Elsevier

The Lancet Oncology

Volume 5, Issue 7, July 2004, Pages 399-408
The Lancet Oncology

Review
Late neurocognitive sequelae in survivors of brain tumours in childhood

https://doi.org/10.1016/S1470-2045(04)01507-4Get rights and content

Summary

As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions.

Section snippets

Epidemiology and contemporary treatment

There are two recognised peaks in the incidence of brain tumours in children and adolescents (<18 years). The first peak, with a value of 2·2–2·5 cases per 100 000 children per year, occurs the first decade of life; there is a slight male predominance at this age. This first incidence peak accounts for most cases of CNS embryonal tumours and ependymomas located in the posterior fossa. A second, much larger peak occurs in late adolescence and early adulthood, and characteristically accounts for

Late effects of tumour and treatment

The most common method used to document neurocognitive effects in children treated for brain tumours has been IQ tests with a normative mean score of 100 and standard deviations of 15 or 16. IQ tests are standardised on large numbers of the general population, so scores can be corrected for the age of the person who is to complete the test. The IQ score of a healthy person is thus not expected to change substantially over time.Table 1 summarises findings from 12 studies of IQ outcomes in

Neurodevelopmental consequences

The pathophysiology of late CNS damage induced by radiation is not fully understood, especially with regard to the vulnerability of white matter to injury. Some hypotheses attribute primary mechanisms of CNS damage to the death of neuronal cells, oligodendrocytes, or endothelial cells and the subsequent microvascular damage. Ultimately, this damage seems to be a primary or secondary effect associated with administration of treatment to the CNS.25 Secondary processes, such as damage to the

Innovations in radiotherapy

The side-effects attributed to radiotherapy have been a main concern in the design of clinical trials for medulloblastoma during the past 20 years. Concern has been greatest for patients with average-risk medulloblastoma, for whom longterm control of disease is likely and the side-effects of therapy might be long-lasting. Radiotherapy for medulloblastoma is technically demanding, requiring both craniospinal radiotherapy and boost treatment of the anatomic posterior fossa. If the prescribed dose

Cognitive remediation

Few published studies have assessed cognitive behavioural interventions for survivors of brain tumours in childhood. One case study investigated whether a compensatory memory notebook would improve neurocognitive function in an adolescent with severe memory impairment.41 A calendar section was used to record forthcoming activities and events, and to keep track of time. The notebook had a section on things to do for forthcoming assignments; an orientation section contained the names of teachers

Pharmacotherapy

Research done over the past 50 years in children diagnosed with attention deficit hyperactivity disorder (ADHD) who are otherwise healthy has shown the effectiveness of stimulant medications—most commonly methylphenidate—to improve cognitive performance.44 Methylphenidate is a mixed dopaminergic–noradrenergic agonist that is thought to improve the function of the attention network in the frontostriatal region of the brain.45 Use of methylphenidate is found to have the most consistent and

Environmental interventions

In addition to cognitive remediation and pharmacological approaches to overcome neurocognitive deficits, the importance of ecological or environmentally based interventions for children with brain injuries—especially with regard to school—should not be underestimated.50 Many such children might need extended time limits for completion of school examinations, use of true-or-false questions and multiple-choice formats in tests rather than essay-based examinations, and encouragement to record

Conclusions

Neurosurgeons, paediatric oncologists, and radiation oncologists have been successful in improving cure rates for most types of childhood brain tumours, including those of the posterior fossa. Nevertheless, the risks of neurocognitive impairment remain substantial, especially among individuals who were treated aggressively and at a young age. Thus, there is an imperative need for effective, but less neurotoxic, tumour therapy. Until such therapy is developed, cognitive, behavioural,

Search strategy and selection criteria

Data for this review were identified by searches of PubMed with the terms “children”, “ependymoma”, “medulloblastoma”, “PNET”, and “posterior fossa”. Only papers published in English since 1990 were selected. Additional papers were identified from references of relevant articles and for historical value.

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