Clinical Manifestations
Necrosis. The incidence of radiation necrosis after therapeutic dosages is uncertain. Quoted incidence data range from 0.1% to 5% after dosages of 50-60 Gy fractionated over 5-6 weeks (
9,
10). The variability in the data is the result of the uncertainty, in some studies, concerning the denominator; the long time delay until the occurrence of necrosis; the lack of histologic confirmation in many surviving patients; and the absence of postmortem data in patients who succumb. The clinical signs and symptoms of radiation necrosis are headache and mass effect. Surgical debulking is performed when possible and is often therapeutic (
10). Corticosteroids may offer transient relief. Anecdotal reports of the benefits of anticoagulation with heparin or warfarin compounds exist (
11,
12).
Necrotizing Leukoencephalopathy and Mineralizing Microangiopathy. Leukoencephalopathy is a late complication of cranial irradiation and systemic methotrexate (MTX). The histologic appearance is of multifocal white matter destruction, especially in the centrum semiovale and periventricular regions, with loss of myelin and oligodendrocytes. Hypodense areas emerge in the white matter, and there is cerebral atrophy, an increase in the sulcal width, and enlargement of the ventricles. Mineralizing microangiopathy can occur and is visualized on computed tomography (CT) scanning as intracerebral calcification (
11). The clinical features include lethargy, seizures, spasticity, paresis, and ataxia. The multifactorial origin and risk of leukoencephalopathy have been studied in acute lymphoblastic leukemia (ALL) survivors. Radiation and MTX appear to be contributing factors (
Fig. 19.4) (
13). Of interest is a report from the German Late Effects Working Group, which documented CT and magnetic resonance imaging (MRI) evidence of atrophy, leukoencephalopathy, calcification, or gray matter changes in approximately 50% of children treated for ALL (
14). The frequency and severity of abnormalities were greater in children treated with cranial RT and MTX than in those treated with MTX alone. It is worth emphasizing that the situation is decidedly worse in children who have CNS involvement with ALL. In these cases, the presence of leukemia can alter the cerebrospinal clearance of MTX and increase the risk of injury.
Neuropsychologic and Intellectual Deficits. Cranial irradiation of children may have significant adverse effects on intelligence, learning, and social and emotional adjustment
(
11,
12,
15,
16,
17). Neurocognitive late effects most commonly follow treatment of malignancies that necessitate CNSdirected therapies, such as cranial radiation, intraventricular or IT or high dose systemic (CNS penetrating) chemotherapy. Thus, children with CNS tumors, head and neck sarcomas, and ALL are most commonly affected. Studies of patients with brain tumors must account for the confounding variables of CNS injury by the tumor, seizures and their therapy, elevated intracranial pressure, and surgery. In patients with leukemia and brain tumors, the use of chemotherapy and the impact of the illness on body image and school attendance may complicate the issue.
Deficits occur in a variety of areas, which include general intelligence, age-appropriate developmental progress, academic achievement (especially in reading language and mathematics), visual and perceptual motor skills, nonverbal and verbal memory, receptive and expressive language, and attention (
11,
12,
15,
16,
17). Younger age at the time of treatment is associated with a greater neurocognitive deficit (
18).
The effects of cranial RT on subsequent intellectual function have been studied in detail, most comprehensively in survivors of CNS tumors and leukemia. However, the effects of radiation on the brain are difficult to define, especially when cranial radiation is often routinely a part of multimodality therapy that may also include surgery and systemic or IT chemotherapy. Moreover, tumor-related deficits caused by direct invasion of the brain, seizures, and hydrocephalus must be recognized.
With detailed assessment of IQ, achievement tests, learning ability, and school performance, it is clear that cranial RT can result in significant neurocognitive dysfunction. With changes in the dosage, fields, and volumes of cranial and craniospinal RT, changes in the incidence and spectrum of these adverse effects of therapy are expected. More recent studies using lower dosages and more targeted volumes have demonstrated better results (
19,
20,
21). Ris et al. (
19) evaluated the intellectual outcome of 43 children treated on Children’s Cancer Group study 9892 for posterior fossa medulloblastoma or primitive neuroectodermal tumor (PNET). The study used a reduced craniospinal RT regimen of 23.4 Gy to the neuraxis and 32.4-Gy boost to the posterior fossa with adjuvant chemotherapy. The mean age at the time of treatment was 6 years, with a range of 3-15 years. The estimated rate of change of FSIQ was 4.3 points/year, for VIQ 4.2 points/year, and for nonverbal IQ (NVIQ) 4.0 points/year. In examining host-related factors, a more significant decline was seen for girls (-8 points/year) than boys (-3 points/year) for VIQ and for children less than 7 years old (-5.2 points/year) as opposed to children 7 years and older (-0.8 points/year) for NVIQ. This latter observation was noteworthy in that the older children’s baseline was lower, with little decline over time, as compared with the younger children, who had a much higher baseline followed by a steep decline. The effect of baseline intelligence was examined for the whole group, and the same phenomenon was seen. Children who had a baseline IQ of 100 or higher had a much steeper decline in FSIQ, VIQ, and NVIQ than children who had a baseline under 100. The effect on FSIQ is shown in
Figure 19.5.
Another recent study supports the hypothesis that patients with medulloblastoma demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to that of their healthy same-age peers rather than a loss of previously acquired information and skills (
15). In a Danish study of 133 children treated for brain tumors, younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiation therapy predicted lower cognitive functions (
22). Finally, a reduction in the volume of normal-appearing white matter has been observed in some survivors of childhood brain tumors, and this was associated with decreased attentional abilities, which led to an IQ deficit and impaired academic achievement (
16).
For ALL, older studies again show significant neurocognitive impairment (
23). Even when combined with IT chemotherapy, reduction in the cranial radiation dosage has resulted in less neurocognitive impairment (
18,
24,
25). Studies on CNS prophylaxis for ALL comparing craniospinal
RT with cranial RT combined with IT MTX showed that children who were less than 5 years old at the time of treatment and had received RT and IT chemotherapy had lower IQ scores than those who received craniospinal RT alone. Meadows et al. (
23) found a significant IQ deficit in children treated with 24-Gy cranial RT combined with IT MTX, as compared with childhood cancer survivors who received no CNS-directed therapy, with the effect greatest among those less than 5 years old. A similar effect on cognition with the addition of IT MTX has been found in children treated for medulloblastoma (
26).
Controversy regarding the role of RT in impairing neurocognition will continue, largely because of differences in the radiation dosages and drugs used in various protocols and different endpoints. Prophylactic cranial irradiation of 24 Gy at 2 Gy per fraction in the treatment of ALL can lower IQ and achievement test scores. IQ loss may be on the order of 8-10 points (i.e., median of normals of 100 down to 90-92). Some studies suggest that the undesirable consequences of 18 Gy are less than 24 Gy, and that 12 Gy (commonly used in current protocols) does not cause identifiable deficits, but the data on this point are not definitive (
23).
The deleterious effects of systemic MTX, especially at dosages greater than 1 g/m
2, may be no different from those of 18-Gy cranial RT (
27,
28). At lower MTX dosages, there does not appear to be a consistent pattern of neurocognitive deficits (
29). A recent long-term study of infants who received high-dose systemic MTX combined with IT cytarabine and MTX for CNS leukemia prophylaxis and were tested 3-9 years after treatment showed that cognitive function was in the average range (
30).
In a small study from Italy, cognitive outcome was evaluated in 21 children who received both cranial RT and IT MTX. Mean total IQ was within normal limits, but there was a large discrepancy between the VIQ and PIQ, with the former being significantly higher than the latter. In addition, intracerebral calcifications on MRI were associated with the number of intrathecal MTX dosages and with low scores on IQ, attention, and visual integration tests. Age at treatment and RT dosage were not associated with neuropsychiatric outcomes (
31).
Chemotherapy without RT for ALL may result in cognitive dysfunction, but study results vary significantly. Some studies have demonstrated impairment in tasks of higherorder cognitive functioning, mathematics (
27), and mild visual and verbal short-term memory deficits (
32) in leukemia survivors treated with intrathecal chemotherapy. Yet, others have demonstrated no significant problems (
24,
33,
34). The substitution of dexamethasone for prednisone in the treatment of ALL has been implicated in increasing cognitive dysfunction (
25), but a recent study examining differences between children treated for ALL on a study, where there was a randomization between prednisone and dexamethasone, found no significant differences in neurocogntive performance (Kadan-Lottick) (
34).
Somnolence Syndrome. Irradiation of the brain of children can result in the somnolence syndrome. The syndrome has its onset 4-8 weeks after irradiation and is characterized by drowsiness, nausea, irritability, anorexia, apathy, and dizziness. The majority of children reported to have developed this syndrome were irradiated for ALL, although it can occur after treatment of a brain tumor. The somnolence syndrome resolves spontaneously, but corticosteroids hasten recovery.
Arterial vasculopathy is an uncommon occurrence, almost always described after irradiation to the parasellar region, primarily in children. Single- or multiple-vessel narrowing or obliteration results in typical stroke deficits (
35).
Myelopathy. The spectrum of radiation injuries to the spinal cord includes transient and irreversible syndromes. A rare, rapidly evolving permanent paralysis is presumed to result from an acute infarction of the cord. A more common form of radiation injury is manifested by the Lhermitte sign or Lhermitte symptom, which consists of an electric shock-like sensation that radiates down the spine and often into the limbs (
36). The location of the sensation can change with time. The symptoms may be precipitated by flexion of the neck, walking on a hard surface, sitting on a hard surface, or other forms of physical exertion. The syndrome generally occurs a few months after spinal irradiation. The mechanism is thought to be transient demyelinization, although detailed human pathologic studies are lacking. There are no known CT or MRI correlations. It is also reported in association with cisplatin administration, where the results may be long-lasting (
37).
Chronic progressive radiation myelitis (CPRM) is rare. The initial symptoms, generally subtle, are usually paresthesias and sensory changes (including diminished temperature sensation or proprioception), which start 9-15 months after therapy and progress over the subsequent year (
38). Much longer intervals to initial symptoms are seen occasionally. The neurologic lesion must be within the irradiated volume. Recurrent or metastatic tumor must be ruled out. Cerebrospinal fluid (CSF) protein may be elevated, and myelography can demonstrate cord swelling or atrophy. MRI and CT provide additional supportive information.
The incidence of CPRM and the radiation dosage causing this event are poorly defined because of the diagnostic difficulties and the variety of radiation techniques (with uncertain dosimetries). A review by Wara et al. (
39) suggests that 42 Gy in 25 fractions carries a 1% risk, 45 Gy a 5% risk, and 61 Gy a 50% risk. Data from Marcus and William (
40) suggest that the cervical cord may be more tolerant to radiation than previously presumed when 1.8- to 1.9-Gy fractional doses are used; in 324 patients treated to dosages of 55 Gy or less, no cases of myelitis were seen. A higher risk of myelopathy is associated with higher individual fraction sizes, shorter overall treatment time, higher total dosages, and long lengths of the cord treated (especially more than 10 cm). Children may be more susceptible to CPRM, developing it after lower radiation dosages and with shorter latency periods (
38).
Table 19.3 reviews several CNS late effects with respect to causative treatments, signs and symptoms, screening and diagnostic tests, and management and intervention (
41).