Neuropsychological Consequences for Survivors of Childhood Brain Tumor in Malaysia.

Objective: This study aimed to evaluate neuropsychological consequences in survivors of childhood brain tumor. Method: A case-control study was conducted over a period of 4 months in a tertiary referral center in Kuala Lumpur, Malaysia. Fourteen survivors of childhood brain tumor aged 7-18 years, who were off-treatment for at least 1 year and were in remission, and 31 unrelated healthy controls were recruited. The median age at diagnosis was 8.20 years (range: 0.92-12.96 years). The diagnoses of brain tumors were medulloblastoma, germ cell tumor, pineocytoma, pilocystic astrocytoma, suprasellar germinoma, and ependymoma. Eleven survivors received central nervous system irradiation. Seven tasks were selected from the Amsterdam Neuropsychological Tasks program to evaluate alertness (processing speed), and major aspects of executive functioning, such as working memory capacity, inhibition, cognitive flexibility, and sustained attention. Speed, stability and accuracy of responses were the main outcome measures. Results: Survivors of childhood brain tumor showed statistically significant poorer performance on all tasks compared to healthy controls. Both processing speed and accuracy were impaired in the survivors, in particular under more complex task conditions. The survivors demonstrated deficits in alertness, sustained attention, working memory capacity, executive visuomotor control, and cognitive flexibility. Longer duration off treatment appeared to be correlated with poorer alertness, memory capacity, and inhibition. Conclusion: Survivors of childhood brain tumor in our center showed impaired neuropsychological functioning. Development of less toxic treatment protocols is important to prevent late effects of cognitive deficits in survivors of childhood brain tumor.

Neurocognitive Outcomes and Interventions in Long-Term Survivors of Childhood Cancer.

Recent research has demonstrated that survivors of childhood cancer are at risk for a myriad of late effects that affect physical and mental quality of life. We discuss the patterns and prevalence of neurocognitive problems commonly experienced by survivors of CNS tumors and acute lymphoblastic leukemia, the two most commonly researched cancer diagnoses. Research documenting the direct effects of tumor location and treatment type and intensity is presented, and patient characteristics that moderate outcomes (eg, age at diagnosis and sex) are discussed. Potential biologic mechanisms of neurotoxic treatment exposures, such as cranial irradiation and intrathecal and high-dose antimetabolite chemotherapy, are reviewed. Genetic, brain imaging, and neurochemical biomarkers of neurocognitive impairment are discussed. Long-term survivors of childhood cancer are also at risk for physical morbidity (eg, cardiac, pulmonary, endocrine) and problems with health behaviors (eg, sleep); research is reviewed that demonstrates these health problems contribute to neurocognitive impairment in survivors with or without exposure to neurotoxic therapies. We conclude this review with a discussion of literature supporting specific interventions that may be beneficial in the treatment of survivors who already experience neurocognitive impairment, as well as in the prevention of impairment manifestation.

Caffeine and seizures: A systematic review and quantitative analysis.

PURPOSE: Caffeine is the most commonly used central nervous system (CNS) stimulant. The relationship between caffeine, seizures, epilepsy, and antiepileptic drugs (AEDs) is complex and not fully understood. Case reports suggest that caffeine triggers seizures in susceptible people. Our systematic review reports on the relationship between caffeine, seizures, and drugs in animal and human studies. Quantitative analyses were also done on animal studies regarding the effects of caffeine on AEDs. METHODS: PubMed was searched for studies assessing the effects of caffeine on seizure susceptibility, epilepsy, and drug interactions in people and in animal models. To quantify the interaction between AEDs and caffeine, the data of six animal studies were pooled and analyzed using a general linear model univariate analysis or One-way Analysis of Variance (ANOVA). RESULTS: In total, 442 items were identified from which we included 105 studies. Caffeine can increase seizure susceptibility and protect from seizures, depending on the dose, administration type (chronic or acute), and the developmental stage at which caffeine exposure started. In animal studies, caffeine decreased the antiepileptic potency of some drugs; this effect was strongest in topiramate. CONCLUSION: Preclinical studies suggest that caffeine increases seizure susceptibility. In some cases, chronic use of caffeine may protect against seizures. Caffeine lowers the efficacy of several drugs, especially topiramate. It is unclear how these findings in models can be translated to the clinical condition. Until clinical studies suggest otherwise, caffeine intake should be considered as a factor in achieving and maintaining seizure control in epilepsy.

Executive Dysfunction 25 Years after Treatment with Cranial Radiotherapy for Pediatric Lymphoid Malignancies.

The first cohorts to survive childhood lymphoid malignancies treated with cranial irradiation are now aging into adulthood, and concerns are growing about the development of radiotherapy-induced cognitive deficits in the aging brain. These deficits are hypothesized to increase over time. Their impact on daily functioning of older survivors, and the accompanying need for interventions, should be anticipated. By describing a detailed profile of executive function deficits and their associations with age, specific targets for neuropsychological intervention can be identified. Fifty survivors of childhood lymphoid malignancies and 58 related controls were assessed with the Amsterdam Neuropsychological Tasks program. The survivors were on average 31.1 (4.9) years old, treated with 22.5 (6.8) Gy cranial irradiation, and examined on average 25.5 (3.1) years after diagnosis. The survivors showed significantly decreased response speed, irrespective of the task at hand. Furthermore, we found deficits in working memory capacity, inhibition, cognitive flexibility, executive visuomotor control, attentional fluctuations, and sustained attention. Older age was associated with poorer performance on executive visuomotor control and inhibition. On executive visuomotor control, 50% of female survivors performed more than 1.5 SD below average, versus 15.4% of male survivors. The combination of visuospatial working memory problems and decreasing executive visuomotor control could result in difficulty with learning new motor skills at older ages, like walking with a cane. Deterioration of executive control and inhibition may result in decreased behavioral and emotional regulation in aging survivors. Especially the deficiency in executive visuomotor control in female survivors should be considered for (prophylactic) intervention.

Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies.

PURPOSE: CNS-directed chemotherapy (CT) and cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia or lymphoma have various neurotoxic properties. This study aimed to assess their impact on the maturing brain 20 to 30 years after diagnosis, providing a much stronger perspective on long-term quality of life than previous studies. PATIENTS AND METHODS: Ninety-three patients treated between 1978 and 1990 at various intensities, with and without CRT, and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging (DTI) and neuropsychological tests. Differences in fractional anisotropy (FA)-a DTI measure describing white matter (WM) microstructure-were analyzed by using whole brain voxel-based analysis. RESULTS: CRT-treated survivors demonstrated significantly decreased FA compared with controls in frontal, parietal, and temporal WM tracts. Trends for lower FA were seen in the CT-treated survivors. Decreases in FA correlated well with neuropsychological dysfunction. In contrast to the CT group and controls, the CRT group showed a steep decline of FA with age at assessment. Younger age at cranial irradiation and higher dosage were associated with worse outcome of WM integrity. CONCLUSION: CRT-treated survivors show decreased WM integrity reflected by significantly decreased FA and associated neuropsychological dysfunction 25 years after treatment, although effects of CT alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after CRT, but not after CT.

Long-term effects of cranial irradiation and intrathecal chemotherapy in treatment of childhood leukemia: a MEG study of power spectrum and correlated cognitive dysfunction.

BACKGROUND: Prophylaxis to prevent relapses in the central nervous system after childhood acute lymphoblastic leukemia (ALL) used to consist of both intrathecal chemotherapy (CT) and cranial irradiation (CRT). CRT was mostly abolished in the eighties because of its neurotoxicity, and replaced with more intensive intrathecal CT. In this study, a group of survivors treated with CRT before 1983 and another group treated without CRT thereafter are investigated 20-25 years later, giving a much stronger perspective on long-term quality of life than previous studies. The outcomes will help to better understand these groups' current needs and will aid in anticipating late effects of prophylactic CRT that is currently applied for other diseases. This study evaluates oscillatory neuronal activity in these long-term survivors. Power spectrum deviations are hypothesized to correlate with cognitive dysfunction. METHODS: Resting state eyes-closed magnetoencephalography (MEG) recordings were obtained from 14 ALL survivors treated with CT + CRT, 18 treated with CT alone and 35 controls. Relative spectral power was calculated in the δ, θ, α1, α2, ß and γ frequency bands. The Amsterdam Neuropsychological Tasks (ANT) program was used to assess cognition in the executive functions domain. MEG data and ANT scores were correlated. RESULTS: In the CT + CRT group, relative θ power was slightly increased (p = 0.069) and α2 power was significantly decreased (p = 0.006). The CT + CRT group performed worse on various cognitive tests. A deficiency in visuomotor accuracy, especially of the right hand, could be clearly associated with the deviating regional θ and α2 powers (0.471 < r < 0.697). A significant association between decreased regional α2 power and less attentional fluctuations was found for CT + CRT patients as well as controls (0.078 < r < 0.666). Patients treated with CT alone displayed a power spectrum similar to controls, except for a significantly increased level of left frontal α2 power (p = 0.030). CONCLUSIONS: The tendency towards global slowing of brain oscillatory activity, together with the fact that dementia has been reported as a late effect of CRT and the neuropsychological deficiencies currently present, suggest that the irradiated brain might be aging faster and could be at risk for early-onset dementia. The CT group showed no signs of early aging.