CHAPTER 44 Neurotoxicity Associated with Pediatric Malignancies
Cancer is the most common cause of death in children up to 14 years of age; nearly 1 child in 600 will develop cancer. By 2010, 1 in 540 adults who are 20 to 34 years of age is predicted to be a survivor of childhood cancer with variable neurologic sequelae. The neurologic sequelae resulting from the therapy for childhood malignancy vary with the age at presentation, the site of origin of the malignancy, and the therapy. The most common pediatric malignancies associated with adverse neurologic affects are acute lymphoblastic leukemia (ALL), which accounts for approximately 25% of childhood malignancies, and brain tumors, accounting for about 20% of pediatric malignancies. The iatrogenic neurotoxicities may be due to chemotherapy—most often methotrexate (MTX), cranial irradiation, or bone marrow transplantation (BMT). The treatment for ALL involves multiple chemotherapeutic agents, the mainstay of which is MTX. Given intravenously, MTX crosses the blood-brain barrier, eradicating leukemic cells in the central nervous system (CNS), a common site of leukemic recurrence. MTX is also given sequentially via direct intrathecal injection to eliminate leukemic cells from the cerebrospinal fluid (CSF). Another chemotherapeutic agent used in ALL is the enzyme L-asparaginase, which is also associated with neurotoxicity but with a lower incidence and different pathophysiology and imaging abnormalities. Craniospinal irradiation is reserved for ALL patients with CNS relapse or for patients who cannot tolerate high-dose MTX; the doses given range from 1200 to 1800 cGy, which is considerably lower than that used for control of primary CNS malignancies.
Medulloblastoma is one of the most common CNS tumors of childhood. It is highly malignant with a propensity to disseminate along the neural axis. Control of medulloblastoma necessitates delivery of radiation to the craniospinal region. Unlike in other pediatric CNS tumors such as ependymoma and nonresectable pilocytic astrocytomas, which can often be controlled with conformational radiation therapy, whole-brain irradiation is needed in patients with medulloblastoma. The effects of cranial irradiation depend on the total dose to normal structures, radiation dose for each daily radiation treatment (daily fraction), combination of radiation therapy with other treatment modalities (chemotherapy and surgery), presence of hydrocephalus at presentation, and patient age when radiation is given. The neurologic impact on the brain from irradiation and chemotherapy is greatest in children younger than 3 years of age, and most therapeutic protocols withhold cranial irradiation until the patient reaches 3 years of age unless there is relapse or progression while the child is on chemotherapy. Allogenic BMT is used in the setting of very high-risk ALL or for those patients with a suboptimal response to chemotherapy. BMT is also used as treatment intensification for a variety of solid tumors of childhood. Complications of BMT include intracranial hemorrhage and strokes, reversible posterior leukoencephalopathy syndrome (PRES), graft-versus-host disease (GVHD), and infection. The focus of this chapter is on the most common pediatric iatrogenic neurotoxicities, which are those associated with treatment of leukemia (including BMT) and primary brain tumors of childhood.
MTX neurotoxicity is characterized as acute, subacute, or chronic.1,2 The incidence of acute MTX neurotoxicity ranges from 3% to 10% and varies with the dose and route of administration of MTX, the frequency with which MTX is given, and the use of leucovorin. The time from induction to the onset of acute neurotoxicity varies from 2 to 127 weeks. However, the temporal relationship between acute neurotoxicity and intrathecal administration of MTX is fairly predictable, because acute neurotoxicity is most often seen 10 to 11 days after an intrathecal dose of MTX has been administered.3 High doses of intravenous MTX are also associated with white matter changes on MRI, which may be clinically occult. Subacute neurotoxicity is most often seen 6 to 11 days after intrathecal therapy, whereas chronic or delayed MTX neurotoxicity is seen months after the initiation of therapy.
Acute MTX toxicity occurs within hours to days after administration of MTX and consists of nausea, vomiting, headache, somnolence, altered mental status, and seizures.1,2 Subacute neurotoxicity consists of seizures, focal motor or sensory deficits, behavioral changes, and aphasia; the neurologic deficits usually resolve within 72 hours. Chronic or delayed MTX neurotoxicity varies from a mild increase in distractibility to severe encephalopathy. Consistent long-term deficits seen in children treated for ALL who did not undergo cranial irradiation include problems with memory, visuospatial/motor skills, processing speed, and attention. Less frequent deficits involve visuospatial nonverbal and verbal and auditory memory. Neurotoxic effects of L-asparaginase include an acute encephalopathy characterized by somnolence, lethargy, disorientation, seizures, and coma, which may be related to hepatic dysfunction and hyperammonemia in addition to the rare complications of coagulopathy.
A dreaded and uncommon complication of combined chemotherapy and radiation therapy in ALL is diffuse necrotizing leukoencephalopathy, which presents as somnolence, lethargy, disorientation, and seizures, which may progress to coma and death.
Reversible posterior leukoencephalopathy syndrome describes an acute reversible neurologic syndrome resulting from immune suppression, usually from cyclosporine given after BMT and also during treatment of myeloproliferative disorders such as ALL. Patients usually present with headache, nausea, vomiting, seizures, visual changes, confusion, and coma. PRES is typically associated with systemic hypertension, which is thought to disrupt cerebral autoregulation. BMT temporarily eliminates immunocompetence. Return of immunocompetence depends on the type of graft (e.g., allogenic, autologous), the presence of GVHD, the marrow/tumor eradication used before transplantation, the type of immunosuppression, and the primary condition necessitating BMT. BMT patients are at risk for common bacterial, viral, and fungal CNS infections and for infection with organisms that are uncommon and rarely pathogenic in humans.
MTX is a cell cycle–specific agent that inhibits the enzyme dihydrofolate reductase, preventing the conversion of folic acid to tetrahydrofolic acid and inhibiting cell replication. Both high-dose intravenous MTX and intrathecal MTX are associated with demyelination, white matter necrosis, loss of oligodendroglia, axonal swelling, microcystic encephalomalacia, and atrophy relatively selective for the deep cerebral white matter. MTX also causes a relative excess of homocysteine, a byproduct of the folate deficiency, which may be responsible for small vessel vasculopathy.
L-Asparaginase is thought to deprive leukemic cells of the essential amino acid L-asparagine, thereby disrupting cell replication. Additional neurotoxic effects of L-asparaginase result from the chemotherapy-induced transient protein-S deficiency and coagulopathy leading to intracranial venous and/or arterial thrombosis and hemorrhage that is usually intraparenchymal.
Potential host factors responsible for heightened sensitivity to MTX and L-asparaginase toxicity include age, sex, race, associated syndromic condition, and pharmacogenetics. Primary chromosomal abnormalities of leukemic cells are known to be associated with different prognoses, and genetic polymorphisms encoding for drug-metabolizing enzymes, transporters, and receptors may account for variable sensitivity to toxic side effects.
The most common neuropathologic abnormality associated with MTX is disseminated or multifocal necrotizing leukoencephalopathy. Gliosis and axonal dystrophy, diffuse and focal subpial gray matter necrosis, mineralizing microangiopathy, and dystrophic calcification are also reported.
In the settings of acute and subacute MTX neurotoxicity, CT is usually normal. In children with chronic MTX neurotoxicity, CT usually shows diffuse cerebral atrophy and low density within the cerebral hemispheric white matter (Fig. 44-1A). MTX-induced microangiopathic leukoencephalopathy is characterized by diffuse white matter low density with scattered calcifications within the deep white matter (see Fig. 44-1B). The white matter lesions typically do not enhance and have no mass effect, although rare cases of tumefactive ring-enhancing lesions simulating brain abscess have been reported. When high-dose MTX therapy is complicated by superimposed meningitis, the progression of white matter disease and calcification may be rapid and atypical in distribution (Fig. 44-2).
FIGURE 44-1 A, White matter changes from methotrexate toxicity. Nonenhanced CT shows diffuse low density within the deep and periventricular white matter; there is mild diffuse cerebral atrophy. B, Mineralizing angiopathy. Nonenhanced CT shows dystrophic calcification within the peripheral white matter.
(From Vazquez E, Lucaya J, Castellote A, et al: Neuroimaging in pediatric leukemia and lymphoma: differential diagnosis. RadioGraphics 2002; 22:1411-1428.)
FIGURE 44-2 A, A 5-year-old girl with high-risk acute lymphoblastic leukemia and CNS involvement presented with Streptococcus sepsis 6 months after systemic and intrathecal chemotherapy; no cranial irradiation had been given. Nonenhanced CT at admission shows small, bilateral, moderately dense subdural collections, generalized cerebral atrophy, and no intraparenchymal calcification. B, Nonenhanced CT 8 days later shows the bilateral subdural empyemas and extensive parenchymal calcification.
The MR appearance of acute MTX neurotoxicity includes regions of restricted diffusion within the deep white matter of the cerebral hemispheres with little or no corresponding areas of abnormal T2 signal (Fig. 44-3). The areas of restricted diffusion do not correspond to a vascular distribution, do not enhance, and have no mass effect. The diffusion abnormalities may resolve completely or be followed by areas of abnormal increased T2 signal.3–8 Occasionally, there may be restricted diffusion within the cortex and/or leptomeningeal enhancement (see Fig. 44-3). Transient T2 prolongation in the cerebellar white matter and cerebral cortex has also been described. From 15% to 75% of patients imaged during treatment for ALL show white matter abnormalities; the incidence is highest at around 20 weeks after induction, during consolidation. The white matter T2-weighted (T2W)/FLAIR abnormalities may be bilateral and symmetric or asymmetric, usually spare the peripheral white matter, and are associated with some degree of generalized cerebral atrophy (Fig. 44-4). White matter lesions observed on conventional MRI are known to be temporary and reversible in some patients; however, progressive and persistent white matter changes may be seen in the absence of symptomatic neurotoxicity.5