoma.[145] Affected patients have a subacute neurologic syndrome characterized by focal neurologic findings and cognitive dysfunction. MRI shows widespread patchy white matter lesions that enhance with administration of gadolinium (Fig. 61-2 ). Histopathologically these lesions are characterized by an intense inflammatory infiltrate with extensive loss of myelin, but the axons generally are spared. Complete recovery occurs over weeks after cessation of 5-FU and levamisole administration. The benefit of corticosteroid treatment is uncertain in accelerating recovery. The pathogenesis of this idiosyncratic reaction is unknown, although levamisole can affect blood-brain barrier function, and this effect may be potentiated by 5-FU. Recognition of this treatment-induced leukoencephalopathy can be important, because the clinical presentation and MRI findings can be misinterpreted as brain metastasis. There are isolated reports of encephalopathy with single-agent therapy with 5-FU and recently reports of encephalopathy and coma with use of capecitabene, the oral prodrug of 5-FU. [146] [147] [148]

 
 

Figure 61-2  Levamisole–5-fluorouracil (5-FU) multifocal inflammatory leukoencephalopathy. The patient was a 54-year-old woman in whom progressive encephalopathy and focal neurologic signs developed 4 months after initiation of adjuvant therapy with levamisole and 5-FU for colon carcinoma. A, Several white matter lesions are present, many of which enhanced with administration of gadolinium–ethylenediaminetetra-acetic acid (EDTA). B, Six months later, the patient had fully recovered. Resolution of the enhanced lesions is evident.

 

 

Fludarabine

Fludarabine can cause somnolence and a mild peripheral neuropathy at low doses.[149] At high doses, white matter changes, particularly in the occipital lobes and brainstem, have been reported.[150]Encephalopathy and cerebellar signs are common with this leukoencephalopathy. Progressive symptoms eventuating in coma and death have been reported. Pathologic evaluation has shown necrotic changes in the involved white matter.[150] The risk of development of progressive multifocal leukoencephalopathy, due to an infection with the JC virus, may be increased with fludarabine treatment. Diagnosis requires biopsy of involved brain or polymerase chain reaction testing of CSF.[151]

Nitrosoureas

Central Nervous System Toxicity

Nitrosoureas, most commonly carmustine (BCNU), can cause encephalopathy characterized by a progressive decline in cognitive function, development of seizures and coma, and death. [152] [153] [154] This complication most commonly is observed with intracarotid or supraophthalmic arterial delivery of nitrosourea, although a similar syndrome has been reported in patients who receive very high-dose intravenous carmustine treatment.[155] Histopathologically the toxicity associated with intra-arterial therapy is characterized by necrosis, regions of demyelination, edema, and axonal loss limited to the region perfused by the intra-arterial therapy. Because the predominant changes have been seen in the white matter, the condition is called leukoencephalopathy, indistinguishable from the changes seen with methotrexate and ara-C treatment. Similar pathologic changes are seen with high-dose intravenous carmustine, but both cerebral hemispheres are involved.[155] In addition, focal brain necrosis has been reported with intra-arterial nitrosourea treatment. This toxicity is thought to be a consequence of “streaming” of the drug along the vessel wall, without mixing with arterial blood.[156] This stream of concentrated drug may flow into a small branch of the artery. A small region of brain (or tumor) thus receives an enormous dose of drug, and focal necrosis results.

A biodegradable polymer containing BCNU has been shown effective in the management of recurrent malignant glioma. The BCNU-impregnated polymer also has been approved for treatment of newly diagnosed glioblastoma. This treatment usually is followed by conventional external beam radiation therapy.[157] This combination may increase the incidence of treatment-associated necrosis. The wafers are placed into the tumor cavity after surgical resection. Results of clinical trials indicate that the local therapy is well tolerated, although an increase in peritumoral edema necessitates a temporary increase in corticosteroid dose, and there are reports of treatment-associated necrosis.[158]

Retinal Toxicity

Retinal toxicity has been reported with intracarotid administration of nitrosoureas, particularly carmustine. [111] [159] This retinopathy is painful and often results in permanent vision loss. Infusion above the ophthalmic artery eliminates this toxicity but may increase the likelihood of streaming (see preceding discussion, “Central Nervous System Toxicity”).

Procarbazine

Early reports of procarbazine use describe neurotoxicity, both peripheral and CNS toxicity, as common side effects of treatment.

Peripheral Neuropathy

The peripheral neuropathy described with procarbazine use most commonly is described as paresthesia, often subjective and generally transient. The incidence of paresthesia ranges from 2% to 20%; this variability may be related to dose or treatment schedule. [160] [161] [162]

Central Nervous System Toxicity

Signs of CNS depression, ranging from mild drowsiness to profound stupor, have been reported. [160] [162] This toxicity worsens with use of phenothiazine to control emesis and may be related to the monoamine oxidase inhibitor-like qualities of procarbazine. No report has discussed the use of dietary restrictions in patients receiving procarbazine. CNS depression was reported to occur in 14% to 33% of patients in these series. [160] [161] [162]

Paclitaxel and Docetaxel

Paclitaxel and docetaxel are novel antineoplastic agents that bind to tubulin and promote formation and stabilization of microtubules. [144] [163] [164] In phase I and II testing of paclitaxel, myelosuppression was the dose-limiting toxicity. Since colony stimulating factors (e.g., granulocyte macrophage and granulocyte colony stimulating factors) have become widely available, however, peripheral neuropathy has become the dose-limiting toxicity. [1] [2] The neuropathy is predominantly sensory, particularly affecting small-caliber (pain and temperature) sensory fibers.[165] The effect on motor fibers and large-caliber sensory fibers (vibration and proprioception) is less severe. Nerve conduction studies of large myelinated nerve fibers show evidence of both axonal injury and demyelination.[165] Neuropathy generally occurs at doses greater than 200 mg/m2, and symptoms develop 1 to 3 days after treatment. Although much of the neurologic dysfunction reverses over several weeks, continued treatment causes progressive neurologic toxicity. The peripheral neuropathy associated with docetaxel appears to be similar to that with paclitaxel in preliminary reports, although in a randomized trial, the incidence and severity were less with docetaxel. [166] [167] Peripheral neuropathy also is being reported with other microtubule-stablizing agents such as the epothilones.[168]

In one series, transient encephalopathy was reported to occur within hours of administration of standard doses of paclitaxel. All patients had undergone previous brain radiation therapy, and all recovered within hours.[169] Acute encephalopathy was reported to occur in six patients receiving a very high intravenous dose of paclitaxel (greater than 600 mg/m2). Encephalopathy developed between 7 and 23 days after treatment. Three patients recovered; the other 3 patients died of progressive coma. Autopsy revealed generalized white matter atrophy.[170] Chronic neurocognitive changes also have been reported with extensive administration of taxanes.[171]

Tamoxifen

Tamoxifen can cause reversible retinal dysfunction at the conventional antiestrogen doses used for breast cancer therapy. [172] [173] [174] At higher doses, reversible encephalopathy with delusions, somnolence, and cerebellar dysfunction has been reported. [175] [176] [177]

BIOLOGIC RESPONSE MODIFIERS

Interleukin-2

Central Nervous System Toxicity

The vascular leak associated with intravenous interleukin-2 (IL-2) administration can result in encephalopathy and coma.[178] A high percentage of patients receiving both systemic IL-2 and lymphocyte-activated killer (LAK) cells experience encephalopathy or a neuropsychiatric syndrome.[178] In most cases, severe but reversible cognitive impairment occurs. In the presence of an intracranial mass lesion, the increase in brain edema leads to an asymmetrical shift in the brain, resulting in herniation. In a single case report, development of multifocal white matter lesions was associated with intravenous administration of IL-2. The lesions resolved completely over several months.[179] Another case report described fatal leukoencephalopathy associated with IL-2 treatment.[180]

Toxicity Associated with Interleukin-2 Treatment

In one series of five patients, the development of neuro-ophthalmic complications was temporally associated with intravenous IL-2 treatment. [181] [182] Reported abnormalities included transient scotomata, diplopia, amaurosis fugax, and visual field cuts.

Interferons

Systemic administration of interferon affects both the CNS and the peripheral nervous system.

Central Nervous System Toxicity

Confusion, lethargy, mood changes, and loss of cognitive function are the most common CNS effects associated with use of interferons. [183] [184] [185] Encephalopathy, with perseveration and aphasia, also has been reported,[184] as has a parkinsonian syndrome with bradykinesia, mask-like facies, and micrographia.[186] In addition, major depression has been described with use of interferon-α (IFN-α).[187]The neurologic effects of interferon are dose-related, but they are more severe in patients with underlying neurologic abnormalities.[188] Although the neurotoxic effects of interferon therapy usually resolve completely within a few weeks, some patients may exhibit persistent behavioral changes.[183] Intraventricular administration of IFN-α caused severe neurologic toxicity in one study. Effects ranged in severity from headache and confusion to coma. Additional side effects of intraventricular administration included parkinsonism, hearing loss, and seizures.[189]

Peripheral Nervous System Toxicity

Mild peripheral neuropathy manifesting as paresthesia has been reported with interferon use,[184] as has a case of brachial neuritis in a patient with underlying neuropathy.[190]

Thalidomide and Lenalidomide

Thalidomide has both immunomodulatory and antiangiogenic properties, has shown significant activity in multiple myeloma, and is being evaluated in the management of several other cancers.[191]Somnolence, the predominant side effect, is dose-related, and the drug can be titrated in most patients to a level of tolerance. Peripheral neuropathy is treatment-limiting. The neuropathy has been characterized as sensory-motor axonal polyneuropathy manifesting as painful paresthesia or numbness.[192] Severity of symptoms correlates with cumulative dose. Nerve biopsy and examination reveal distal axonal degeneration and demyelination. A longitudinal study in patients with dermatologic disease confirmed the high incidence of neuropathy (25% in this study) and the association with daily dosing.[193] Early studies of lenalidomide indicate that peripheral neuropathy may occur in a small percentage of patients.[194] The available data are insufficient to determine if the incidence will be less than with thalidomide.

Bevacizumab

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has shown activity in a wide variety of cancer types including colon, lung, and renal cell cancers and glioblastoma. Exacerbation of hypertension is a commonly reported toxicity and may be related to the development of PRES, described in detail later on. [195] [196]

Sorafenib

Sorafenib is an oral agent that is a RAF kinase inhibitor that inhibits VEGF receptors 2 and 3 and platelet-derived growth factor receptor-β. Hypertension is a common toxicity with this agent, and as with bevacizumab therapy, reports of PRES are now emerging.[197]

Bortezomib

Bortezomib is a proteosome inhibitor that has demonstrated activity in multiple myeloma. Peripheral neuropathy, predominantly a sensory neuropathy, initially was reported during early phase I trials. A prospective study evaluated the occurrence of neuropathy in a group of 256 patients with refractory myeloma treated with standard dosing schedules of bortezomib.[198] The incidence of neuropathy was estimated to be approximately 35%, and neuropathy was more common in patients receiving bortezomib at 1.3 mg/m2 than in those dosed at 1.0 mg/m2. Cumulative dose also correlated with severity of the neuropathy, as did the presence of neuropathy before initiation of treatment. Most patients experienced either partial or complete resolution with cessation of treatment.

RADIATION NEUROTOXICITY

Radiation neurotoxicity is becoming an increasingly important and recognized complication of cancer therapy. New therapeutic strategies for systemic cancer and for CNS metastasis have improved survival, uncovering a greater incidence of late, chronic toxicity from radiation and combined chemoradiotherapy treatments. Advances in technology, such as radiosurgery and brachytherapy, allow local dose intensification of radiation treatment for brain tumors. Furthermore, advances in development of radiosensitizers will increase the effects of radiation therapy on tumor and surrounding normal tissue.

Central Nervous System Effects

Cranial radiation therapy can cause acute, subacute, and chronic neurotoxicity. Volume of brain treated, total dose, and dose fraction are the most important determinants of toxicity, although some variation in patient susceptibility is apparent.

Acute Toxicity

Acute toxicity manifests as rapid onset of alteration in level of consciousness. This disorder generally occurs within weeks of initiation of cranial radiation therapy.[199] Acute toxicity is most common in patients receiving whole-brain radiation therapy. The pathogenesis is unknown, and most patients experience complete recovery of neurologic function.

Early-Delayed Toxicity

Early-delayed toxicity is noticed weeks to 3 months after completion of radiation treatment.[200] Most commonly, patients have drowsiness, nausea, headaches, ataxia, and worsening of underlying neurologic dysfunction. Complete resolution is expected, although rare patients have an idiosyncratic reaction with widespread brain necrosis.[201] The pathogenesis of early-delayed toxicity is unknown, but the reaction has been speculated to be related to reversible demyelination. CT reveals decreased attenuation in the cerebral white matter; MRI reveals increased signal intensity in white matter on T2-weighted images.

Recently, early treatment-related brain injury has been reported with the use of concurrent daily temozolomide with external beam radiation in patients with glioblastoma.[202] Changes are seen on brain imaging studies that emulate tumor growth with increasing edema and an increase in uptake of contrast material. These changes, now referred to as “pseudo-progression,” may reflect an increase in blood-brain barrier breakdown that is the consequence of an augmentation of radiation effect from the coadministration of chemotherapy.

Chronic, Late Radiation Injury

Chronic, late radiation injury usually appears 9 months to 2 years after completion of radiation treatment, although some patients have experienced onset of symptoms 10 years after treatment. [201] [203]Patients exhibit focal areas of radiation necrosis or evidence of diffuse radiation injury. The incidence of each type of injury depends on the dose of treatment, fractionation schedule, and area of treatment.[204] [205] Focal necrosis often manifests as focal neurologic deficits, such as hemiparesis or aphasia. Global signs such as obtundation can occur when the localized necrosis causes increased intracranial pressure and herniation. Similarly, focal necrotic regions can cause seizures. Pathologic examination of the necrotic region reveals vascular injury to the small arteries and arterioles and evidence of coagulative necrosis, with destruction of all elements of the nervous tissue.[45] Treatment is directed at decreasing edema and mass effect. Patients generally respond to corticosteroids.[206] Surgical resection, if feasible, can be curative.

Diffuse Injury

Diffuse injury manifests as global neurologic dysfunction, with personality change, confusion, and lethargy, and can progress to dementia, obtundation, or coma. [200] [205] Diffuse white matter changes are found on CT or MRI, manifesting as low attenuation on CT scans and high signal intensity in the periventricular and subcortical white matter on T2-weighted and proton density MR images. [207] [208] [209]Mass effect and focal neurologic signs are not common, although late in the course, seizures and motor dysfunction can occur. The main risk factors for diffuse injury include the volume of brain treated, concurrent or adjuvant chemotherapy directed at the CNS, and use of short-course, high-dose-fraction regimens. The incidence is difficult to determine, but reports have shown neurologic and imaging changes in 32% to 50% of patients subjected to radiation therapy. [208] [209] [210]

The pathogenesis of diffuse radiation injury is not known, although distinctive neuropathologic changes have been described. The most prominent pathologic finding is vascular changes in the small arteries and arterioles. Hyalinization of the vessel walls with occlusion is common. [205] [209] In addition, areas of necrosis, gliosis, and demyelination are found. No established treatment is recognized. Corticosteroids may provide transient relief of associated edema but do not alter the course of the syndrome.

Necrotizing Leukoencephalopathy

Necrotizing leukoencephalopathy is the most severe form of neurologic toxicity associated with radiation therapy. It is most common when CNS-directed chemotherapy is combined with radiation therapy. This syndrome is described earlier in the discussion of methotrexate-associated toxicity. The incidence of leukoencephalopathy is much greater in patients who receive chemotherapy after cranial radiation therapy than in patients receiving either treatment alone, or in those receiving chemotherapy before the initiation of radiation therapy. [211] [212]

Mineralizing angiopathy has occurred in pediatric patients receiving both intrathecal methotrexate and radiation therapy.[211] The changes frequently are diagnosed as dystrophic calcifications during neuroradiologic examinations. Histopathologic analysis reveals deposits of calcium in small blood vessels, often with surrounding regions of necrotic brain. The clinical significance of these changes is uncertain.

Cranial radiation therapy has been associated with a wide spectrum of endocrinologic effects.[213] Most of these effects are attributed to damage to the hypothalamic-pituitary axis. These effects are generally dose dependent and may manifest several years after completion of the radiation treatment. Results of several studies have suggested differing vulnerability among the various endocrine loops.[214] Growth hormone deficiency and stimulation of precocious puberty have occurred at doses as low as 18 Gy.[215] Deficiency of gonadotropins, thyroid-stimulating hormone, and corticotropin usually results only when the hypothalamic-pituitary axis receives more than 40 Gy.[216] Similarly, hyperprolactinemia occurs most often in young women receiving more than 40 Gy of radiation therapy. Careful long-term monitoring of these patients is critical.[217] Appropriate replacement therapy or prolactin suppression treatment should prevent sequelae.

Radiation Myelopathy

Several distinct syndromes have resulted from the effects of radiation injury to the spinal cord: an acute syndrome manifesting as paraplegia or quadriplegia; early transient myelopathy; delayed progressive myelopathy; and an anterior horn, lower motor neuron syndrome.

The acute syndrome is rare with today's dosing schedules. Case reports state that weakness evolves over a few hours or days.[218] The syndrome probably is caused by acute necrotizing radiation injury due to rapidity of onset and failure of neurologic recovery.

The early transient form appears 6 to 12 weeks after treatment.[219] Most patients exhibit Lhermitte's sign—an electrical shock-like sensation down the spine with neck flexion. No neurologic deficits are found, and the symptoms resolve spontaneously over several weeks. Transient demyelination is hypothesized to be the cause of the symptoms.

Delayed progressive radiation myelopathy is the most common radiation therapy-induced spinal cord disorder, although it is relatively rare. Signs and symptoms generally develop 6 months to 1 year after completion of radiation therapy, although some data suggest that the latent period may be as long as 18 months to 2 years.[220] The clinical picture may vary from patient to patient. Some patients have monoplegia, others paraplegia or quadriplegia. Sensory symptoms are generally more severe than motor symptoms. Some patients have Brown-Séquard syndrome. Progression may take several years.[218]The pathogenesis is thought to be similar to that of delayed neurotoxicity after cranial radiation therapy (see earlier discussion). [218] [219] Pathologic examination reveals rarefaction of spinal cord white matter with small areas of necrosis. Degeneration of myelin sheaths and loss of oligodendrocytes have been noted. Other causes of spinal cord dysfunction need to be excluded, including intramedullary tumor or infection, multiple sclerosis, vitamin B12 deficiency, sarcoidosis, and Lyme disease. There is no treatment, and most patients experience progressive neurologic dysfunction over months to years.

Lower motor neuron syndrome occurs after spinal cord radiation therapy. Patients exhibit pure motor signs of weakness, atrophy, and fasciculations.[218] The syndrome manifests 3 months to 2 years after radiation treatment and is similar to polio. The pathogenesis is unknown. Hypotheses include loss of anterior horn cell neurons and radiation-induced injury to motor nerve roots. No treatment except supportive care exists.

Peripheral Nerve Toxicity

Peripheral nerves are relatively resistant to the effects of radiation therapy. Early effects, developing within 2 days of a single large-fraction treatment in an experimental animal system, include changes in vascular permeability of the nerve, changes in bioelectrical activity, and abnormal microtubule assembly in the axon.[221] Late changes include fibrosis in the nerve sheath and angiopathic changes in the small arterioles providing the vascular supply to the nerve.[222] Use of large (greater than 25 Gy) single doses or extended fractionated treatment to a very high total dose (greater than 80 Gy) is thought to be necessary for injury to the peripheral nerve. Similar changes have been found for some cranial nerves.

Brachial and lumbar plexopathies warrant a separate discussion. These syndromes result from radiation injury to the nerve fibers in the plexus. Brachial plexopathy is most common, caused by axillary radiation therapy for breast cancer.[223] Lumbar plexopathy is more commonly associated with pelvic external-beam radiation therapy, although local radioactive seed implantation (brachytherapy) may result in local nerve damage.[221]

The diagnosis of radiation plexopathy can be difficult and requires excluding tumor infiltration as the cause of the symptoms. This process is most difficult with brachial plexus dysfunction and in patients with apical lung cancer or metastatic breast cancer. The distinguishing features in comparing radiation with tumor brachial plexopathy have been described extensively.[223] None of the criteria are absolute, although tumor infiltration is more likely to be painful and involve the lower nerve roots (C7–T1) than is radiation injury, which is less likely to cause severe pain and generally involves higher roots (C5 and C6). Acute reversible radiation injury to the brachial plexus has been described. This condition often is painful, although the pain generally is mild. Patients experience weakness and atrophy in a C6–T1 distribution. Spontaneous recovery is typical.

Radiation has been reported to accelerate vascular injury, causing segmental obstruction of the subclavian artery.[224] This condition usually is painless. The motor and sensory loss evolves quickly, without subsequent progression or improvement.

Lumbosacral plexopathy is less common than radiation-related brachial plexopathy.[225] Onset of signs and symptoms usually is delayed until at least 1 year after radiation treatment. Pain is usual and mild. The pathogenesis is uncertain, although fibrosis causing nerve compression and ischemia is a likely cause. The diagnosis of radiation-related lumbosacral plexopathy is made by excluding tumor infiltration. Imaging (MRI or CT) often is useful, although in select cases, surgical exploration is indicated.

Muscle Injury from Radiation Treatment

Muscle is thought to be relatively resistant to the effects of radiation therapy, although results of several studies have suggested that at higher doses (greater than 50 Gy), significant late toxicity may occur.[222] Early effects are uncommon, symptoms generally are found after 1 year, and the onset of changes has been reported as late as 10 years after radiation therapy. Signs and symptoms include muscle contractures, loss of function, pain, extremity edema, and pathologic fractures. The synergy of the toxic effects with those of chemotherapy is uncertain, although most patients have received both modalities of treatment.[222] No treatment other than conservative measures including physical therapy is helpful.

DIFFERENTIAL DIAGNOSIS

Dementia and Encephalopathy

Acute Encephalopathy

A common neurologic problem in patients with cancer is acute encephalopathy.[226] The differential diagnosis includes an extensive array of potential causes. Most commonly, however, acute encephalopathy is caused by toxic or metabolic derangement. Frequent causes include narcotic effects, electrolyte abnormalities, hypoxia, and renal or hepatic dysfunction. Neoplastic meningitis frequently manifests as mental status changes as a result of increased intracranial pressure, seizures, or infiltration of the cortex through the Virchow-Robin spaces surrounding surface blood vessels. Likewise, brain metastasis can cause an acute change in mental status when a sudden increase in tumor size (often hemorrhage) results in a rapid change in intracranial pressure or when tumor-induced seizures occur. A paraneoplastic syndrome, limbic encephalitis, can manifest as a progressive dementia, which often is subacute. This paraneoplastic syndrome most frequently is associated with small cell lung cancer, but it has been described in association with other tumors. Patients often are found to have serum anti-Hu antibodies, also a feature of paraneoplastic sensory neuropathy. [227] [228] [229]

Cancer treatment can directly or indirectly cause acute encephalopathy. High doses of intravenous methotrexate or ara-C can cause reversible encephalopathy, often accompanied by lethargy. [5] [13] [35]Results of studies with animals and with patients in which positron emission tomography was used after high-dose methotrexate showed temporary reduction in brain metabolic activity in both glucose utilization and protein synthesis. [36] [230] Folinic acid (leucovorin) administration improved metabolic activity in laboratory studies.[37] Other agents known to cause encephalopathy include vincristine, ifosfamide, procarbazine, fludarabine, paclitaxel, cisplatin, and L-asparaginase. The immunostimulant levamisole combined with 5-FU causes reversible encephalopathy and has been associated with a demyelinating condition known as multifocal inflammatory leukoencephalopathy.[145] The hormonal agent tamoxifen has been reported to cause encephalopathy at high doses. Biologic response modifiers such as the interferons and interleukins commonly cause reversible encephalopathy, although permanent neurologic sequelae may result from prolonged use of interferon. [183] [184] Radiation therapy can cause an acute syndrome manifesting as lethargy that generally is reversible.

PRES has been seen most frequently with use of the immunomodulators cyclosporine and tacrolimus, but cisplatin, gemcitabine, and combination chemotherapy regimens also have been associated with the syndrome. More recently, drugs that modulate the VEGF pathway, such as bevacizumab and sorafenib, have been associated with PRES. The clinical manifestations are encephalopathy, cortical blindness, and variable loss of other higher cortical functions, such as aphasia and apraxia. Brain imaging with CT and MRI reveals characteristic patchy white matter changes ( Fig. 61-3 ). The pathogenesis of the syndrome is unknown, although hypertension and hypomagnesemia have been associated. Full recovery has occurred with cessation of treatment or adjustment of the dose of the immunosuppressant. [231] [232] [233] [234] [235]

 
 

Figure 61-3  Posterior reversible encephalopathy syndrome. The patient was a 47-year-old man with acute monocytic leukemia who had undergone allogeneic bone marrow transplantation and was receiving tacrolimus. He presented with headache, nausea, and vomiting. A,Magnetic resonance fast fluid-attenuated inversion recovery (FLAIR) image shows changes consistent with the syndrome. The patient's symptoms resolved within days of cessation of tacrolimus treatment. B and C, Repeated magnetic resonance images show resolution of the posterior abnormalities.

 

 

Many chemotherapeutic agents provoke a change in mental status by causing secondary metabolic derangement. Cyclophosphamide and vincristine can stimulate SIADH. [89] [90] [123] [124] The resulting hyponatremia can lead to seizures and encephalopathy. Hyponatremia secondary to cisplatin-induced salt-wasting nephropathy can cause the same neurologic problems. Treatment with L-asparaginase, corticosteroids, and streptozocin can lead to glucose intolerance. Left untreated, this condition can result in nonketotic hyperosmolar coma. Many chemotherapeutic agents can cause hepatic and renal dysfunction with consequent development of secondary neurologic symptoms.

Chronic Encephalopathy and Dementia

Dementia, or chronic progressive loss of cognitive function, most commonly is associated with treatment directed at the CNS. Leukoencephalopathy, characterized histologically by white matter changes consisting of axonal swelling and loss with regions of demyelination, is the classic chronic or late neurotoxic syndrome. [4] [6] Cognitive changes are first noticed 6 months to 2 years after completion of treatment and often are progressive, leading to profound dementia, coma, or death. [4] [5] [6] [8] [43] Intrathecal chemotherapy with methotrexate, ara-C, or thiotepa is most closely associated with leukoencephalopathy, although a similar syndrome occurs with high-dose intravenous methotrexate and ara-C and with intra-arterial chemotherapy (with BCNU or cisplatin). [236] [237] Previous treatment with cranial radiation therapy significantly increases the risk of leukoencephalopathy. [5] [52] Cranial radiation therapy alone can cause leukoencephalopathy, although the incidence increases markedly when radiation therapy is combined with chemotherapy. Other agents such as ifosfamide can cause prolonged encephalopathy and are associated with acute toxicity.[132]

Diagnostic Evaluation

A thorough search for a treatable underlying cause of encephalopathy should be undertaken in all affected patients. The diagnosis of chemotherapy-induced encephalopathy is made by excluding other potential causes. The order of diagnostic tests is dictated by the findings on the physical and neurologic evaluations. Patients with focal neurologic abnormalities need early imaging studies (CT or MRI), although certain metabolic disorders (e.g., hypoglycemia) can manifest as focal neurologic deficits. A metabolic evaluation, including measurement of electrolytes, renal and liver function tests, measurement of oxygenation, serum calcium and magnesium, serum ammonia, and possibly thyroid and adrenal function testing, should be performed for most patients. Careful review of prescribed and over-the-counter medications may provide critical information. In some cases, blood and urine toxicology screening may be necessary. EEG often is helpful in directing the evaluation by indicating the presence of structural abnormalities (e.g., periodic localizing epileptiform discharges or focal slowing) or may indicate a global metabolic process (e.g., diffuse slowing with D waves or triphasic waves in hepatic encephalopathy). Patients in subclinical status epilepticus may have encephalopathy; in these cases, the EEG findings are diagnostic. Lumbar puncture often is needed to exclude infectious or neoplastic meningitis. In most cases, head MRI or CT should be performed before lumbar puncture to look for a mass lesion in the brain that would make lumbar puncture unsafe. The search for the underlying cause often is revealing. One group of investigators reported uncovering the cause of encephalopathy in 31 of 37 patients.[226]

Seizures

Clinical Manifestations and Differential Diagnosis

The differential diagnosis for seizures in cancer patients includes an extensive list of possible causes. Causal factors can be broadly classified into toxic-metabolic and structural causes. Metabolic factors include hepatic and renal failure resulting from tumor growth or treatment toxicity, electrolyte abnormalities such as hypercalcemia from bone destruction or parathyroid hormone effect, hypomagnesemia from chemotherapy (cisplatin) or excessive vomiting, hyponatremia from SIADH or salt-wasting nephropathy (cisplatin), hypoxia, hyperglycemia from pancreatic failure (streptozocin), and glucose intolerance (corticosteroids). Several chemotherapeutic agents are known to be the direct cause of seizures ( Table 61-1 ).


Table 61-1   -- Chemotherapeutic Agents That Cause Seizures

Agent

Route of Administration

Comment(s)

L-Asparaginase

Intravenous

Associated with cerebrovascular events

Bevacizumab

Intravenous

Associated with PRES

Busulfan

Oral

Bone marrow transplantation–preparative regimen

Cisplatin, oxaliplatin

Intravenous

Rare; may be associated with cortical blindness, PRES

Cytosine arabinoside

High-dose intravenous (acute)

Late with leukoencephalopathy

Ifosfamide

Intravenous

Associated with encephalopathy

Methotrexate

High-dose intravenous (acute)

Late with leukoencephalopathy

Metronidazole

Intravenous, oral

 

Nitrosoureas

Intracarotid or supraophthalmic arterial

Often associated with focal brain necrosis

Sorafenib

Oral

Associated with PRES

Vincristine

Intravenous

 

PRES, posterior reversible encephalopathy syndrome.

 

 

 

Structural causes of seizures include brain metastasis, dural metastasis, and meningeal carcinoma. Ischemic and hemorrhagic vascular events also may provoke seizures. A tumor-induced hypercoagulable state may greatly increase risk of stroke or venous sinus thrombosis.[238] A similar hypercoagulable state can be seen with L-asparaginase treatment. The paraneoplastic syndrome marantic endocarditis often results in cerebrovascular events, as can infectious endocarditis, a potential complication of treatment-induced neutropenia.[188] Cisplatin can cause vasospasm of the intracranial vessels, producing a stroke.[239] Furthermore, immunocompromised patients are at greater risk for CNS infection (including bacterial and fungal meningitis), brain abscess, and viral encephalitis (including progressive multifocal leukoencephalopathy).

Diagnostic Evaluation

The type of seizure dictates the initial evaluation. Focal seizures more commonly are associated with structural brain lesions, although metabolic disorders can precipitate focal seizures if an underlying structural problem is present. Generalized seizures may be the consequence of structural or metabolic processes or both.

The diagnostic evaluation generally involves a metabolic evaluation similar to that described for encephalopathy. Electrolyte imbalances, such as hyponatremia, hypomagnesemia, hypocalcemia or hypercalcemia, hyperglycemia, and hyperphosphatemia, are possible metabolic causes. Similarly, hepatic and renal dysfunction increase the likelihood of seizures, particularly in a patient with an underlying structural brain lesion. Most patients with cancer who experience a seizure require an imaging study of the brain (CT or MRI). These studies should be performed both with and without the administration of contrast material. EEG may be helpful in recognizing (or ruling out) ongoing seizure activity, in confirming the diagnosis of seizure if the event was not witnessed or not accompanied by tonic-clonic activity, or possibly in localizing a focal lesion or process. For example, EEG in patients with herpes encephalitis often demonstrates bitemporal periodic localizing epileptiform discharges, even before abnormalities are seen on MR images. Lumbar puncture may be needed to evaluate for infectious and neoplastic meningitis. Lumbar puncture should be performed after brain imaging, except in patients with suspected bacterial meningitis, in whom obtaining the scan would delay lumbar puncture and administration of antibiotic therapy.

The diagnosis of chemotherapy-induced seizures is made after other causes are excluded. For most chemotherapeutic agents, seizures develop acutely, either during or immediately after treatment. Seizures often are accompanied by encephalopathy. In most instances, the prognosis for recovery from the acute episode is good. Unfortunately, when seizures develop as a component of chronic or delayed neurotoxicity (leukoencephalopathy), the prognosis is poor, and neurologic dysfunction often progresses. In such instances, the seizures are a manifestation of widespread brain destruction.

Cerebellar Dysfunction

Clinical Manifestations and Differential Diagnosis

Cerebellar dysfunction in patients who have cancer occurs most commonly with metastatic spread to the cerebellum or brainstem. Meningeal carcinoma occasionally causes cerebellar signs by infiltrating cerebellar pathways. Patients with structural cerebellar lesions often show asymmetrical dysfunction, which can be useful in differentiating this condition from drug-induced cerebellar toxicity. Paraneoplastic cerebellar degeneration is is characterized by subacute progressive loss of cerebellar function. [228] [240] [241] Patients usually have symmetrical loss of all cerebellar function and exhibit appendicular and truncal ataxia, nystagmus, and scanning speech. This paraneoplastic syndrome occurs most commonly with lung cancer but also has been associated with gynecologic cancers and Hodgkin's disease. Many patients have antibodies in the serum, designated anti-Yo, that bind to cerebellar tissue, specifically Purkinje cells, and cross-react with tumor tissue.[240]

5-FU and ara-C can cause cerebellar toxicity from specific irreversible damage to the cerebellar Purkinje cells. The result is truncal ataxia, unsteady gait, dysarthria, and nystagmus. [12] [13] [14] [15] [137] [138] [139] [140] [141] [142] [143] [144] The dysfunction usually is symmetrical. MRI findings immediately after chemotherapy are normal, but cerebellar atrophy often is detected at MRI months later.

Diagnostic Evaluation

Patients with cerebellar dysfunction should undergo MRI with and without gadolinium enhancement in an evaluation for metastatic lesions. In addition, the MRI findings may suggest the presence of neoplastic meningitis if enhancement is observed in the subarachnoid space. Patients with no evidence of brain metastasis need lumbar puncture to evaluate for neoplastic meningitis. Examination for the presence of serum anti-Yo antibodies should be performed, particularly in patients who have malignant lesions associated with this paraneoplastic syndrome.

In patients with only appendicular ataxia, the possibility of sensory ataxia must be kept in mind. The presence of sensory ataxia suggests the presence of severe sensory neuropathy, such as paraneoplastic sensory neuronopathy, dorsal column dysfunction from a structural lesion (e.g., epidural cord compression), or metabolic abnormality (e.g., vitamin B12 deficiency).

Cranial Neuropathy

Clinical Manifestations and Differential Diagnosis

Cranial neuropathy in patients with cancer most commonly indicates the presence of meningeal carcinoma, tumor involvement of the bones of the cranial base with encroachment of neural foramina, or rarely, brainstem metastasis.[242] Chemotherapy-induced cranial neuropathy is rare. Vincristine can cause cranial nerve palsy; extraocular eye movement abnormalities are most common. [62] [66] [79] [80]Intraventricular administration of drugs and of biologic response-modifying agents can cause transient cranial nerve palsy, often due to abnormalities in CSF circulation.[243]

In both neoplastic meningitis and drug-induced cranial nerve palsy, the seventh (facial) cranial nerve most commonly is affected. Unfortunately, there is little to differentiate the clinical manifestations of drug-induced nerve palsy from those of neoplastic meningitis. Both conditions can involve several cranial nerves, be indolent in onset, and demonstrate spontaneous resolution. Therefore, examination of the CSF is critical in the care of patients with suggestive signs and symptoms. In addition to neoplastic meningitis, tumor encroachment on neural foramina at the skull base from bone metastasis can cause cranial nerve palsy, as can small intraparenchymal lesions (tumor, infarct, or hemorrhage), although such lesions are rare.

Diagnostic Evaluation

In the care of patients with cranial nerve palsy, serial examinations of the CSF often are needed to determine whether tumor cells are present. Evaluation of the bones of the skull base with thin-section CT helps determine the presence of metastatic bone lesions. MRI of the brainstem is performed to evaluate for intraparenchymal lesions, although in most instances, other brainstem signs are present, in which case this test should be part of the initial evaluation.

Optic Neuropathy and Ocular Toxicity

Clinical Manifestations and Differential Diagnosis

Optic neuropathy can be seen in patients with neoplastic meningitis, lymphoma, or leukemia with infiltration of the optic nerve. [244] [245] In addition, compression from cranial base tumors can cause similar loss of vision. Optic neuritis, characterized by unilateral or bilateral loss of vision, has been reported as a rare paraneoplastic syndrome associated with small cell lung cancer.[246] Loss of vision often is accompanied by photosensitivity and papilledema. Antiretinal antibodies have been found in the serum of affected patients. Retinopathy most commonly is associated with intracarotid administration of nitrosoureas and cisplatin. [112] [113] [158] [159] High concentrations of drug flow into the ophthalmic artery, which supplies the retina, causing severe pain and often complete loss of vision. Newer techniques, allowing administration above the ophthalmic artery, have reduced the incidence of this local toxicity.

Intravenous cisplatin administration has been associated with optic disk swelling and optic neuropathy. [104] [105] This reaction is idiosyncratic, and the mechanism is unknown.

Diagnostic Evaluation

Chemotherapy-induced retinopathy from intra-arterial administration occurs soon after treatment and is rarely difficult to diagnose. Optic neuropathy from cisplatin is more indolent, and other causes must be considered, such as isoniazid, chlorpropamide, or ethambutol toxicity or paraneoplastic optic neuropathy. Optic nerve tumors and frontal lobe mass lesions can cause optic atrophy, although they are uncommon causes of isolated optic atrophy. MRI or CT may be helpful.

Spinal Cord Toxicity

Clinical Manifestations and Differential Diagnosis

The most common cause of spinal cord dysfunction in patients is epidural cord compression, either from direct extension of bone metastasis or from paravertebral spread through the intervertebral foramina. Intramedullary tumor and extramedullary intradural tumors can have myelopathic manifestations.[247] Similarly, epidural abscess and hematoma can be clinically indistinguishable from epidural tumor. Encephalomyelitis is a frequently described paraneoplastic syndrome associated with several types of tumors, particularly small cell lung cancer.[248] A rare paraneoplastic myelopathy has been described with lung cancer, renal cell carcinoma, and Hodgkin's disease. This syndrome is characterized by subacute progression of spinal cord dysfunction, usually in the thoracic region, although damage occasionally occurs at several levels. Pathologic examination reveals segmental necrosis.

Lumbar intrathecal administration of methotrexate and ara-C can result in focal myelopathy. [19] [20] [21] [22] [23] [24] [25] Symptoms and signs appear hours to days after treatment and can include sensory loss, upper and lower motor neuron dysfunction, radiating pain (similar to Lhermitte's sign), and bowel and bladder incontinence. The myelopathy may be transient or progressive; complete irreversible paraplegia usually is seen with progressive dysfunction. Myelopathy also has been reported with spinal radiation therapy. A rare, acute syndrome develops over days. The more common chronic myelopathy with radiation therapy develops months after completion of treatment.

Diagnostic Evaluation

The diagnostic evaluation of patients with spinal cord dysfunction is directed by findings on physical examination and the history. Rapid progression of symptoms suggests the presence of a rapidly growing tumor causing cord compression, epidural hematoma, or abscess. This finding warrants emergency evaluation with MRI. Early loss of bowel and bladder function or a suspended sensory level suggests the presence of an intramedullary lesion, best visualized by contrast-enhanced MRI.

Evidence of chemotherapy myelopathy may include edema on MRI and elevated myelin basic protein levels in CSF. The diagnosis of chemotherapy myelopathy often is made on the basis of temporal association with intrathecal treatment in the absence of other potential causes. Neoplastic meningitis can mimic spinal cord compression and requires CSF examination for diagnosis.

Peripheral Neuropathy

Clinical Manifestations and Differential Diagnosis

Peripheral neuropathy is a common paraneoplastic syndrome. Mild sensorimotor neuropathy is the most common neuropathy in patients with cancer.[249] The cause is unknown, but the condition is a distinct entity, separate from the diffuse weakness associated with cachexia. Rare pure motor and pure sensory paraneoplastic neuropathies also have been described. Sensory neuronopathy, most common with small cell lung cancer, causes severe sensory loss. [250] [251] The intense inflammatory reaction and neuronal destruction in the dorsal root ganglia have led to use of the term dorsal root ganglionitis. Some patients are found to have anti-Hu antibodies in serum. [228] [251] Motor neuronopathy manifests as isolated lower motor neuron loss.[252] This syndrome has been found in both patients with Hodgkin's lymphoma and those with non-Hodgkin's lymphoma. The pathogenesis of this pure motor syndrome is unknown. Other causes of neuropathy that should be considered are diabetes, thyroid dysfunction, vitamin B12 deficiency, and alcoholic neuropathy.

Several cancer chemotherapeutic agents cause peripheral neuropathy. These are listed in Table 61-2 . The peripheral neuropathy secondary to chemotherapy is temporally related to administration for most agents. Cisplatin is an exception, and delayed neuropathy occurs in some patients.


Table 61-2   -- Agents That Cause Peripheral Neuropathy

Agent

Comment(s)

Bortexomib

Primarily sensory, dose- and cumulative dose–related

Cisplatin

Large sensory fiber (vibration, proprioception); dose- and cumulative dose–related; dose-limiting

Cytosine arabinoside

Rare, symmetrical sensorimotor polyneuropathy

Interferons

Transient paresthesia

Oxaliplatin

Large sensory fiber (vibration, proprioception); dose- and cumulative dose–related; dose-limiting; acute hyperexcitability syndrome

Paclitaxel, docetaxel

Dose-related sensorimotor; dose-limiting

Procarbazine

Transient paresthesia

Thalidomide, lenalidomide

Sensory-motor axonal polyneuropathy; incidence related to duration and dose of treatment

Vincristine

Frequent; dose-related; autonomic and sensorimotor; exacerbated in patients with underlying neuropathy; dose-limiting

 

 

Carcinomatous meningitis can manifest as multilevel radiculopathy, initially mimicking peripheral neuropathy. Likewise, brachial and lumbar plexopathy from tumor infiltration or radiation therapy can mimic neuropathy, but careful neurologic examination determines the localized nature of the process.

Diagnostic Evaluation

The evaluation of a patient with neuropathy depends on the results of the neurologic examination. Determination of the components of the peripheral nervous system involved is critical in guiding evaluation. Pure motor loss in a patient with lymphoma strongly suggests the presence of a paraneoplastic process, although CSF analysis should be performed to exclude Guillain-Barré syndrome. Likewise, the presence of pure sensory neuropathy involving both small and large sensory fibers suggests dorsal root ganglionitis. Pure large-fiber sensory neuropathy is most common with cisplatin treatment. Nerve conduction testing and electromyelography (EMG) may be helpful in determining whether the process is axonal or demyelinating. Some patients should undergo lumbar puncture to exclude carcinomatous meningitis, or evaluation for Guillain-Barré syndrome.

Myopathy

Clinical Manifestations and Differential Diagnosis

Myopathy is a rare symptom in cancer, usually being the consequence of treatment. Dermatomyositis and polymyositis are paraneoplastic syndromes characterized by inflammatory myopathy and by the presence and the absence of a rash, respectively. [253] [254] Dermatomyositis and polymyositis have been associated with many tumors, most commonly lung and gastrointestinal tumors. Patients have an elevated serum creatine kinase (CK) level. Although myopathy is a rare complication of chemotherapy, it has been described with use of paclitaxel and vincristine. [63] [86] [255]

Interferon and other biologic response-modifying agents can cause myalgia, but no evidence of muscle dysfunction or breakdown is found on histopathologic examination of muscle biopsy specimens. Cisplatin and other agents that induce electrolyte abnormalities (e.g., hypomagnesemia) can cause muscle cramping.

Diagnostic Evaluation

For patients with clinical evidence of myopathy, serum CK should be measured before EMG is performed. An elevated CK level suggests active muscle destruction, as in polymyositis or dermatomyositis or with use of paclitaxel or vincristine. Measurement of electrolytes (e.g., magnesium, potassium) may be useful. In patients with loss of strength or with muscle pain, EMG and muscle biopsy may be necessary.

GRADING OF NEUROTOXICITY

None of the uniform grading systems of neurotoxicity are suitable for use in serial clinical evaluations. The most commonly used neurotoxicity measures are based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)—Neurology, as shown in Table 61-3 . Although these toxicity tables are useful in the evaluation of groups of patients, they are not suitable for monitoring the clinical status of individual patients. Standard neurologic testing with careful recording is best suited for individual patient care. The techniques required for performing an in-depth neurologic evaluation are reviewed in classic neurology textbooks. [256] [257] Quantitative measures of mental status function, motor examination results, and sensory function have been published. [258] [259] [260]


Table 61-3   -- National Cancer Institute Common Terminology Criteria for Adverse Events: Neurologic Toxicities

 

 

GRADE

Adverse Event

Short Name

1

2

3

4

5

Navigation note: ADD is graded as Cognitive disturbance.

Navigation note: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia).

Apnea

Apnea

Present

Intubation indicated

Death

Arachnoiditis/meningismus/radiculitis

Arachnoiditis

Symptomatic, not interfering with function; medical intervention indicated

Symptomatic (e.g., photophobia, nausea), interfering with function but not interfering with ADLs

Symptomatic, interfering with ADLs

Life-threatening; disabling (e.g., paraplegia)

Death

Also consider: Fever (in the absence of neutropenia, defined as ANC <1.0 × 109/L); Infection (documented clinically or microbiologically) with grade 3 or 4 neutrophils (ANC <1.0 × 109/L)–Select; Infection with normal ANC or grade 1 or 2 neutrophils–Select; Infection with unknown ANC–Select; Pain–Select; Vomiting.

Ataxia (incoordination)

Ataxia

Asymptomatic

Symptomatic, not interfering with ADLs

Symptomatic, interfering with ADLs; mechanical assistance indicated

Disabling

Death

Remark: Ataxia (incoordination) refers to the consequence of medical or operative intervention.

Brachial plexopathy

Brachial plexopathy

Asymptomatic

Symptomatic, not interfering with ADLs

Symptomatic, interfering with ADLs

Disabling

Death

CNS cerebrovascular ischemia

CNS ischemia

Asymptomatic, radiographic findings only

Transient ischemic event or attack (TIA) ≤24 hr duration

Cerebral vascular accident (CVA, stroke), neurologic deficit >24 hr

Death

Navigation note: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the Hemorrhage/Bleeding category.

CNS necrosis/cystic progression

CNS necrosis

Asymptomatic, radiographic findings only

Symptomatic, not interfering with ADLs; medical intervention indicated

Symptomatic and interfering with ADLs; hyperbaric oxygen indicated

Life-threatening; disabling; operative intervention indicated to prevent or treat CNS necrosis/cystic progression

Death

Cognitive disturbance

Cognitive disturbance

Mild cognitive disability; not interfering with work/school/life performance; specialized educational services/devices not indicated

Moderate cognitive disability; interfering with work/school/life performance but capable of independent living; specialized resources on part-time basis indicated

Severe cognitive disability; significant impairment of work/school/life performance

Unable to perform ADLs; full-time specialized resources or institutionalization indicated

Death

Remark: Cognitive disturbance may be used for ADD.

Confusion

Confusion

Transient confusion, disorientation, or attention deficit

Confusion, disorientation, or attention deficit interfering with function, but not interfering with ADLs

Confusion or delirium interfering with ADLs

Harmful to others or self; hospitalization indicated

Death

Remark: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance.

Navigation note: Cranial neuropathy is graded as Neuropathy–cranial–Select.

Dizziness

Dizziness

With head movements or nystagmus only; not interfering with function

Interfering with function, but not interfering with ADLs

Interfering with ADLs

Disabling

Remark: Dizziness includes disequilibrium, lightheadedness, and vertigo.

Also consider: Neuropathy: cranial–Select; Syncope (fainting).

Navigation note: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia).

Encephalopathy

Encephalopathy

Mild signs or symptoms; not interfering with ADLs

Signs or symptoms interfering with ADLs; hospitalization indicated

Life-threatening; disabling

Death

Also consider: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration–Select; Psychosis (hallucinations/delusions); Somnolence/depressed level of consciousness.

Extrapyramidal/involuntary movement/restlessness

Involuntary movement

Mild involuntary movements not interfering with function

Moderate involuntary movements interfering with function, but not interfering with ADLs

Severe involuntary movements or torticollis interfering with ADLs

Disabling

Death

Navigation note: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, postinfectious neuralgia, or painful neuropathies) is graded as Pain–Select in the Pain category.

Hydrocephalus

Hydrocephalus

Asymptomatic, radiographic findings only

Mild to moderate symptoms not interfering with ADLs

Severe symptoms or neurological deficit interfering with ADLs

Disabling

Death

Irritability (children <3 years of age)

Irritability

Mild; easily consolable

Moderate; requiring increased attention

Severe; inconsolable

Laryngeal nerve dysfunction

Laryngeal nerve

Asymptomatic, weakness on clinical examination/testing only

Symptomatic, but not interfering with ADLs; intervention not indicated

Symptomatic, interfering with ADLs; intervention indicated (e.g., thyroplasty, vocal cord injection)

Life-threatening; tracheostomy indicated

Death

Leak, cerebrospinal fluid (CSF)

CSF leak

Transient headache; postural care indicated

Symptomatic, not interfering with ADLs; blood patch indicated

Symptomatic, interfering with ADLs; operative intervention indicated

Life-threatening; disabling

Death

Remark: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours.

Leukoencephalopathy (radiographic findings)

Leukoencephalopathy

Mild increase in subarachnoid space (SAS); mild ventriculomegaly; small (± multiple) focal T2 hyperintensities, involving periventricular white matter or <1/3 of susceptible areas of cerebrum

Moderate increase in SAS; moderate ventriculomegaly; focal T2 hyperintensities extending into centrum ovale or involving 1/3 to 2/3 of susceptible areas of cerebrum

Severe increase in SAS; severe ventriculomegaly; near total white matter T2hyperintensities or diffuse low attenuation (CT)

Remark: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunae, which are areas that become void of neural tissue.

Memory impairment

Memory impairment

Memory impairment not interfering with function

Memory impairment interfering with function, but not interfering with ADLs

Memory impairment interfering with ADLs

Amnesia

Mental status[*]

Mental status

1–3 points below age and educational norm in Folstein Mini-Mental Status Exam (MMSE)

>3 points below age and educational norm in Folstein MMSE

Mood alteration–Select:

Mood alteration–Select

Mild mood alteration not interfering with function

Moderate mood alteration interfering with function, but not interfering with ADL; medication indicated

Severe mood alteration interfering with ADLs

Suicidal ideation; danger to self or others

Death

  

   

Agitation

 

 

 

 

 

 

  

   

Anxiety

 

 

 

 

 

 

  

   

Depression

 

 

 

 

 

 

  

   

Euphoria

 

 

 

 

 

 

Myelitis

Myelitis

Asymptomatic, mild signs (e.g., Babinski's or Lhermitte's sign)

Weakness or sensory loss not interfering with ADLs

Weakness or sensory loss interfering with ADLs

Disabling

Death

Navigation note: Neuropathic pain is graded as Pain–Select in the Pain Category.

Neuropathy: cranial–Select

Neuropathy: cranial–Select

Asymptomatic, detected on exam/testing only

Symptomatic, not interfering with ADLs

Symptomatic, interfering with ADLs

Life-threatening; disabling

Death

  

   

CN I

Smell

  

   

CN II

Vision

  

   

CN III

Pupil, upper eyelid, extraocular movements

  

   

CN IV

Downward, inward movement of eye

  

   

CN V

Motor–jaw muscles; Sensory–facial

  

   

CN VI

Lateral deviation of eye

  

   

CN VII

Motor–face; Sensory–taste

  

   

CN VIII

Hearing and balance

  

   

CN IX

Motor–pharynx; Sensory–ear, pharynx, tongue

  

   

CN X

Motor–palate; pharynx, larynx

  

   

CN XI

Motor-sternomastoid and trapezius

  

   

CN XII

Motor–tongue

Neuropathy: motor

Neuropathy–motor

Asymptomatic, weakness on exam/testing only

Symptomatic weakness interfering with function, but not interfering with ADLs

Weakness interfering with ADLs; bracing or assistance to walk (e.g., cane or walker) indicated

Life-threatening; disabling (e.g., paralysis)

Death

Remark: Cranial nerve motor neuropathy is graded as Neuropathy: cranial–Select.

Also consider: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.

Neuropathy: sensory

Neuropathy–sensory

Asymptomatic; loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function

Sensory alteration or paresthesia (including tingling), interfering with function, but not interfering with ADLs

Sensory alteration or paresthesia interfering with ADLs

Disabling

Death

Remark: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial–Select.

Personality/behavioral

Personality

Change, but not adversely affecting patient or family

Change, adversely affecting patient or family

Mental health intervention indicated

Change harmful to others or self; hospitalization indicated

Death

Phrenic nerve dysfunction

Phrenic nerve

Asymptomatic weakness on exam/testing only

Symptomatic but not interfering with ADLs; intervention not indicated

Significant dysfunction; intervention indicated (e.g., diaphragmatic plication)

Life-threatening respiratory compromise; mechanical ventilation indicated

Death

Psychosis (hallucinations/delusions)

Psychosis

Transient episode

Interfering with ADLs; medication, supervision or restrains indicated

Harmful to others or self, life-threatening consequences

Death

Pyramidal tract dysfunction (e.g., ↑ tone, hyperreflexia, Babinski's sign, ↓ fine motor coordination)

Pyramidal tract dysfunction

Asymptomatic, abnormality on exam or testing only

Symptomatic; interfering with function but not interfering with ADLs

Interfering with ADLs

Disabling; paralysis

Death

Seizure

Seizure

One brief generalized seizure; seizure(s) well controlled by anticonvulsants or infrequent focal motor seizures not interfering with ADLs

Seizures in which consciousness is altered; poorly controlled seizure disorder, with breakthrough generalized seizures despite medical intervention

Seizures of any kind which are prolonged, repetitive, or difficult to control (e.g., status epilepticus, intractable epilepsy)

Death

Somnolence/depressed level of consciousness

Somnolence

Somnolence or sedation interfering with function, but not interfering with ADLs

Obtundation or stupor; difficult to arouse; interfering with ADLs

Coma

Death

Speech impairment (e.g., dysphasia or aphasia)

Speech impairment

Awareness of receptive or expressive dysphasia, not impairing ability to communicate

Receptive or expressive dysphasia, impairing ability to communicate

Inability to communicate

Remark: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction.

Also consider: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis).

Syncope (fainting)

Syncope (fainting)

Present

Life-threatening consequences

Death

Also consider: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block–Select: Dizziness; Supraventricular and nodal arrhythmia–Select; Vasovagal episode; Ventricular arrhythmia–Select.

Navigation note: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the Gastrointestinal category.

Tremor

Tremor

Mild and brief or intermittent but not interfering with function

Moderate tremor interfering with function, but not interfering with ADLs

Severe tremor interfering with ADLs

Disabling

Neurology—Other (Specify)

Neurology—Other (Specify)

Mild

Moderate

Severe

Life-threatening; disabling

Death

ADD, attention deficit disorder; ADLs, activities of daily living; ANC, absolute neutrophil count; CNS, central nervous system; CT, computed tomography.

 

*

Folstein MF, Folstein SE, McHugh PR: Mini-mental state: a practical method for grading the state of patients for the clinician. J Psychiatr Res 1975;12:189–198. From http://ctep.cancer.gov/forms/CTCAEv3.pdf, published August 9, 2006; accessed September 10, 2007.

 

TREATMENT

No specific treatment exists to prevent or reverse neurotoxicity from most chemotherapeutic agents and regimens in use. Therefore, the focus should be on monitoring for development of toxicity so that treatment can be modified before the development of severe dysfunction. Rational treatment guidelines for minimizing neurotoxicity are needed.

Prevention

The key to prevention of permanent neurologic damage is to initiate a system for monitoring for toxicity. For example, patients receiving intrathecal chemotherapy are at risk of chemotherapy-induced myelopathy, an often irreversible toxicity. These patients may report vague neurologic symptoms or radicular back pain during the course of treatment that may be an early sign of neurologic damage. Findings at neurologic examination may not indicate loss of function, but an elevated CSF myelin basic protein level indicates that with subsequent treatment, the risk of myelopathy is high. [24] [25]

Vincristine treatment can cause peripheral neuropathy. Some patients exhibit autonomic neuropathy out of proportion to the sensorimotor neuropathy. The autonomic dysfunction can lead to intestinal dysmotility, ileus, and viscus perforation. Therefore, all patients undergoing vincristine chemotherapy should be carefully evaluated for the development of abdominal symptoms. Obstipation from vincristine would mandate avoiding further vincristine treatment.

Modification of Drug Dosing or Order

In certain treatment regimens, altering the order of the drugs administered can result in a marked decrease in the risk of neurotoxic complications. The risk of methotrexate-induced leukoencephalopathy after therapy for meningeal leukemia or carcinoma is reduced if the chemotherapy treatments, particularly intrathecal chemotherapy, precede cranial radiation therapy.[5] The reason for this schedule-dependent toxicity is unknown. It has been suggested that radiation opens the blood-brain barrier, thereby increasing exposure of the brain to subsequent chemotherapy effects. Other regimens in which dose order seems important include combination chemotherapy with cisplatin and ifosfamide. Patients receiving cisplatin before ifosfamide are at greater risk for ifosfamide-induced encephalopathy.[135]

Despite concern for synergistic neurotoxicity, certain regimens have been shown not to cause excessive neurotoxic effects. For example, a phase I study of paclitaxel and cisplatin included frequent neurologic examinations as a critical component.[261] Despite the well-recognized effects of both drugs on the peripheral nervous system, minimal overlapping toxicity occurred. Cisplatin treatment caused dose-related loss of vibratory sensation, whereas paclitaxel treatment correlated with loss of peripheral motor function. These findings underscore the importance of including careful neurologic testing as a component of phase I and II trials of new drugs and combination therapies.

Protective Agents

Interest continues in developing agents that either block development of certain chemotherapy-induced neuropathies or help reverse toxicity. Published reports of studies of neuroprotection during chemotherapy have recently been reviewed.[262] In the former category, the agent ORG 2766 has been reported to protect against cisplatin neuropathy. This drug, a synthetic analog of corticotropin, was tested in a double-blind, placebo-controlled trial in which patients with ovarian cancer underwent intensive cisplatin therapy. A dose-related protective effect was found.[30] Although the mechanism of action is unknown, results of laboratory studies suggest that ORG 2766 works synergistically with trophic factors (e.g., nerve growth factors) to promote nerve regeneration. [263] [264] Results of a study conducted with a tissue culture model suggested that corticotropin fragments may have a direct cellular protective role.[265] Amifostine, an organic thiophosphate, protects normal cells from the effects of radiation. Amifostine has been tested as a neuroprotectant with paclitaxel therapy in two phase III studies: A study of non-small-cell lung cancer found a reduction in incidence of radiation esophagitis but not in paclitaxel-induced neuropathy.[266] In a second study of ovarian cancer, the incidence of grade 3 and grade 4 peripheral neuropathy was significantly reduced.[267] Glutamine also has been evaluated as a neuroprotectant for the peripheral nervous system.[268] In a study with a small group of patients, the incidence of peripheral neuropathy among patients receiving paclitaxel plus glutamine (10 g orally, three times a day for 4 days after paclitaxel) was compared with the incidence when paclitaxel was given alone.[268] A statistically significant reduction in severe neuropathy was found in the glutamine treatment group, with significant decreases in the incidence and severity of dysesthesia, motor weakness, worsening of gait, and impairment of activities of daily living. Acetyl-l-carnitine has been reported to lessen neuropathic symptoms in patients receiving paclitaxel or cisplatin.[269] Alpha-lipoic acid, a broad-spectrum antioxidant, reportedly may help ameliorate symptoms from docetaxel and cisplatin or oxaliplatin neuropathy. Leucovorin may be helpful in reversing acute methotrexate-induced encephalopathy and somnolence.[37] The administration of methylene blue has been reported to accelerate recovery from ifosphamide-induced encephalopathy.[270] There is no known therapy for chemotherapy-induced leukoencephalopathy once brain injury has developed.

The acute neuropathic syndrome associated with oxaliplatin has generated special interest because of the painful nature of this toxicity. Various treatments including infusions of calcium gluconate, oral gabapentin, oral carbamazepine, intravenous amifostine, and intravenous glutathione have been used to prevent the development of this complication. [113] [271] Infusions of calcium gluconate and alpha-lipoic acid also have been used to treat the acute neuropathy once it has developed.

Recognition of Groups at High Risk for Development of Neurotoxicity

Certain patients are at high risk for the development of treatment-related neurotoxicity. Patients with underlying peripheral neuropathy (e.g., Charcot-Marie-Tooth disease, diabetic neuropathy) have been reported to be much more susceptible to development of severe neuropathy, including potentially fatal autonomic neuropathy. [272] [273] Such patients need careful monitoring with immediate cessation of treatment if autonomic dysfunction develops. Similarly, in patients in whom peripheral neuropathy may be a component of the cancer, such as multiple myeloma, the use of a neurotoxic agent such as bortezomib may increase the likelihood and severity of neuropathy.[194]

Patients with meningeal tumors (carcinoma, leukemia, lymphoma) often require extensive intrathecal chemotherapy. An intraventricular reservoir often is placed for this purpose. Before the reservoir system is used to administer chemotherapy, it is essential that correct placement and normal CSF flow be confirmed. This procedure is most readily performed by injecting indium 111-labeled albumin into the lateral ventricle through the reservoir system. [274] [275] Not only does this test help confirm catheter placement, but also monitoring the flow of tracer at 6, 24, and 48 hours helps determine the presence of abnormalities of clearance from the ventricular system or drug resorption at the arachnoid granulations. Figure 61-4 shows normal CSF flow and resorption of tracer through the arachnoid granulations. By contrast, Figures 61-5 and 61-6 [5] [6] show poor outflow from the lateral ventricles persisting 24 hours after contrast injection. Poor clearance of drug markedly increases the neurotoxicity of intraventricular treatment. Patients with poor ventricular outflow may need local radiation therapy for restoration of normal flow before instillation of chemotherapeutic agents.

 
 

Figure 61-4  Normal cerebrospinal fluid indium 111–diethylenetriaminepenta-acetic acid (DTPA) flow scan. Anterior cortical views immediately after injection (left), at 4 hours (middle), and at 24 hours (right). A, reservoir.

 

 

 
 

Figure 61-5  Ventricular outlet obstruction, lateral cortical view. Scans immediately after injection (left) and hours later (right). The reservoir (A), lateral ventricles (B), and fourth ventricle (C) are visible.

 

 

 
 

Figure 61-6  Obstruction of flow over cortical convexities. Scans immediately after injection (left), at 4 hours (middle), and at 24 hours (right). Visible are the reservoir (A), lateral ventricles (B), fourth ventricle (C), and tracer rising over the low portion of the cortical convexities (D).

 

 

Irreversible ototoxicity from cisplatin administration is more severe in patients with underlying hearing loss. Hearing loss with cisplatin also may be accelerated when the inner ear region and temporal lobe are included in the irradiated field.[118] Radiation treatment before or after cisplatin administration can cause this synergistic ototoxicity.

CONCLUSIONS

The incidence of chemotherapy-induced neurotoxicity is increasing as a consequence of advances in supportive care, use of higher doses of drugs, newer treatments targeted at the CNS, and prolonged patient survival, which allows toxicities with long latencies to become evident. The diagnosis of treatment-associated neurotoxicity is made after other diagnostic possibilities are excluded and when the pattern of toxicity is consistent with recognized neurotoxic effects. In most cases, options for management of treatment-associated neurotoxicity are limited. The optimal strategy is early recognition of neurotoxicity, careful monitoring of patients at increased risk for toxicity, and modification of regimens to avoid synergistic toxicity when possible. Future directions should include investigation of the mechanisms of toxicity and development of techniques for protecting the nervous system without altering the antineoplastic effect of treatment.

REFERENCES

  1. Rowinsky EK, Chaudhry V, Forastiere AA, et al: Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.  J Clin Oncol1993; 11:2010.
  2. Chaudhry V, Rowinsky EK, Sartorius SE, et al: Peripheral neuropathy from Taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies.  Ann Neurol1994; 5:304.
  3. Neijstrom E, Gabriel DA, Capizzi RL: High-dose methotrexate-induced neurotoxicity associated with elevation of CSF myelin basic protein [letter].  J Clin Oncol1985; 3:593.
  4. Price RA, Jamieson PA: The central nervous system in childhood leukemia. II. Subacute leukoencephalopathy.  Cancer1975; 35:306.
  5. Bleyer WA: Neurologic sequelae of methotrexate and ionizing radiation: a new classification.  Cancer Treat Rep1981; 65(Suppl 1):89.
  6. Ch'ien LT, Aur RJA, Verzosa MS, et al: Progression of methotrexate-induced leukoencephalopathy in children with leukemia.  Med Pediatr Oncol1981; 9:133.
  7. Hara T, Kishikawa T, Miyazaki S, et al: Central nervous system complications in childhood leukemia.  Am J Pediatr Hematol Oncol1984; 6:129.
  8. Meadows AT, Evans AE: Effects of chemotherapy on the central nervous system.  Cancer1976; 37:1079.
  9. Omuro AM, Ben-Porat LS, Panageas KS, et al: Delayed neurotoxicity in primary central nervous system lymphoma.  Arch Neurol2005; 62:1595.
  10. Hiesiger EM, Voorhies RM, Basler GA, et al: Opening the blood-brain barrier and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow.  Ann Neurol1986; 19:50.
  11. McGovern PC, Lautenbach E, Brennan PJ, et al: Risk factors for postcraniotomy surgical site infection after 1,3-bis(2-chloroethyl)-1-nitrosourea (Gliadel) wafer placement.  Clin Infect Dis2003; 36:759.
  12. Grossman L, Baker MA, Sutten DMC: Central nervous system toxicity of high-dose cytosine arabinoside.  Med Pediatr Oncol1983; 11:246.
  13. Hwang T, Yung WKA, Estey EH, Fields WS: Central nervous system toxicity with high-dose ara-C.  Neurology1985; 35:1475.
  14. Benger A, Browman GP, Walker IR, Preisler HD: Clinical evidence of a cumulative effect of high-dose cytarabine on the cerebellum in patients with acute leukemia: a leukemia intergroup report.  Cancer Treat Rep1985; 69:240.
  15. Winkelman MD, Hines JD: Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study.  Ann Neurol1983; 14:520.
  16. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms.  Ann Intern Med1989; 111:273.
  17. Gottlieb D, Bradstock K, Koutts J, et al: The neurotoxicity of high-dose cytosine arabinoside is age-related.  Cancer1987; 60:1439.
  18. Damon LE, Mass R, Linker CA: The association between high-dose cytarabine neurotoxicity and renal insufficiency.  J Clin Oncol1989; 7:1563.
  19. Wolff L, Zighelboim J, Gale RP: Paraplegia following intrathecal cytosine arabinoside.  Cancer1979; 43:83.
  20. Breuer AC, Pitman SW, Dawson DM, Schoene WC: Paraparesis following intrathecal cytosine arabinoside: a case report with neuropathologic findings.  Cancer1977; 40:2817.
  21. Mena H, Garcia JH, Velandia F: Central and peripheral myelinopathy associated with systemic neoplasia and chemotherapy.  Cancer1981; 48:1724.
  22. Dunton SF, Nitschke R, Spruce WE, et al: Progressive ascending paralysis following administration of intrathecal and intravenous cytosine arabinoside. A Pediatric Oncology Group study.  Cancer1986; 57:1083.
  23. Hahn AF, Feasby TE, Gilbert JJ: Paraparesis following intrathecal chemotherapy.  Neurology1983; 33:1032.
  24. Clark AW, Cohen SR, Nissenblatt MJ, Wilson SK: Paraplegia following intrathecal chemotherapy. Neuropathologic findings and elevation of myelin basic protein.  Cancer1982; 50:42.
  25. Bates SE, Raphaelson MI, Price RA, et al: Ascending myelopathy after chemotherapy for central nervous system acute lymphoblastic leukemia: correlation with cerebrospinal fluid myelin basic protein.  Med Pediatr Oncol1985; 13:4.
  26. Gagliano RG, Costanzi JJ: Paraplegia following intrathecal methotrexate: report of a case and review of the literature.  Cancer1976; 37:1663.
  27. Bunge RP, Settlage PH: Neurological lesions in cats following cerebrospinal fluid manipulation.  J Neuropathol Exp Neurol1957; 16:471.
  28. Borgeat A, De Muralt B, Stadler M: Peripheral neuropathy associated with high-dose ara-C therapy.  Cancer1986; 58:852.
  29. Feinberg WM, Swenson MR: Cerebrovascular complications of l-asparaginase therapy.  Neurology1988; 38:127.
  30. van der Hoop RG, Vecht CJ, van der Burg ME, et al: Prevention of cisplatin neurotoxicity with an ACTH(4–9) analogue in patients with ovarian cancer.  N Engl J Med1990; 322:89.
  31. Priest JR, Ramsay NKC, Steinherz PG, et al: A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia.  J Pediatr1982; 100:984.
  32. Holland J, Fasanello S, Ohnuma T: Psychiatric symptoms associated with l-asparaginase administration.  J Psychiatr Res1974; 10:105.
  33. Pichini S, Altieri I, Bacosi A, et al: High performance liquid chromatographic–mass spectrometric assay of busulfan in serum and cerebrospinal fluid.  J Chromatogr1992; 581:143.
  34. Gregg AP, Shepherd JD, Phillips GL: Busulphan and phenytoin [letter].  Ann Intern Med1989; 111:1049.
  35. Walker RW, Allen JC, Rosen G, Caparros B: Transient cerebral dysfunction secondary to high-dose methotrexate.  J Clin Oncol1986; 4:1845.
  36. Phillips PC, Thaler HT, Berger CA, et al: Acute high-dose methotrexate neurotoxicity in the rat.  Ann Neurol1986; 20:583.
  37. Phillips PC, Thaler HT, Allen JC, Rottenberg DA: High-dose leucovorin reverses acute high-dose methotrexate neurotoxicity in the rat.  Ann Neurol1989; 25:365.
  38. Ch'ien LT, Aur RJA, Stagner S, et al: Long-term neurological implications of somnolence syndrome in children with acute lymphocytic leukemia.  Ann Neurol1990; 8:273.
  39. Cohen Y, Lossos A, Polliack A: Neurotoxicity with leukoencephalopathy after a single intravenous high dose of methotrexate in a patient with lymphoma.  Acta Haematol2002; 107:185.
  40. Norrell H, Wilson CB, Slagel DE, Clark DB: Leukoencephalopathy following the administration of methotrexate into the cerebrospinal fluid in the treatment of primary brain tumors.  Cancer1974; 33:923.
  41. Nelson RW, Frank JT: Intrathecal methotrexate–induced neurotoxicities.  Am J Hosp Pharm1981; 38:65.
  42. Bleyer WA, Drake JC, Chabner BA: Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in meningeal leukemia.  N Engl J Med1973; 289:770.
  43. Bleyer WA, Griffin TW: White matter necrosis, mineralizing microangiopathy, and intellectual abilities in survivors of childhood leukemia: associations with central nervous system irradiation and methotrexate therapy.   In: Gilbert HA, Kagan AR, ed. Radiation Damage to the Nervous System,  New York: Raven Press; 1980:155.
  44. Gangji D, Reaman GH, Cohen SR, et al: Leukoencephalopathy and elevated levels of myelin basic protein in the cerebrospinal fluid of patients with acute lymphoblastic leukemia.  N Engl J Med1990; 303:19.
  45. Perry A, Schmidt RE: Cancer therapy-associated CNS neuropathology: an update and review of the literature.  Acta Neuropathol (Berl)2006; 111:197.
  46. Allen JC, Rosen G, Mehta BM, Horten B: Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue.  Cancer Treat Rep1980; 64:1261.
  47. Shalen PR, Ostrow PT, Glass PJ: Enhancement of the white matter following prophylactic therapy of the central nervous system for leukemia.  Radiology1981; 140:409.
  48. Geiser CF, Bishop Y, Jaffe N, et al: Adverse effects of intrathecal methotrexate in children with acute leukemia in remission.  Blood1975; 45:189.
  49. Kay HEM, Knapton PJ, O'Sullivan JP, et al: Encephalopathy in acute leukemia associated with methotrexate therapy.  Arch Dis Child1972; 47:344.
  50. Duttera MJ, Bleyer WA, Pomeroy TC, et al: Irradiation, methotrexate toxicity, and the treatment of meningeal leukemia.  Lancet1973; 1:703.
  51. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma: rationale for preoperative chemotherapy and delayed surgery.  Cancer1979; 43:2163.
  52. Ochs J, Mulhern R, Fairclough D, et al: Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: a prospective study.  J Clin Oncol1991; 9:145.
  53. Chessels JM, Cox TC, Kendall B, et al: Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation.  Arch Dis Child1990; 65:416.
  54. Suzuki K, Takemura T, Okeda R, Hatakeyama S: Vascular changes of methotrexate-related disseminated necrotizing leukoencephalopathy.  Acta Neuropathol1984; 65:145.
  55. Gilbert MR, Harding BL, Grossman SA: Methotrexate neurotoxicity: in vitro studies using cerebellar explants from rats.  Cancer Res1989; 49:2502.
  56. Cohen ME, Duffner PK, Terplan KL: Myelopathy with severe structural derangement associated with combined modality therapy.  Cancer1983; 52:1590.
  57. Skullerud K, Halvorsen K: Encephalomyelopathy following intrathecal methotrexate treatment in a child with acute leukemia.  Cancer1978; 42:1211.
  58. Back EH: Death after intrathecal methotrexate.  Lancet1969; 2:1005.
  59. Bagshawe KD, Magrath IT, Golding PR: Intrathecal methotrexate.  Lancet1969; 2:1258.
  60. Luddy RE, Gilman PA: Paraplegia following intrathecal methotrexate.  J Pediatr1973; 83:988.
  61. Bradley VG, Lassman LP, Pearce GW, Walton JN: The neuromyopathy of vincristine in man. Clinical, electrophysiological and pathological studies.  J Neurol Sci1907; 10:107.
  62. Sandler SG, Tobin W, Henderson ES: Vincristine-induced neuropathy: a clinical study of fifty leukemic patients.  Neurology1969; 19:367.
  63. Casey EB, Jellife AM, Le Quesne PM, Millett YL: Vincristine neuropathy: clinical and electrophysiological observations.  Brain1973; 96:69.
  64. Guiheneuc P, Ginet J, Groleau JY, Rojouan J: Early phase of vincristine neuropathy in man.  J Neurol Sci1990; 45:355.
  65. Burdman JA: A note on the selective toxicity of vincristine sulfate on chick-embryo sensory ganglia in tissue culture.  J Natl Cancer Inst1966; 37:331.
  66. Rosenthal S, Kaufman S: Vincristine neurotoxicity.  Ann Intern Med1974; 80:733.
  67. Mena MA, Pardo B, Casarejos MJ, et al: Neurotoxicity of levodopa on catecholamine-rich neurons.  Mov Disord1992; 7:23.
  68. Shelanski ML, Wisniewski H: Neurofibrillary degeneration induced by vincristine therapy.  Arch Neurol1969; 20:199.
  69. Seil FJ: Neurofibrillary tangles induced by vincristine and vinblastine sulfate in central and peripheral neurons in vitro.  Exp Neurol1968; 21:219.
  70. Journey LJ, Burdman J, Whaley A: Electron microscopic study of spinal ganglia from vincristine-treated mice.  J Natl Cancer Inst1969; 43:603.
  71. Donoso JA, Green LS, Heller-Bettinger IE, Samson FE: Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on axonal fibrillar organelles in vitro.  Cancer Res1977; 37:1401.
  72. Sato M, Miyoshi K: Ultrastructural observations on the vincristine-induced neuronal crystalloid inclusion in young rats.  Acta Neuropathol (Berl)1984; 63:150.
  73. Green LS, Donoso JA, Heller-Bettinger IE, Samson FE: Axonal transport disturbances in vincristine-induced peripheral neuropathy.  Ann Neurol1977; 1:255.
  74. Trobaugh-Lotrario AD, Smith AA, Odom LF: Vincristine neurotoxicity in the presence of hereditary neuropathy.  Med Pediatr Oncol2003; 40:39.
  75. Chauvenet AR, Shashi V, Selsky C, et al: Vincristine-induced neuropathy as the initial presentation of Charcot-Marie-Tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study.  J Pediatr Hematol Oncol2003; 25:316.
  76. Naumann R, Mohm J, Reuner U, et al: Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity.  Br J Haematol2001; 115:323.
  77. Cassady JR, Tonnesen GL, Wolfe LC, Sallan SE: Augmentation of vincristine neurotoxicity by irradiation of peripheral nerves.  Cancer Treat Rep1980; 64:963.
  78. Wheeler JS, Siroky MB, Bell R, Babayan RK: Vincristine-induced bladder neuropathy.  J Urol1983; 30:342.
  79. Sanderson PA, Kuwabara T, Cogan DG: Optic neuropathy presumably caused by vincristine therapy.  Am J Ophthalmol1976; 81:146.
  80. Vecchi V, Maccolini E, Bravetti GO, et al: Transient optic neuropathy secondary to MOPP chemotherapy in Hodgkin's disease: report of a case.  Tumori1984; 70:571.
  81. Johnson FL, Bernstein ID, Hartmann JR, Chard RL: Seizures associated with vincristine sulfate therapy.  J Pediatr1973; 82:699.
  82. Martin J, Mainwaring D: Coma and convulsions associated with vincristine therapy.  BMJ1973; 4:782.
  83. Whittaker JA, Parry DH, Bunch C, Weatherall DJ: Coma associated with vincristine therapy.  BMJ1973; 4:335.
  84. Slater LM, Wainer RA, Serpick AA: Vincristine neurotoxicity with hyponatremia.  Cancer1969; 23:122.
  85. Scheithauer W, Ludwig H, Maida E: Acute encephalopathy associated with continuous vincristine sulfate combination therapy: case report.  Invest New Drugs1985; 3:315.
  86. Suskind RM, Brusilow SW, Zehr J: Syndrome of inappropriate secretion of antidiuretic hormone produced by vincristine toxicity (with bioassay of ADH level).  J Pediatr1972; 81:90.
  87. Fine RS, Clarke RR, Shore NA: Hyponatremia and vincristine therapy.  Am J Dis Child1966; 112:256.
  88. Stuart MJ, Cuaso C, Miller M, Oski FA: Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine.  Blood1975; 45:315.
  89. Robertson GL, Bhoopalam N, Zelkowitz LJ: Vincristine neurotoxicity and abnormal secretion of antidiuretic hormone.  Arch Intern Med1973; 132:717.
  90. Mueller JM, Flaherty MJ: Vincristine-induced quadriparesis.  South Med J1978; 71:1310.
  91. Wheeler RH, Votaw M: Vincristine and quadriparesis.  Ann Intern Med1974; 81:709.
  92. Norman M, Elinder G, Finkel Y: Vincristine neuropathy and Guillain-Barré syndrome: a case with acute lymphatic leukemia and quadriparesis.  Eur J Haematol1987; 39:75.
  93. Slotwiner P, Song SK, Anderson PJ: Spheromembranous degeneration of muscle induced by vincristine.  Arch Neurol1966; 15:172.
  94. Roelofs RI, Hrushesky W, Rogin J, Rosenberg L: Peripheral sensory neuropathy and cisplatin chemotherapy.  Neurology1984; 34:934.
  95. Pollera Cf, Pietrangeli A, Giannarelli D: Cisplatin-induced peripheral neurotoxicity: relationship to dose intensity [letter].  Ann Oncol1991; 2:212.
  96. Mollman JE, Glover DJ, Hogan WM, Furman RE: Cisplatin neuropathy: risk factors, prognosis, and protection by WR-2721.  Cancer1988; 61:2192.
  97. Cavaletti G, Marzorati L, Bogliun G, et al: Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity.  Cancer1992; 69:203.
  98. von Schlippe M, Fowler CJ, Harland SJ: Cisplatin neurotoxicity in the treatment of metastatic germ cell tumour: time course and prognosis.  Br J Cancer2001; 85:823.
  99. Thompson SW, Davis LE, Kornfeld M, et al: Cisplatin neuropathy: clinical, electrophysiologic, morphologic, and toxicologic studies.  Cancer1984; 54:1269.
  100. Walsh TJ, Clark AW, Parhad IM, Green WR: Neurotoxic effects of cisplatin therapy.  Arch Neurol1982; 39:719.
  101. Eeles R, Tait DM, Peckham MJ: Lhermitte's sign as a complication of cisplatin-containing chemotherapy for testicular cancer.  Cancer Treat Rep1986; 70:905.
  102. Walther PJ, Rossitch E, Bullard DE: The development of Lhermitte's sign during cisplatin chemotherapy.  Cancer1987; 60:2170.
  103. Lyass O, Lossos A, Hubert A, et al: Cisplatin-induced non-convulsive encephalopathy.  Anticancer Drugs1998; 9:100.
  104. Wilding G, Caruso R, Lawrence TS, et al: Retinal toxicity after high-dose cisplatin therapy.  J Clin Oncol1985; 3:1683.
  105. Becher R, Schutt P, Osieka R, Schmidt CG: Peripheral neuropathy and ophthalmologic toxicity after treatment with cis-dichlorodiaminoplatinum II.  J Cancer Res Clin Oncol1980; 96:219.
  106. Berman IJ, Mann MP: Seizures and transient cortical blindness associated with cis-platinum (II)diamminedichloride (PDD) therapy in a thirty-year-old man.  Cancer1990; 45:764.
  107. Cattaneo MT, Filipazzi V, Piazza E, et al: Transient blindness and seizure associated with cisplatin therapy.  J Cancer Res Clin Oncol1988; 114:528.
  108. Mead GM, Arnold AM, Green JA, et al: Epileptic seizures associated with cisplatin administration.  Cancer Treat Rep1982; 66:1719.
  109. Steeghs N, De Jongh FE, Smitt PA, Bent MJ: Cisplatin-induced encephalopathy and seizures.  Anticancer Drugs2003; 14:443.
  110. Maiese K, Walker RW, Gargan R, Victor JD: Intra-arterial cisplatin-associated optic and otic toxicity.  Arch Neurol1992; 49:83.
  111. Kupersmith MJ, Frohman LP, Choi IS, et al: Visual system toxicity following intra-arterial chemotherapy.  Neurology1988; 38:284.
  112. Schaefer SD, Post JD, Close LG, Wright CG: Ototoxicity of low- and moderate-dose cisplatin.  Cancer1985; 56:1934.
  113. Aguilar-Markulis NV, Beckley S, Priore R, Mettlin C: Auditory toxicity effects of long-term cis-dichlorodiammineplatinum II therapy in genitourinary cancer patients.  J Surg Oncol1981; 16:111.
  114. Helson L, Okonkwo E, Anton L, Cvitkovic E: Cis-platinum ototoxicity.  Clin Toxicol1978; 13:469.
  115. Durrant JD, Rodgers G, Myers EN, Johnson JT: Hearing loss: risk factor for cisplatin ototoxicity? Observations.  Am J Otol1990; 11:375.
  116. Cersosimo RJ: Oxaliplatin-associated neuropathy: a review.  Ann Pharmacother2005; 39:128.
  117. Wilson RH, Lehky T, Thomas RR, et al: Acute oxaliplatin-induced peripheral nerve hyperexcitability.  J Clin Oncol2002; 20:1767.
  118. Brienza S, Vignoud J, Itzhaki M, Krikorian A: Oxaliplatin (l-OHP): Global safety in 682 patients (pts).  Proc Am Soc Clin Oncol1995; 14:209.
  119. Krishnan AV, Goldstein D, Friedlander M, Kiernan MC: Oxaliplatin-induced neurotoxicity and the development of neuropathy.  Muscle Nerve2005; 32:51.
  120. Taieb S, Trillet-Lenoir V, Rambaud L, et al: Lhermitte sign and urinary retention: atypical presentation of oxaliplatin neurotoxicity in four patients.  Cancer2002; 94:2434.
  121. Pietrangeli A, Leandri M, Terzoli E, et al: Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up.  Eur Neurol2006; 56:13.
  122. Fausti SA, Henry JA, Schaffer HI, et al: High-frequency monitoring for early detection of cisplatin toxicity.  Arch Otolaryngol Head Neck Surg1993; 119:661.
  123. DeFronzo RA, Braine H, Colvin OM, Davis PJ: Water intoxication in man after cyclophosphamide therapy.  Ann Intern Med1973; 78:861.
  124. Webberley MJ, Murray JA: Life-threatening acute hyponatremia induced by low dose cyclophosphamide and indomethacin.  Postgrad Med J1989; 65:950.
  125. DeFronzo RA, Colvin OM, Braine H, et al: Cyclophosphamide and the kidney.  Cancer1974; 33:483.
  126. Sterns RH, Riggs JE, Schochet Jr SS: Osmotic demyelination syndrome following correction of hyponatremia.  N Engl J Med1986; 314:1535.
  127. Gieron MA, Barak LS, Estrada J: Severe encephalopathy associated with ifosfamide administration in two children with metastatic tumors.  J Neurooncol1988; 6:29.
  128. Meanwell CA, Blake AE, Kelly KA, et al: Prediction of ifosfamide/mesna associated encephalopathy.  Eur J Clin Oncol1986; 22:815.
  129. Miller LJ, Eaton VE: Ifosfamide-induced neurotoxicity: a case report and review of the literature.  Ann Pharmacother1992; 26:183.
  130. Pratt CB, Green AA, Horowitz ME, et al: Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna.  J Clin Oncol1986; 4:1253.
  131. Curtin JP, Koonings PP, Gutierrez M, et al: Ifosfamide-induced neurotoxicity.  Gynecol Oncol1991; 42:193.
  132. Cabral FR: Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of Taxol for cell division.  J Cell Biol1983; 97:22.
  133. Rieger C, Fiegl M, Tischer J, et al: Incidence and severity of ifosfamide-induced encephalopathy.  Anticancer Drugs2004; 15:347.
  134. Cabral F, Wible L, Brenner S, Brinkley BR: Taxol-requiring mutant of Chinese hamster ovary cells with impaired mitotic spindle assembly.  J Cell Biol1983; 97:30.
  135. Pratt CB, Goren MP, Meyer WH, et al: Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors.  J Clin Oncol1990; 8:1399.
  136. Anderson NR, Tandon DS: Ifosfamide extrapyramidal neurotoxicity.  Cancer1991; 68:72.
  137. Riehl JB, Brown WB: Acute cerebellar syndrome secondary to 5-fluorouracil therapy.  Neurology1964; 14:961.
  138. Bixenman WW, Nicholls JVV, Warwick OH: Oculomotor disturbances associated with 5-fluorouracil chemotherapy.  Am J Ophthalmol1977; 83:789.
  139. Moertel CG, Reitemeier RJ, Bolton CF, Shorter RG: Cerebellar ataxia associated with fluorinated pyrimidine therapy.  Cancer Chemother Rep1964; 41:15.
  140. Moore DH, Fowler Jr WC, Crumpler LS: 5-Fluorouracil neurotoxicity.  Gynecol Oncol1990; 36:152.
  141. Antin PB, Forry-Schaudies S, Friedman TM, et al: Taxol induces postmitotic myoblasts to assemble interdigitating microtubule-myosin arrays that exclude actin filaments.  J Cell Biol1981; 90:300.
  142. Mole-Bajer J, Bajer AS: Action of Taxol on mitosis: modification of microtubule arrangements and function of the mitotic spindle in Haemanthus endosperm.  J Cell Biol1983; 96:527.
  143. Vallee RB: A Taxol-dependent procedure for the isolation of microtubules and microtubule-associated proteins (MAPs).  J Cell Biol1982; 92:435.
  144. Manfredi JJ, Parness J, Horwitz SB: Taxol binds to cellular microtubules.  J Cell Biol1982; 94:688.
  145. Hook CC, Kimmel DW, Kvols LK, et al: Multifocal inflammatory leukoencephalopathy with 5-fluorouracil and levamisole.  Ann Neurol1992; 31:262.
  146. Videnovic A, Semenov I, Chua-Adajar R, et al: Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.  Neurology2005; 65:1792.discussion 1685
  147. Formica V, Leary A, Cunningham D, Chua YJ: 5-Fluorouracil can cross brain-blood barrier and cause encephalopathy: should we expect the same from capecitabine? A case report on capecitabine-induced central neurotoxicity progressing to coma.  Cancer Chemother Pharmacol2006; 58:276.
  148. Niemann B, Rochlitz C, Herrmann R, Pless M: Toxic encephalopathy induced by capecitabine.  Oncology2004; 66:331.
  149. Grever MR, Kopecky KJ, Cottman CA, et al: Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia.  Nouv Rev Fr Hematol1988; 30:457.
  150. Chun HG, Leyland-Jones B, Caryk SM, et al: Central nervous system toxicity of fludarabine phosphate.  Cancer Treat Rep1986; 70:1225.
  151. Vidarsson B, Mosher DF, Salamat MS, et al: Progressive multifocal leukoencephalopathy after fludarabine therapy for low-grade lymphoproliferative disease.  Am J Hematol2002; 70:51.
  152. Mahaley Jr MS, Whaley RA, Blue M, Bertsch L: Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas.  J Neurooncol1986; 3:297.
  153. Kleinschmidt-DeMasters BK: Intracarotid BCNU leukoencephalopathy.  Cancer1986; 57:1276.
  154. Rosenblum MK, Delattre JY, Walker RW, Shapiro WR: Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study.  J Neurooncol1989; 7:269.
  155. Burger PC, Kamenar E, Schold SC, et al: Encephalomyelopathy following high-dose BCNU therapy.  Cancer1981; 48:1318.
  156. Blacklock JB, Wright DC, Dedrick RL, et al: Drug streaming during intra-arterial chemotherapy.  J Neurosurg1986; 64:284.
  157. Westphal M, Hilt D, Bortey , et al: A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.  Neurooncology2003; 5:79.
  158. Brem H, Mahaley MSJ, Vick NA, et al: Interstitial chemotherapy with drug polymer implants for the treatment of malignant gliomas.  J Neurosurg1991; 74:441.
  159. Grimson BS, Mahaley Jr MS, Dubey HD, Dudka L: Ophthalmic and central nervous system complications following intracarotid BCNU (carmustine).  J Clin Neuroophthalmol1981; 1:261.
  160. Stolinsky DC, Solomon J, Pugh RP, et al: Clinical experience with procarbazine in Hodgkin's disease, reticulum cell sarcoma, and lymphosarcoma.  Cancer1970; 26:984.
  161. Brunner KW, Young CW: A methylhydrazine derivative in Hodgkin's disease and other malignant neoplasms.  Ann Intern Med1965; 63:69.
  162. Samuels ML, Leary WV, Alexanian R, et al: Clinical trials with N-isopropyl-a-(2-methylhydrazino)-p-toluamide hydrochloride in malignant lymphoma and other disseminated neoplasia.  Cancer1967; 20:1187.
  163. Horwitz SB, Lothstein L, Manfredi JJ, et al: Taxol: mechanisms of action and resistance.  Ann N Y Acad Sci1986; 466:733.
  164. Black MM: Taxol interferes with the interaction of microtubule-associated proteins with microtubules in cultured neurons.  J Neurosci1987; 7:3695.
  165. Lipton RB, Apfel SC, Dutcher JP, et al: Taxol produces a predominantly sensory neuropathy.  Neurology1989; 39:368.
  166. Bissett D, Setanoians A, Cassidy J, et al: Phase I and pharmacokinetic study of taxotere (RP56976) administered as a 24-hour infusion.  Cancer Res1993; 53:532.
  167. Vasey PA, Atkinson R, Coleman R, et al: Docetaxel-carboplatin as first line chemotherapy for epithelial ovarian cancer.  Br J Cancer2001; 84:170.
  168. Lee JJ, Swain SM: Peripheral neuropathy induced by microtubule-stabilizing agents.  J Clin Oncol2006; 24:1633.
  169. Ziske CG, Schottker B, Gorschluter M, et al: Acute transient encephalopathy after paclitaxel infusion: report of three cases.  Ann Oncol2002; 13:629.
  170. Nieto Y, Cagnoni PJ, Bearman SI, et al: Acute encephalopathy: a new toxicity associated with high-dose paclitaxel.  Clin Cancer Res1999; 5:501.
  171. Wefel JS, Lenzi R, Theriault RL, et al: The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial.  Cancer2004; 100:2292.
  172. Gorin MB, Day R, Costantino JP, et al: Long-term tamoxifen citrate use and potential ocular toxicity.  Am J Ophthalmol1998; 125:493.
  173. Noureddin BN, Seoud M, Bashshur Z, et al: Ocular toxicity in low-dose tamoxifen: a prospective study.  Eye1999; 13:729.
  174. Ashford AR, Doney I, Tiwari RP, et al: Reversible ocular toxicity related to tamoxifen therapy.  Cancer1988; 61:33.
  175. Pluss JL, DiBella NJ: Reversible central nervous system dysfunction due to tamoxifen in a patient with breast cancer.  Ann Intern Med1984; 10:652.
  176. Love RR: Tamoxifen therapy in primary breast cancer: biology, efficacy, and side effects.  J Clin Oncol1989; 7:803.
  177. Ron IG, Inbar MJ, Barak Y, et al: Organic delusional syndrome associated with tamoxifen treatment.  Cancer1992; 69:1415.
  178. Denicoff KD, Rubinow DR, Papa MZ, et al: The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells.  Ann Intern Med1987; 107:293.
  179. Somers SS, Reynolds JV, Guillou PJ: Multifocal neurotoxicity during interleukin-2 therapy for malignant melanoma.  Clin Oncol (R Coll Radiol)1992; 4:135.
  180. Vecht C, Keohane C, Menon RS, et al: Acute fatal leukoencephalopathy after interleukin-2 therapy.  N Engl J Med1990; 323:1146.
  181. Bernard JT, Ameriso S, Kempf RA, et al: Transient focal neurologic deficits complicating interleukin-2 therapy.  Neurology1990; 40:154.
  182. Friedman DI, Hu EH, Sadun AA: Neuro-ophthalmic complications of interleukin-2 therapy.  Am J Ophthalmol1991; 109:1679.
  183. Collins CA, Vallee RB: Temperature-dependent reversible assembly of Taxol-treated microtubules.  J Cell Biol1987; 105:2847.
  184. Mattson K, Niiranen A, Iivanainen M, et al: Neurotoxicity of interferon [letter].  Cancer Treat Rep1983; 67:958.
  185. Mattson K, Niiranen A, Laaksonen R, Cantell K: Psychometric monitoring of interferon neurotoxicity [letter].  Lancet1984; 1:275.
  186. Rosen P, Armstrong D: Nonbacterial thrombotic endocarditis in patients with malignant neoplastic disease.  Am J Med1973; 54:23.
  187. Capuron L, Gumnick JF, Musselman DL, et al: Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.  Neuropsychopharmacology2002; 26:643.
  188. Schibler MJ, Cabral F: Taxol-dependent mutants of Chinese hamster ovary cells with alterations in alpha- and beta-tubulin.  J Cell Biol1986; 102:1522.
  189. Meyers CA, Obbens EA, Scheibel RS, Moser RP: Neurotoxicity of intraventricularly administered alpha-interferon for leptomeningeal disease.  Cancer1991; 68:88.
  190. Bernsen PLJA, Chung REW, Vingerhoets HM, Janssen JTP: Bilateral neuralgic amyotrophy induced by interferon treatment.  Arch Neurol1988; 45:449.
  191. Singhal S, Mehta J: Thalidomide in cancer.  Biomed Pharmacother2002; 56:4.
  192. Chaudhry V, Cornblath DR, Corse A, et al: Thalidomide-induced neuropathy.  Neurology2002; 59:1872.
  193. Bastuji-Garin S, Ochonisky S, Bouche P, et al: Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients.  J Invest Dermatol2002; 119:1020.
  194. Richardson PG, Blood E, Mitsiades CS, et al: A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.  Blood2006; 108:3458.
  195. Glusker P, Recht L, Lane B: Reversible posterior leukoencephalopathy syndrome and bevacizumab.  N Engl J Med2006; 354:980.
  196. Ozcan C, Wong SJ, Hari P: Reversible posterior leukoencephalopathy syndrome and bevacizumab.  N Engl J Med2006; 354:980.discussion 980
  197. Govindarajan R, Adusumilli J, Baxter DL, et al: Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43–9006.  J Clin Oncol2006; 24:e48.
  198. Richardson PG, Briemberg H, Jagannath S, et al: Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.  J Clin Oncol.2006; 24:3113.
  199. McLean AS: Early adverse effects of radiation.  Br Med Bull1973; 29:69.
  200. Valk PE, Dillon WP: Radiation injury of the brain.  AJNR Am J Neuroradiol1991; 12:45.
  201. Watne K, Hager B, Heier M, et al: Reversible oedema and necrosis after irradiation of the brain: diagnostic procedures and clinical manifestations.  Acta Oncol1990; 29:891.
  202. Chamberlain MC, Glantz MJ, Chalmers L, et al: Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma.  J Neurooncol2007; 82:81.
  203. Late complications of radiotherapy.  Drug Ther Bull1997; 35:13.
  204. Morris JG, Gratton-Smith P, Panegyres PK, et al: Delayed cerebral radiation necrosis.  Q J Med1994; 87:119.
  205. Marks JE, Wong J: The risk of cerebral radionecrosis in relation to dose, time and fractionation: a follow-up study.  Prog Exp Tumor Res1985; 29:210.
  206. Shaw PJ, Bates D: Conservative treatment of delayed cerebral radiation necrosis.  J Neurol Neurosurg Psychiatry1984; 47:1338.
  207. Packer RJ, Zimmerman RA, Bilaniuk CT: Magnetic resonance imaging in the evaluation of treatment related central nervous system damage.  Cancer1986; 58:635.
  208. Constine LS, Konski A, Ekholm S, et al: Adverse effects of irradiation correlated with MR and CT imaging.  Int J Radiat Oncol Biol Phys1988; 15:319.
  209. Marshall VG, Bradley WGJ, Marshall CE, et al: Deep white matter infarction: correlation of MR imaging with histopathologic findings.  Radiology1988; 167:517.
  210. Curnes JT, Laster DW, Ball MR, et al: MRI of radiation injury to the brain.  Am J Neuroradiol1986; 147:119.
  211. Price RA: Histopathology of CNS leukemia and complications of therapy.  Am J Pediatr Hematol Oncol1979; 1:21.
  212. Pizzo PA, Poplack DG, Bleyer WA: Neurotoxicities of current leukemia therapy.  Am J Pediatr Hematol Oncol1979; 1:127.
  213. Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy.  Int J Radiat Oncol Biol Phys1995; 31:1113.
  214. Littley MD, Shalet SM, Bearwell CG: Radiation and the hypothalamic-pituitary axis.   In: Gutin PH, Leibel SA, Sheline GE, ed. Radiation Injury of the Nervous System,  New York: Raven Press; 1991:303.
  215. Leventhal BG, Shearer PD: Recognizing and managing the late effects of cancer treatment.  Oncology (Huntingt)1989; 3:73.
  216. Lam KS, Tse VK, Wang C, et al: Effects of cranial irradiation on hypothalamic-pituitary function: a 5-year longitudinal study in patients with nasopharyngeal carcinoma.  Q J Med1991; 286:165.
  217. Byrd RL: Late effects of treatment of cancer in children.  Pediatr Ann1983; 12:450.
  218. Goldwein JW: Radiation myelopathy: a review.  Med Pediatr Oncol1987; 15:89.
  219. Schultheiss TE, Stephens LC: Invited review: permanent radiation myelopathy.  Br J Radiol1992; 65:737.
  220. Schultheiss TE, Higgins EM, El-Mahdi AM: The latent period in clinical radiation myelopathy.  Int J Radiat Oncol Biol Phys1984; 10:1109.
  221. Kinsella TJ, Weichgelbaum RR, Sheline GE: Radiation injury of cranial and peripheral nerves.   In: Gilbert HA, Kagan AR, ed. Radiation Damage to the Nervous System: A Delayed Therapeutic Hazard,  New York: Raven Press; 1980:145.
  222. Gillette EL, Mahler PA, Powers BE, et al: Late radiation injury to muscle and peripheral nerves.  Int J Radiat Oncol Biol Phys1995; 31:1309.
  223. Olsen NK, Pfeiffer P, Mondrup K, et al: Radiation-induced brachial plexus neuropathy in breast cancer patients.  Acta Oncol1990; 29:885.
  224. Gerard JM, Franck N, Moussa Z, et al: Acute ischemic brachial plexus neuropathy following radiation therapy.  Neuropathy1989; 39:450.
  225. Kinsella TJ, Sindelar WF, DeLuca AM, et al: Tolerance of peripheral nerve to intraoperative radiotherapy (IORT): clinical and experimental studies.  Int J Radiat Oncol Biol Phys1985; 11:1579.
  226. Gilbert MR, Grossman SA: The incidence and nature of neurologic problems in patients with solid tumors.  Am J Med1986; 81:951.
  227. Henson RA, Hoffman HL, Ulrich H: Encephalomyelitis with carcinoma.  Brain1965; 88:449.
  228. Posner JB, Furneaux HM: Paraneoplastic syndromes.   In: Waksman BH, ed. Immunologic Mechanisms in Neurologic and Psychiatric Disease,  New York: Raven Press; 1990:187.
  229. Jaekle KA: Autoimmune paraneoplastic limbic encephalitis.  Neurology1988; 38(Suppl 1):390.
  230. Phillips PC, Dhawan V, Strother SC, et al: Reduced cerebral glucose metabolism and increased brain capillary permeability following high-dose methotrexate chemotherapy: a positron emission tomographic study.  Ann Neurol1987; 21:59.
  231. Sanchez-Carpintero R, Narbona J, Lopez de Mesa R, et al: Transient posterior encephalopathy induced by chemotherapy in children.  Pediatr Neurol2001; 24:145.
  232. Honkaniemi J, Kahara V, Dastidar P, et al: Reversible posterior leukoencephalopathy after combination chemotherapy.  Neuroradiology2000; 42:895.
  233. Russell MT, Nassif AS, Cacayorin ED, et al: Gemcitabine-associated posterior reversible encephalopathy syndrome: MR imaging and MR spectroscopy findings.  Magn Reson Imaging2001; 19:129.
  234. Wong R, Beguelin GZ, De Lima M, et al: Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation.  Br J Haematol2003; 122:128.
  235. Cosottini M, Lazzarotti G, Ceravolo R, et al: Cyclosporine-related posterior reversible encephalopathy syndrome (PRES) in non-transplant patient: a case report and literature review.  Eur J Neurol2003; 10:461.
  236. Gutin PH, Weiss HD, Wiernik PH, Walker MD: Intrathecal N,N′,N″-triethylenethiophosphoramide [thio-TEPA (NSC 6396)] in the treatment of malignant meningeal disease: phase I-II study.  Cancer1976; 38:1471.
  237. Gutin PH, Levi JA, Wiernik PH, Walker MD: Treatment of malignant meningeal disease with intrathecal thioTEPA: a phase II study.  Cancer Treat Rep1977; 61:885.
  238. Collins RC, Al-mondhiry H, Chernik NL, Posner JB: Neurologic manifestations of intravascular coagulation in patients with cancer: a clinical-pathological analysis of 12 cases.  Neurology1975; 25:795.
  239. Stefenelli T, Kuzmits R, Ulrich W, Glogar D: Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine, and bleomycin for testicular cancer.  Eur Heart J1988; 9:552.
  240. Anderson NE, Rosenblum MK, Posner JB: Paraneoplastic cerebellar degeneration: clinico-immunological correlations.  Ann Neurol1988; 24:559.
  241. Furneaux HM, Rosenblum MK, Dalmau J, et al: Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration.  N Engl J Med1990; 322:1844.
  242. Greenberg HS, Deck MD, Vikram B, et al: Metastasis to the base of the skull: clinical findings in 43 patients.  Neurology1981; 31:530.
  243. Brown T, Havlin K, Weiss G, et al: A phase I trial of Taxol given by a 6-hour intravenous infusion.  J Clin Oncol1991; 9:1261.
  244. Moore RY, Oda Y: Malignant lymphoma with diffuse involvement of peripheral nerves.  Neurology1962; 12:186.
  245. Teoh R, Barnard RO, Gautier-Smith PC: Polyneuritis cranialis as a presentation of malignant lymphoma.  J Neurol Sci1990; 48:399.
  246. Grunwald GB, Kornguth SE, Towfighi J, et al: Autoimmune basis of visual paraneoplastic syndrome in patients with small cell lung carcinoma.  Cancer1987; 60:780.
  247. Byrne TN: Spinal cord compression from epidural metastases.  N Engl J Med1992; 327:614.
  248. Henson RA, Ulrich H: Encephalomyelitis.  In Cancer and the Nervous System,  Oxford: Blackwell Scientific; 1980:314.
  249. Croft PB, Wilkinson M: The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma.  Brain1965; 88:427.
  250. Horwich MS, Cho L, Porro RS, Posner JB: Subacute sensory neuropathy: a remote effect of carcinoma.  Ann Neurol1977; 19:2.
  251. Grisold W, Drlicek M, Popp W, Jellinger K: Paraneoplastic sensory neuropathy, revisited.  Neurology1988; 38:508.
  252. Schold SC, Cho ES, Somasundaram M, Posner JB: Subacute motor neuropathy: a remote effect of lymphoma.  Ann Neurol1979; 5:271.
  253. DeVere R, Bradley WG: Polymyositis: its presentation, morbidity and mortality.  Brain1976; 98:637.
  254. Barnes BE: Dermatomyositis and malignancy: a review of the literature.  Ann Intern Med1976; 84:68.
  255. Hildebrand J, Joffroy A, Vauthier J, Flament-Durand J: [Neurotoxicity of formyl leurosine: an experimental and clinical study (author's transl)].  Acta Neurol Belg1979; 79:322.
  256. Mayo Clinic and Mayo Foundation : Clinical Examinations in Neurology,  6th ed.. St. Louis, Mosby–Year Book, 1991.
  257. Haerer AF: DeJong's The Neurologic Examination,  5th ed.. Philadelphia, JB Lippincott, 1992.
  258. Strub RA, Black FW: The Mental Status Examination in Neurology,  2nd ed.. Philadelphia, FA Davis, 1992.
  259. In: O'Brien MD, ed. Aids to the Examination of the Peripheral Nervous System,  London: Bailliere-Tindall; 1986.
  260. Elderson A, Gerritsen van der Hoop R, Haanstra W, et al: Vibration perception and thermoperception as quantitative measurements in the monitoring of cisplatin induced neurotoxicity.  J Neurol Sci1989; 93:167.
  261. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of Taxol and cisplatin: a phase I and pharmacologic study.  J Clin Oncol1991; 9:1692.
  262. Walker M, Ni O: Neuroprotection during chemotherapy: a systematic review.  Am J Clin Oncol2007; 30:82.
  263. Gerritsen van der Hoop R, de Koning P, Boven E, et al: Efficacy of the neuropeptide ORG.2766 in the prevention and treatment of cisplatin-indued neurotoxicity in rats.  Eur J Cancer Clin Oncol1988; 24:637.
  264. Muller LJ, Gerritsen van der Hoop R, Moorer-van Delft CM, et al: Morphological and electrophysiological study of the effects of cisplatin and ORG-2766 on rat spinal ganglion neurons.  Cancer Res1990; 50:2437.
  265. Windebank AJ, Smith AG, Russell JW: The effect of nerve growth factor, ciliary neurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro.  Neurology1994; 44:488.
  266. Leong SS, Tan EH, Fong KW, et al: Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer.  J Clin Oncol2003; 21:1767.
  267. Lorusso D, Ferrandina G, Greggi S, et al: Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients.  Ann Oncol2003; 14:1086.
  268. Vahdat L, Papadopoulos K, Lange D, et al: Reduction of paclitaxel-induced peripheral neuropathy with glutamine.  Clin Cancer Res2001; 7:1192.
  269. Maestri A, De Pasquale Ceratti A, Cundari S, et al: A pilot study on the effect of acetyl-l-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy.  Tumori2005; 91:135.
  270. Park IS, Lee HJ, Lee YS, et al: Ifosfamide-induced encephalopathy with or without using methylene blue.  Int J Gynecol Cancer2005; 15:807.
  271. Cascinu S, Catalano V, Cordella L, et al: Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial.  J Clin Oncol2002; 20:3478.
  272. Griffiths JD, Stark RJ, Ding JC, Cooper IA: Vincristine neurotoxicity in Charcot-Marie-Tooth syndrome.  Med J Aust1985; 143:305.
  273. Hogan-Dunne CM, Fellmeth WG, McGuire SA, Kiley VA: Polyneuropathy following vincristine therapy in two patients with Charcot-Marie-Tooth syndrome.  JAMA1984; 252:2862.
  274. Grossman SA, Trump DL, Chen DC, et al: Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis: an evaluation using 111indium-DTPA ventriculography.  Am J Med1982; 73:641.
  275. Chamberlain MC, Corey-Bloom J: Leptomeningeal metastases: 111indium-DTPA CSF flow studies.  Neurology1991; 41:1765.