Neurologic Complications

Cerebellar Toxicity

Systemic administration of high-dose (greater than 1 g/m ² ) intravenous ara-C can cause acute cerebellar toxicity. Onset of neurologic symptoms typically is acute and often is noticed during administration of a multiday regimen. Patients exhibit evidence of global cerebellar dysfunction, which manifests as truncal, limb, and gait ataxia, dysarthria, and nystagmus. In some patients, permanent cerebellar dysfunction results; in others, a mild cerebellar syndrome develops that resolves promptly after completion of the chemotherapy.

Patients with irreversible cerebellar damage have a characteristic and selective loss of Purkinje cells in the cerebellum. 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), abnormal alkaline phosphatase (alkaline phosphatase greater than or equal to three times normal), and renal status (renal dysfunction with impaired drug clearance is associated with increased risk). Whether patients in whom reversible cerebellar dysfunction develops with previous treatment are at higher risk for permanent dysfunction is unknown.

Recent data show that, in animal models, oral application of the antioxidant N -acetylcysteine is able to prevent ara-C–induced behavioral deficits and cellular alterations of the adult cerebellum in a rat model. However, this treatment has not yet been tested in humans.

Encephalopathy

Acute encephalopathy, often accompanied by seizures, occurs less frequently than cerebellar dysfunction in patients receiving high-dose intravenous ara-C. 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 or metabolic abnormalities. 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.

Spinal Cord Toxicity

Direct administration of ara-C into the lumbar thecal space has been reported to cause myeloradiculopathy. Patients exhibit evidence of both spinal cord and nerve root dysfunction. This complication is uncommon and usually is found only after an extensive course of intrathecal chemotherapy. In many instances, patients have received both intrathecal ara-C and methotrexate. When the exclusive use of intrathecal ara-C resulted in spinal cord injury, it was either administered at relatively high doses (100–150 mg, three cases) or in liposomal form (50 mg, two cases) wherein prolonged release of ara-C in the CSF overlapped with systemic high-dose methotrexate and high-dose ara-C.

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 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, barbotage from injection, and direct toxic effects of chemotherapy on the spinal cord parenchyma are the most common proposed mechanisms of subacute myelopathy. Histologic examination of the spinal cord shows focal areas of necrosis that are most marked along the periphery of the spinal cord. Microscopic examination shows axonal swelling with accompanying demyelination. With chemotherapy-induced spinal cord injury, myelin basic protein levels in the CSF may be elevated before marked neurologic damage occurs. For patients with early symptoms, such as paresthesia, back pain, or Lhermitte 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.

Liposomal Ara-C

Liposomal cytarabine is frequently used because of its convenience—that is, every-2-week administration because of a long CSF half-life (approximately 140 hours)—and its potential improved efficacy compared with free cytarabine and methotrexate. Although the pharmacokinetics of drug delivery in the CSF is improving with the liposomal ara-C, an increase in the incidence of arachnoiditis has been observed, and isolated cranial nerve palsies may be more frequent. In a recently published retrospective series of 120 adult patients with lymphomatous meningitis who were treated with liposomal ara-C, serious treatment-related neurologic complications developed in 12.5% of patients. Toxicity included bacterial meningitis, chemical meningitis, communicating hydrocephalus, conus medullaris or cauda equine syndrome, decreased visual acuity, encephalopathy, leukoencephalopathy, myelopathy, radiculopathy, and seizures. Distribution of toxicity was similar regardless of the route of administration (ventricular versus lumbar).

Other Neurotoxicity Associated With Cytosine Arabinoside

Peripheral neuropathy has been reported after administration of high-dose ara-C. In this report, symmetric 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. Onset of tremor, bradykinesia, and masklike facies were observed 3 weeks after completion of treatment. Treatment with carbidopa-levodopa provided only transient improvement. However, all parkinsonian features resolved over 12 weeks.

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. Thrombosis of cerebral venous sinuses also has occurred in patients receiving this agent.

The clinical manifestations of sinus thrombosis, which usually are acute, include 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.

Patients in whom neurologic symptoms develop during l -asparaginase therapy should be evaluated with either head computed tomography (CT and CT venography) or magnetic resonance imaging (MRI and magnetic resonance venography). 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, most notably depression, delusions, hallucinations, disorientation, and altered level of consciousness. In the series described by Holland and colleagues, 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.

Acute Neurotoxicity

Acute methotrexate neurotoxicity occurs in 3% to 10% of patients and varies with the dose and route of administration, occurring more often after intrathecal administration and higher doses. The acute encephalopathy is characterized primarily by somnolence, confusion, and seizures. Headache, chorea, Klüver-Bucy syndrome, blurred vision, aphasia, and transient or persistent hemiparesis have also been described.

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. 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, a finding that suggested a possible role for leucovorin in decreasing the severity of methotrexate-induced somnolence syndrome. Methotrexate is known to cause inhibition of the enzyme dihydrofolate reductase, which prevents the conversion of folic acid to tetrahydrofolic acid and thereby increases the levels of homocysteine and excitotoxic neurotransmitters and inhibits cell replication. Furthermore, methotrexate neurotoxicity is associated with polymorphic mutations of folate and methionine metabolism. Other mechanisms that have been suggested include the direct toxic effect on myelin, disruption of mitochondrial energy metabolism resulting in oxidative stress, increased vulnerability of neurons to physiologic glutamate concentrations, and breakdown of the blood-brain barrier. 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. Cases have been reported in which, despite resolution of the clinical symptoms, white matter changes persist on magnetic resonance images.

Subacute Toxicity

Subacute methotrexate neurotoxicity is a rare syndrome, usually occurring in children, that manifests with an abrupt onset of focal neurologic deficits, such as aphasia and hemiparesis. It typically develops weeks after methotrexate administration and is associated with increased cumulative exposure, route of administration (intrathecal and intravenous), age (older than 10 years) and a high methotrexate-to-leucovorin ratio. Transient inhibition of myelin formation is thought to be the mechanism of toxicity. Methotrexate-associated subacute toxicity syndrome can be confidently diagnosed when diffusion-weighted MRI shows areas of restricted diffusion across multiple vascular beds and involving deep cerebral white matter, in the clinical context of waxing and waning neurologic signs and symptoms. Follow-up diffusion-weighted imaging typically shows resolution of restricted diffusion. 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. Cranial radiation therapy, particularly when it precedes methotrexate administration, greatly increases the risk of leukoencephalopathy. In addition, elevated CSF methotrexate concentration has been associated with an increased risk of neurotoxicity. Younger patients are at higher risk for leukoencephalopathy. Clinically, patients show progressive loss of cognitive function and focal neurologic signs, which may progress to profound dementia, coma, or death. Some patients experience seizures as a consequence of widespread neuronal injury. No treatment is known, and the neurologic deficits typically are irreversible. Brain imaging with MRI or CT often shows large areas of abnormalities in cerebral white matter ( Fig. 45.1 ). Elevated levels of myelin basic protein in CSF have been reported in patients with progressive neurologic dysfunction from methotrexate-induced leukoencephalopathy.

Neuropathologic examination shows wide areas of coagulative necrosis with swollen axonal cylinders and demyelination. Regions with vascular changes, particularly microangiopathic calcifications, are characteristic. 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.

Spinal Cord Toxicity

Chemotherapy-induced myelopathy is an uncommon toxicity of intrathecal treatment with methotrexate. Myelopathy typically 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 the earlier section Cytosine Arabinoside ). Loss of neurologic function may be progressive; only approximately half of patients experience either complete or partial recovery. The onset of symptoms usually 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.

Peripheral Neuropathy

Peripheral neuropathy is the toxicity associated most frequently with vincristine and correlates with the cumulative dose of the drug. Loss of deep tendon reflexes occurs in nearly all patients who receive several vincristine treatments. Distal sensorimotor polyneuropathy develops with continued treatment. 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 and reversible neurofilament-containing crystalloid inclusions. These effects are very likely to influence axonal transport, which depends on microtubules as the transport mechanism.

Study findings have suggested that vincristine might cause an increase in nerve excitability and induce a state of glutamate excitotoxicity by enhancing N -methyl- d -aspartate (NMDA) receptor expression and diminishing calcitonin gene-related peptide expression. In this study erythropoietin had a neuroprotective effect, probably through decreasing NMDA receptor expression and increasing calcitonin gene–related peptide expression.

In patients with underlying neuropathy, such as diabetic neuropathy or Charcot-Marie-Tooth disease (hereditary motor sensory neuropathy type 1), vinca-induced neuropathy may be severe even with low cumulative doses. Severe, even life-threatening neuropathy has been reported after administration of as little as 2 mg to patients with Charcot-Marie-Tooth disease, and evidence suggests that patients should be screened for this disorder before administration of vincristine. Previous radiation treatment of peripheral nerves also increases the neurotoxic effects of vincristine.

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. 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. In addition, patients occasionally report facial pain with vincristine treatment, which possibly is due to a transient effect on the trigeminal nerve or ganglion.

Central Nervous System Effects

Vincristine has been reported to cause encephalopathy, coma, and seizures. 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. 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. The time of onset 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.

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

Peripheral Neuropathy

The most common neurotoxicity associated with cisplatin is peripheral neuropathy, which is so significant that it is a dose-limiting adverse effect. 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 typically 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/m ² . The 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 dosage schedule but the same cumulative dose.

Continued treatment with cisplatin in patients with neuropathy can result in severe sensory ataxia that often impairs ambulation. The neuropathy is partially reversible, and patients with mild impairment are more likely in general to experience full recovery. A longitudinal study confirmed that 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, with only 17% having persistent symptoms. A trial demonstrated that long-term serum platinum levels are significantly associated with the severity of neurotoxicity 5 to 20 years after cisplatin-based chemotherapy. Important to note, the relationship remained significant after adjustment for the initial cisplatin dose.

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. 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. Cisplatin has been shown to induce apoptosis in dorsal root ganglion sensory neurons by covalently binding to nuclear DNA, resulting in DNA damage, subsequent p53 activation, and BAX-mediated apoptosis via the mitochondria and also by causing a reduction in mitochondrial DNA transcription.

Platinum concentration in peripheral nerve and spinal ganglia was 20 times greater than in the brain in patients at autopsy. 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 sign, which is an electric shock–like sensation down the spine or into the extremities with neck flexion. The phenomenon most commonly is associated with spinal cord demyelinating lesions in persons with 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. These complications are rare. Patients with optic neuropathy may have prolonged vision loss and demonstrate pallor of the optic disk. The reported cases of seizures and cortical blindness have been self-limited, with all patients recovering fully. The cause of the seizures and cortical blindness from cisplatin treatment is unknown but may be similar to toxicity observed from other heavy metals (e.g., lead and thallium), although endovascular injury has been proposed as a possible mechanism. Many of these patients have white matter abnormalities on brain MRI, consistent with posterior reversible encephalopathy syndrome (PRES; see later section, 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.

Toxicity Associated With Intraarterial Administration

Intraarterial administration of cisplatin causes focal toxicity. Administration into the internal carotid artery can cause severe retinal toxicity. Supraophthalmic administration can cause focal areas of brain parenchymal necrosis with resulting seizures and neurologic impairment.

Ototoxicity

Ototoxicity is a dose-related effect of cisplatin. Long-term ototoxicity was found to be correlated to serum platinum levels. Patients receiving more than 200 mg/m ² are at high risk for the development of hearing loss. Hearing loss, particularly when it is moderate to severe, often is permanent. 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. Additional risk factors include age (older than 46 years) and previous cranial radiation therapy involving the ears or temporal lobes. Patients with normal hearing lose high-frequency hearing first, but with continued treatment, hearing may be lost in all frequency ranges. A rapid screening audiogram technique has been developed to monitor patients undergoing cisplatin treatment. Postmortem pathologic examination of cochleae from patients with cisplatin-induced ototoxicity revealed extensive loss of the outer hair cells and less effect on the inner hair cells.

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. 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.

Neuropsychiatric Symptoms

Organic brain syndrome has been reported with 5-FU treatment. Confusion and disorientation can 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. Seizures have also been reported. A possible association of 5-FU treatment with recurrent acute toxic neuropathy has been reported.

Other Neurotoxicity Associated With 5-Fluorouracil Treatment

The literature includes isolated reports of encephalopathy with single-agent therapy with 5-FU and reports of encephalopathy and coma with use of capecitabine, the oral prodrug of 5-FU.