Systemic administration of high-dose (greater than 1 g/m²) intravenous ara-C can cause acute cerebellar toxicity.12–15 Onset of neurologic symptoms generally is acute and often is noticed during administration of a multiday regimen.^12,13 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 pathological 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).13,14,16–18 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.19,20 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.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 or metabolic abnormalities.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.21–25 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.^26,27 When the exclusive use of intrathecal ara-C resulted in spinal cord injury, it was either administered at relatively high doses (100 to 150 mg, three cases) or in liposomal form (50 mg, two cases) where prolonged release of ara-C in the CSF overlapped with systemic high-dose methotrexate and high-dose ara-C.²⁸

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,²⁹ barbotage from injection,³⁰ 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.^22,23,26 Microscopic examination shows axonal swelling with accompanying demyelination.^22,23,26 With chemotherapy-induced spinal cord injury, myelin basic protein levels in the CSF may be elevated before marked neurologic damage occurs.^26,27 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.²⁷

Liposomal Ara-C

Liposomal cytarabine is frequently used because of its convenience, that is, every-2-week dosing because of a long CSF half-life (approximately 140 hours), and its potential improved efficacy compared with free cytarabine and methotrexate.29,30 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/cauda equine syndrome, decreased visual acuity, encephalopathy, leukoencephalopathy, myelopathy, radiculopathy, and seizures. Distribution of toxicity was similar regardless of the route of administration (ventricular vs. lumbar).^31,32

Other Neurotoxicity Associated with Cytosine Arabinoside

Peripheral neuropathy has been reported after administration of high-dose ara-C.³³ 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 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.

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.36–36 Thrombosis of cerebral venous sinuses also has occurred in patients receiving this agent.³⁷

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.³⁴

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 MR 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,³⁸ most notably depression, delusions, hallucinations, disorientation, and altered level of consciousness. In the series described by Holland and colleagues,³⁸ 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. Neuropathological 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.³⁹ This reaction has been reported with high-dose treatment as a preparative regimen for bone marrow transplantation. Prophylactic treatment with anticonvulsant agents, particularly phenytoin, has been shown to reduce the risk of seizures.⁴⁰ However, phenytoin is contraindicated because of its ability to induce busulfan metabolism and because of possible toxicities. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.⁴¹

Methotrexate

Methotrexate can cause acute, subacute, or chronic neurotoxicity.

Acute Neurotoxicity

Acute MTX neurotoxicity ranges from 3% to 10% and varies with the dose and route of administration, occurring more often after intrathecal administration and higher doses.⁴² The acute encephalopathy is characterized primarily by somnolence, confusion, and seizures.^5,43 Headache, chorea, Klüver-Bucy syndrome, blurred vision, aphasia, and transient or persistent hemiparesis have also been described.⁴⁴

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.⁴⁵ 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,⁴⁶ 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/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 physiological glutamate concentrations, and breakdown of the blood-brain barrier.^47,48 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.⁴⁹ Cases have been reported in which, despite resolution of the clinical symptoms, white matter changes persist on MR images.⁵⁰

Subacute Toxicity

Subacute methotrexate neurotoxicity is a rare syndrome, usually occurring in children, that is manifested by 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 : leucovorin ratio.⁵ 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 imaging on 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.⁵¹ 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.4–8,52–62 Cranial radiation therapy, particularly when it precedes methotrexate administration, greatly increases the risk of leukoencephalopathy.^5,63,64 In addition, elevated CSF methotrexate concentration has been associated with an increased risk of neurotoxicity.⁵⁴ Younger patients are at higher risk for leukoencephalopathy.^67–67 Clinically, patients show progressive loss of cognitive function and focal neurologic signs, which may progress to profound dementia, coma, or death.^4–6,8,55 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. 57-1). Elevated levels of myelin basic protein in CSF have been reported in patients with progressive neurologic dysfunction from methotrexate-induced leukoencephalopathy.⁵⁶

Figure 57-1 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, Computed tomography scans obtained 6 months after completion of intrathecal chemotherapy. Widespread destruction of white matter and diffuse atrophy are evident.

Neuropathological examination shows wide areas of coagulative necrosis with swollen axonal cylinders and demyelination.4,52 Regions with vascular changes, particularly microangiopathic calcifications, are characteristic.^58,61 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.⁶⁸

Spinal Cord Toxicity

Chemotherapy-induced myelopathy is an uncommon toxicity of intrathecal treatment with methotrexate.69–74 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 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 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.75–80 Loss of deep tendon reflexes occur in nearly all patients who receive several vincristine treatments. Distal sensorimotor polyneuropathy develops with continued treatment.^76,77 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 79,81–85 and reversible neurofilament-containing crystalloid inclusions.⁸⁶ These effects are very likely to influence axonal transport, which depends on microtubules as the transport mechanism.⁸⁷

A recently published study suggests that vincristine might cause an increase in nerve excitability and induce a state of glutamate excitotoxicity by enhancing N-methyl-D-aspartate receptor expression and diminishing calcitonin gene-related peptide expression. In this study erythropoietin had a neuroprotective effect, probably through decreasing N-methyl-D-aspartate receptor expression and increasing calcitonin gene-related peptide expression.⁸⁸

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.⁸⁹ 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.^91–91 Previous radiation treatment of peripheral nerves also increases the neurotoxic effects of vincristine.⁹²

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.⁹³ 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.^96–96 In addition, patients occasionally report facial pain with vincristine treatment, which possibly is due to a transient effect on the trigeminal nerve or ganglion.⁸⁰

Central Nervous System Effects

Vincristine has been reported to cause encephalopathy, coma, and seizures.97–101 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.^{100,102–105} 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.106–109 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.¹⁰⁶

Myopathy has occurred with vincristine therapy.¹¹⁰ No clinical correlate has been found in cases in which histopathological examination of muscle tissue has revealed spheromembranous degeneration.

Cisplatin

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 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/m².¹¹¹ The schedule of administration may be a significant factor, because the reported incidence of neuropathy has been higher in patients receiving treatment on five consecutive days than in patients on a regimen with a shorter dosing schedule but the same cumulative dose.^114–114

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 generally are more likely to experience full recovery.¹¹³ 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.¹¹⁵ A recently published trial demonstrated that long-term serum platinum levels are significantly associated with the severity of neurotoxicity 5 to 20 years after cisplatin-based chemotherapy. Importantly, the relationship remained significant after adjustment for the initial cisplatin dose.¹¹⁶

The pathogenesis of cisplatin-induced neuropathy is unknown. Neuropathological studies have shown involvement of the large sensory fibers with regions of axonal swelling and myelin breakdown and, in more severe cases, axonal loss.¹¹⁷ 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.¹¹⁸ 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.¹¹⁹

Platinum concentration in peripheral nerve and spinal ganglia was 20 times greater than in the brain in patients at autopsy.¹¹⁵ 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.120,121 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.¹²² These complications are rare. Patients with optic neuropathy may have prolonged vision loss and demonstrate pallor of the optic disk.^123,124 The reported cases of seizures and cortical blindness have been self-limited, with all patients recovering fully.^127–127 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.^122,126 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.¹²⁷

Toxicity Associated with Intraarterial Administration

Intraarterial administration of cisplatin causes focal toxicity. Administration into the internal carotid artery can cause severe retinal toxicity.128,129 Supraophthalmic administration can cause focal areas of brain parenchymal necrosis with resulting seizures and neurologic impairment.¹³⁰

Ototoxicity

Ototoxicity is a dose-related effect of cisplatin. Long-term ototoxicity was found to be correlated to serum platinum levels.¹¹⁶ Patients receiving more than 200 mg/m² are at high risk for the development of hearing loss.¹³¹ Hearing loss, particularly when it is moderate to severe, often is permanent.^131,132 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.^131,133,134 Additional risk factors include age (older than 46 years) and previous cranial radiation therapy involving the ears or temporal lobes.^132,133 Patients with normal hearing lose high-frequency hearing first, but with continued treatment, hearing may be lost in all frequency ranges.¹³¹ A rapid screening audiogram technique has been developed to monitor patients undergoing cisplatin treatment.¹³⁴ Postmortem pathological 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.¹³¹

Oxaliplatin

Oxaliplatin has been shown to cause two distinct types of neuropathy: acute and chronic.¹³⁵ The acute neuropathy syndrome may begin during oxaliplatin infusion or up to 1 to 2 days after completion of treatment. Patients experience paresthesias and dysesthesias of the hands and feet, jaw tightness, and a sensation of loss of breathing without respiratory distress. This latter syndrome has been named pharyngolaryngodysesthesia.¹³⁶ Dysesthesias constitute the most prominent symptom, although many patients describe pain that is more like muscle spasms of the jaw, tongue, and extremities. Hemibody paresthesias with muscle cramping have been described as an acute syndrome.¹³⁷ 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 increases to 50% by the ninth cycle of treatment.¹³⁸ Most patients experience some resolution of symptoms, but most patients have residual neuropathic symptoms up to 6 months after treatment cessation. The symptoms often return upon subsequent administration of oxaliplatin.¹³⁹ The pathogenesis of acute oxaliplatin neuropathy is thought to be related to drug-induced alterations in voltage-gated sodium channels^140,141 in response to oxalate, a metabolic byproduct of oxaliplatin. In addition, oxalate may interact indirectly with the voltage-gated sodium channels through chelation of calcium and magnesium.

The development of chronic neuropathy from oxaliplatin is related to cumulative dose, with most studies reporting that early neuropathy is 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 predominant clinical manifestation. Additionally, the Lhermitte-like phenomenon described with cisplatin also has been reported with oxaliplatin.142,143 The chronic neuropathy may abate over several months after the cessation of treatment, although some reports suggest that symptoms may persist.^144,145

Several approaches have been used to prevent oxaliplatin-induced neurotoxicity, including use of an intermittent oxaliplatin dosing schedule that reduced the incidence of grade 3 neurotoxicity ¹⁴⁶ and the concurrent use of neuromodulatory agents, such as antidepressant drugs, antiepileptic agents, or calcium and magnesium infusions.¹⁴⁷

Cyclophosphamide

Cyclophosphamide can indirectly cause metabolic encephalopathy and seizures. High-dose cyclophosphamide can result in SIADH.150–150 When unrecognized, this syndrome can lead to severe hyponatremia, coma, and seizures. Although it is 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.¹⁵¹ 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.152–156 This neurotoxicity is dose dependent and may be fatal. Neurologic deterioration usually begins within hours of administration of ifosfamide.^152,154,156 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.^152,155 Electroencephalography (EEG) shows severe slowing with delta wave activity and can display evidence of seizure activity.^152,155 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.¹⁵⁷ A recent study of 60 patients reported the incidence of ifosfamide neurotoxicity to be 26%.¹⁵⁸ Several risk factors have been reported to predispose patients to development of neurotoxicity from ifosfamide. These factors include low serum albumin concentration,¹⁵⁶ high serum creatinine concentration, pelvic cancer,¹⁵⁹ and previous treatment with cisplatin.¹⁶⁰ Altered mental status before treatment and bolus or rapid infusion have also been described as a predisposing factor to development of neurotoxicity from ifosfamide.^161,162 A recent report, however, could not confirm any risk factor except age, with an increased incidence of encephalopathy in younger patients.¹⁵⁸ Ifosfamide treatment has been associated with an extrapyramidal syndrome characterized by choreoathetosis, blepharospasm, and opisthotonic posturing.^163,164 Data from case reports indicate that methylene blue is an option in the treatment of ifosfamide-induced encephalopathy. However, the lack of controlled clinical trials and the possibility of spontaneous resolution of encephalopathy calls the effectiveness of methylene blue into question.¹⁶⁵ Thiamine and albumin have also been described as options for treatment and prophylaxis of ifosfamide-induced encephalopathy.¹⁶⁶

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.167–170 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.¹⁷⁰

Neuropsychiatric Symptoms

Organic brain syndrome has been reported with 5-FU treatment.¹⁷² 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.¹⁷³ Seizures have also been reported.¹⁷⁴ A possible association of 5-FU treatment with recurrent acute toxic neuropathy has been reported.¹⁷⁵

Other Neurotoxicity Associated with 5-FU Treatment

The literature includes isolated reports of encephalopathy with single-agent therapy with 5-FU and recent reports of encephalopathy and coma with use of capecitabine, the oral prodrug of 5-FU.180–180

Fludarabine

Fludarabine can cause a variety of neurologic toxicities ranging from a mild peripheral neuropathy to severe altered mental status with hallucinations, motor weakness, paralysis, or seizures. At high doses, white matter changes, particularly in the occipital lobes and brainstem, have been reported.¹⁸¹ The severe neurotoxicity may produce progressive worsening to death over the course of weeks to months. Visual disturbances are the most commonly reported symptom and result from cortical blindness, visual pathway demyelination, and/or retinal bipolar cell loss. Resolution of neurotoxicity rarely occurs, with most patients experiencing irreversible and severe dysfunction. The risk factors for toxicity at recommended doses have not been identified.

Fludarabine is distinctive among agents causing central nervous system toxicity in that its clinical effects do not manifest until weeks to months after exposure.¹⁸² 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.¹⁸³

Nitrosoureas

Central Nervous System Toxicity

Nitrosoureas, most commonly carmustine (BCNU), can cause encephalopathy characterized by a progressive decline in cognitive function, development of seizures, coma, and death.186–186 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.¹⁸⁷ Histopathologically, the toxicity associated with intraarterial therapy is characterized by necrosis, regions of demyelination, edema, and axonal loss limited to the region perfused by the intraarterial therapy. Because the predominant changes have been seen in the white matter, the condition is called leukoencephalopathy; the changes are indistinguishable from those seen with methotrexate and ara-C treatment. Similar pathological changes are seen with high-dose intravenous carmustine, but both cerebral hemispheres are involved.¹⁸⁷ In addition, focal brain necrosis has been reported with intraarterial nitrosourea treatment. This toxicity is thought to be a consequence of “streaming” of the drug along the vessel wall, without mixing with arterial blood.¹⁸⁸ 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 to be 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.¹⁸⁹ The treatment 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 reports of treatment-associated infections and necrosis have been made.^192–192

Retinal Toxicity

Retinal toxicity has been reported with intracarotid administration of nitrosoureas, particularly carmustine.¹⁹³ 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 the preceding section, “Central Nervous System Toxicity”).

Procarbazine

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

Peripheral Neuropathy

The peripheral neuropathy described with procarbazine use is most commonly described as paresthesia; it is often subjective and generally transient. The incidence of paresthesia ranges from 2% to 20%. This variability may be related to dose or treatment schedule.196–196

Central Nervous System Toxicity

Signs of CNS depression, ranging from mild drowsiness to profound stupor, have been reported.194,196 This toxicity worsens with use of phenothiazine to control emesis and may be related to the monoamine oxidase inhibitor–like qualities of procarbazine. CNS depression was reported to occur in 14% to 33% of patients in these series.^196–196

Paclitaxel and Docetaxel

Paclitaxel is associated with a syndrome of subacute aches and pains, “paclitaxel-associated acute pain syndrome” (P-aps), and with peripheral neuropathy. This pain syndrome causes significant morbidity, with an incidence of up to 70% in patients receiving treatment with paclitaxel. It manifests with diffuse aching discomfort, most often in the legs, hips, and lower back, although it can be widespread.¹⁹⁷

The nature and temporal profile of P-aps distinguishes it as a separate entity from chemotherapy-induced peripheral neuropathy, which can be a devastating long-term consequence of this drug. Chemotherapy-induced peripheral neuropathy has been described in up to 70% of patients receiving treatment with paclitaxel. An association exists between the presence and severity of P-aps and the eventual development of sensory neuropathy.198,199

In phases 1 and 2 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.199,200 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.²⁰⁰ Neuropathy generally occurs at doses greater than 200 mg/m² and is more frequent when the drug is given every three weeks at a higher dose compared with once a week at a lower dose.²⁰¹ Symptoms usually develop 1 to 3 days after treatment. Overall the prognosis is good, because much of the neurologic dysfunction reverses over several weeks. However, continued treatment in the setting of existing neuropathy causes progressive neurologic toxicity that may not resolve. 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.^204–204 Peripheral neuropathy also is being reported with other microtubule-stabilizing agents such as the epothilones.^205,206

A case report of transient vocal cord paralysis resulting from use of paclitaxel has been described.²⁰⁷

Encephalopathy has also been described as an adverse effect of paclitaxel. 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.²⁰⁸ 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, and the other three patients died of progressive coma. Autopsy revealed generalized white matter atrophy.²⁰⁹ Chronic neurocognitive changes also have been reported with extensive administration of taxanes.²¹⁰

Tamoxifen

Tamoxifen, as with other hormonal agents, is associated with headache.²¹¹ Tamoxifen can cause reversible retinal dysfunction at the conventional antiestrogen doses used for breast cancer therapy.^214–214 At higher doses, reversible encephalopathy with delusions, somnolence, and cerebellar dysfunction has been reported.^217–217 Several cases of sinus vein thrombosis in patients treated with tamoxifen have been described.^218,219

Biological 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.²²⁰ A high percentage of patients receiving both systemic IL-2 and lymphocyte-activated killer cells experience encephalopathy or a neuropsychiatric syndrome.²²⁰ 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 asymmetric 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.²²¹ Another case report described fatal leukoencephalopathy associated with IL-2 treatment.²²²

The neurologic effects of interferon are dose related, but they are more severe in patients with underlying neurologic abnormalities.²³² Although the neurotoxic effects of interferon therapy usually resolve completely within a few weeks, some patients may exhibit persistent behavioral changes.²²⁶ Intraventricular administration of interferon-alpha caused severe neurologic toxicity in one study. Effects ranged in severity from headache and confusion to coma. Additional adverse effects of intraventricular administration included Parkinsonism, hearing loss, and seizures.²³³

Peripheral Nervous System Toxicity

Mild peripheral neuropathy manifesting as paresthesia has been reported with interferon use,²²⁷ as has a case of brachial neuritis in a patient with underlying neuropathy.²³⁴

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.²³⁵ Somnolence, the predominant adverse effect, is dose-related, and the drug can be titrated in most patients to a level of tolerance. Peripheral neuropathy is treatment limiting. Rates of neuropathy after thalidomide treatment vary from 15% to 70%. The neuropathy has been characterized as sensory-motor axonal polyneuropathy manifesting as painful paresthesia or numbness.²³⁶ Severity of symptoms correlates with cumulative dose and duration of therapy. Factors influencing the risk of neurotoxicity include prior neuropathy, age, previous chemotherapy, and vitamin B12 and/or folate deficiency. The mainstay of neuropathy prevention is dose reduction or withdrawal of thalidomide, which can lead to symptom resolution in up to 16 weeks; however, in some cases, the neuropathy is irreversible.^237,238

A person’s risk of developing a peripheral neuropathy after thalidomide treatment has been linked to single nucleotide polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system.²³⁹ Nerve biopsy and examination reveal distal axonal degeneration and demyelination. Studies of lenalidomide indicate that peripheral neuropathy may occur in a smaller percentage of patients compared with thalidomide.^240,241

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 in this chapter.242,243 Bevacizumab increases the risks of hemorrhage and thromboembolism, although an analysis identifying four trials of anti-VEGF therapy in patients with brain metastases found a negligible rate of intracranial bleeding.²⁴⁴ Patients with high-grade glioma who are undergoing anticoagulation in addition to treatment with bevacizumab have an elevated hemorrhage risk, although the serious hemorrhage rate remains low (3%), suggesting that bevacizumab can be safely administered with anticoagulation in most patients.^245,246

In multiple studies, bevacizumab has been reported to increase the risk of stroke. A pooled analysis of five randomized trials showed an increase in stroke from 0.5% to 1.7%.²⁴⁷ In addition, two cases of dural sinus venous thrombosis have been reported in patients during treatment with bevacizumab.^248,249

Sorafenib

Sorafenib is an oral agent that is an RAF kinase inhibitor. Sorafenib 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.250,251

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 1 trials. A prospective study evaluated the occurrence of neuropathy in a group of 256 patients with refractory myeloma who were treated with standard dosing schedules of bortezomib.²⁵² 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 who received a dosage of 1.0 mg/m². The cumulative dose also correlated with severity of the neuropathy, as did the presence of neuropathy before the initiation of treatment. Most patients experienced either partial or complete resolution with cessation of treatment.

Two cases of acute axonal motor neuropathies associated with paralytic ileus, urinary retention, and impotence occurring early in the course of bortezomib treatment have been described. Both patients had previously been exposed to other neurotoxic agents including vincristine and thalidomide and had co-morbid conditions associated with neurologic damage, namely chronic renal failure and autoimmune hepatitis.²⁵³

Sunitinib

Sunitinib is a polytyrosine kinase inhibitor that inhibits the intracellular tyrosine kinase domain of the VEGF, platelet-derived growth factor, and c-KIT receptor; it is used for gastrointestinal stromal tumors and advanced kidney cancer. This drug may be related to the development of PRES.²⁵⁴

Imatinib

Imatinib is an oral tyrosine kinase inhibitor that is used in treating chronic myelogenous leukemia and gastrointestinal stromal tumors. The main neurologic side effects of imatinib are muscle cramping and myalgias.²⁵⁵ Intracranial bleeding is a rare complication of imatinib therapy. In a retrospective study of 121 patients with chronic myelogenous leukemia who were treated with imatinib, subdural hematomas developed in seven patients. In three of the patients the subdural hematomas were not associated with thrombocytopenia or other risk factors.²⁵⁶ In addition, in clinical trials when patients with high-grade glioma were treated with imatinib, significant intratumoral hemorrhages were observed.^257,258 One case report described muscle edema, creatine kinase elevation, and rhabdomyolysis with myoglobinuria in a young woman treated with imitanib.²⁵⁹

Ipilimumab

Ipilimumab is a human monoclonal antibody against cytotoxic T lymphocyte antigen-4 that activates the immune system. It is approved for the treatment of metastatic melanoma. Ipilimumab is associated with multiple autoimmune adverse effects, including hypophysitis with hypopituitarism, which has been reported in 0% to 17% of patients involved in ipilimumab trials.262–262

Radiation Neurotoxicity

Radiation neurotoxicity is becoming an increasingly important and recognized complication of cancer therapy (see Chapter 39). 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. The volume of brain treated, total dose, and dose fraction are the most important determinants of toxicity, although some variation in patient susceptibility is apparent. Additionally, radiotherapy can indirectly affect the CNS by damaging the blood vessels and increasing the risk of brain cancer.²⁶⁵

Acute Toxicity

Acute toxicity is characterized by headache, nausea, vomiting, and sometimes also somnolence. This disorder generally occurs within the first few days of initiation of cranial radiation therapy.²⁶⁶ The symptoms are thought to be a result of disruption of the blood-brain barrier and secondary edema.²⁶⁷ Acute toxicity is most common in patients receiving a large dose of radiation per fraction, mainly as whole-brain radiation therapy. Most patients experience complete recovery of neurologic function. Corticosteroids can treat and sometimes prevent the acute toxicity.²⁶⁷

Early-Delayed Toxicity

Early-delayed toxicity is noticed weeks to 3 months after completion of radiation treatment.²⁶⁸ 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.²⁶⁹ Corticosteroids can speed recovery. The pathogenesis of early-delayed toxicity is unknown, but the reaction may 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.

An increase (up to 30%) in early treatment–related brain injury has been reported with the use of concurrent daily temozolomide with external beam radiation in patients with glioblastoma.²⁷⁰ 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 “pseudoprogression,” may reflect an increase in blood-brain barrier breakdown that is the consequence of an augmentation of radiation effect from the co-administration of chemotherapy.²⁷⁰

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.²⁷¹ Late radiation injuries are often progressive and irreversible. Patients exhibit focal areas of radiation necrosis or evidence of diffuse radiation injury. The incidence of each type of injury depends on the dose, fractionation schedule, and area of treatment.^272,273

Radionecrosis

Focal necrosis primarily affects the white matter of the brain or spinal cord. It usually occurs within 18 months of radiation but can develop years later.²⁷⁴ The risk of developing radiation necrosis depends on the dose and the volume of radiation (mainly above 65 Gy and 2 Gy daily fractions). Focal delivery of one large radiation fraction during radiosurgery can lead to radiation necrosis adjacent to the irradiated lesion in 5% to 20% of cases. The latency of these changes can be as short as 3 months.²⁷⁵ Radiation 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. Conventional MRI findings cannot discriminate radiation necrosis from recurrent tumor (in the case of treated brain metastases or primary brain tumors). Positron emission tomography, single-photon emission computed tomography, and new MRI techniques, including perfusion and spectroscopy, may help distinguish tumor from radiation necrosis, but their sensitivity and specificity are between 50% and 90%.²⁷⁶ Pathological 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.⁵⁷ Treatment is directed at decreasing edema and mass effect. Patients generally respond to corticosteroids; however, the effect is short lived, and long-term steroid requirements are common.²⁷⁷ Antiplatelet agents, anticoagulants, and hyperbaric oxygen have been studied, but currently, high-quality evidence to support their use in routine clinical practice is minimal.²⁷⁸ Bevacizumab has also been suggested as a therapeutic option. A randomized controlled study that included 14 patients showed clinical and radiographic efficacy of bevacizumab with radiation necrosis.²⁷⁹ Surgical resection, if feasible, can be curative, although even with extensive resection, additional areas of necrosis may develop.

Diffuse Injury

Diffuse injury manifests as global neurologic dysfunction, with cognitive decline, personality change, confusion, and lethargy, and it can progress to dementia, obtundation, or coma.267,273 Clinically, mild to moderate forms of cognitive impairment are more common than severe dementia. Short-term memory, executive functions, attention, and judgment are mainly affected.²⁸⁰ Symptoms usually appear several years after the radiation exposure. 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.^283–283 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 and high-dose fraction regimens. Other risk factors are increasing age and vascular risk factors such as diabetes and hypertension.²⁸⁴ The incidence is difficult to determine, but reports have shown neurologic and imaging changes in 32% to 50% of patients subjected to radiation therapy.^282,283,285

The pathogenesis of diffuse radiation injury is not known, although distinctive neuropathological changes have been described. The most prominent pathological finding is vascular changes in the small arteries and arterioles. Hyalinization of the vessel walls with occlusion is common.²⁸³ In addition, areas of necrosis, gliosis, and demyelination are found. Impaired neuronal stem cell function and decreased neurogenesis have also been described.²⁸⁶ Modern radiation techniques have been developed to protect the hippocampus to reduce memory defect; however, the efficacy of these techniques has not yet been proven.²⁸⁷ No treatment has been established for global brain injury. However, donepezil may be useful for the cognitive decline.²⁸⁸

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 was described earlier in this chapter 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.²⁸⁹

Mineralizing angiopathy has occurred in pediatric patients receiving both intrathecal methotrexate and radiation therapy.²⁹⁰ The changes frequently are diagnosed as dystrophic calcifications during neuroradiologic examinations. Histopathological analysis reveals deposits of calcium in small blood vessels, often with surrounding regions of necrotic brain. The clinical significance of these changes is uncertain.

Endocrinologic Effects

Cranial radiation therapy has been associated with a wide spectrum of endocrinologic effects.²⁹¹ 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.²⁹² Growth hormone deficiency and stimulation of precocious puberty have occurred at doses as low as 18 Gy.²⁹³ Deficiency of gonadotropins, thyroid-stimulating hormone, and corticotropin usually results only when the hypothalamic-pituitary axis receives more than 40 Gy.²⁹⁴ Similarly, hyperprolactinemia occurs most often in young women who receive more than 40 Gy of radiation therapy. Careful long-term monitoring of these patients is critical.²⁹⁵ Appropriate hormone replacement therapy or prolactin suppression treatment should prevent sequelae.

Indirect Effects of Radiation on the CNS

Radiation can damage the endothelia of cerebral vasculature, causing accelerated atherosclerosis, stenosis, and occlusion, leading to stroke. The typical latency of these phenomena is several years.296,297 In children, radiation can cause occlusion of blood vessels and development of a moyamoya-like pattern of collateral vessels. This phenomenon has been described mainly in association with neurofibromatosis 1, which is a known risk factor for vasculopathy.²⁹⁸ Brain and spinal vascular malformations, including cavernomas and, rarely, aneurysms, have also been described.²⁹⁹ The risk of developing other brain tumors in patients treated with CNS radiation is seven times that of the general population. Three types of brain tumors have been associated with prior cranial radiation: meningioma, glioma, and sarcoma.³⁰⁰

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 the dosing schedules currently being used. Case reports state that weakness evolves over a few hours or days.³⁰¹ 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.³⁰² Most patients exhibit Lhermitte sign—an electrical shock–like sensation down the spine with neck flexion. No neurologic deficits are found, imaging is usually intact, 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.³⁰³ The clinical picture may vary from patient to patient. Some patients have monoplegia, and others may have paraplegia or quadriplegia. Sensory symptoms are generally more severe than motor symptoms. Some patients have Brown-Séquard syndrome. Progression may take several years.³⁰¹ The pathogenesis of spinal radiation injury is not completely understood. Radiation might damage myelin production and might induce secretion of cytokines that might cause inflammatory response.^301,302 Pathological 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. No treatment exists, and most patients experience progressive neurologic dysfunction over months to years.³⁰⁴

Lower motor neuron syndrome occurs after spinal cord radiation therapy. Patients exhibit pure motor signs of weakness, atrophy, and fasciculations.³⁰¹ 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 exists, with supportive care being the only option.