Radiotherapy-induced vascular cognitive impairment 20 years after childhood brain tumor.

BACKGROUND: Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. METHODS: In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. RESULTS: Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. CONCLUSIONS: The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

Health-related quality of life in long-term survivors of childhood brain tumors: a population-based cohort study.

PURPOSE: Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT. METHODS: Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36. RESULTS: Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL. CONCLUSION: Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Neurocognitive impairment, employment, and social status in radiotherapy-treated adult survivors of childhood brain tumors.

BACKGROUND: Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. METHODS: Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. RESULTS: Survivors' (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, -3.5 SD [range: -25.0 to 1.3 SD]), and processing speed and attention (median z score, -2.5 SD [range: -24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. CONCLUSIONS: Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.

A 13-year follow-up of Finnish patients with Salla disease.

BACKGROUND: Salla disease (SD) is a rare lysosomal storage disorder leading to severe intellectual disability. SD belongs to the Finnish disease heritage, and it is caused by mutations in the SLC17A5 gene. The aim of the study was to investigate the course of neurocognitive features of SD patients in a long-term follow-up. METHODS: Neuropsychological and neurological investigations were carried out on 24 SD patients, aged 16-65 years, 13 years after a similar examination. RESULTS: The survival analysis showed excess mortality among patients with SD after the age of 30 years. The course of the disease was progressive, but follow-up of SD patients revealed that motor skills improved till the age of 20 years, while mental abilities improved in most patients till 40 years of age. Verbal comprehension skills did not diminish during the follow-up, but productive speech deteriorated because of dyspraxia and dysarthria. Motor deficits were marked. Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens. Spasticity became more obvious with age especially in severely disabled SD patients. CONCLUSIONS: Younger SD patients performed better in almost every task measuring mental abilities that then seem to remain fairly constant till early sixties. Thus, the results indicate better prognosis in cognitive skills than earlier assumed. There is an apparent decline in motor skills after the age of 20 years. The early neurocognitive development predicts the later course of motor and cognitive development.

Reading, listening and memory-related brain activity in children with early-stage temporal lobe epilepsy of unknown cause-an fMRI study.

BACKGROUND AND AIMS: The changes in functional brain organization associated with paediatric epilepsy are largely unknown. Since children with epilepsy are at risk of developing learning difficulties even before or shortly after the onset of epilepsy, we assessed the functional organization of memory and language in paediatric patients with temporal lobe epilepsy (TLE) at an early stage in epilepsy. METHODS: Functional magnetic resonance imaging was used to measure the blood oxygenation level-dependent (BOLD) response to four cognitive tasks measuring reading, story listening, memory encoding and retrieval in a population-based group of children with TLE of unknown cause (n = 21) and of normal intelligence and a healthy age and gender-matched control group (n = 21). RESULTS: Significant BOLD response differences were found only in one of the four tasks. In the story listening task, significant differences were found in the right hemispheric temporal structures, thalamus and basal ganglia. Both activation and deactivation differed significantly between the groups, activation being increased and deactivation decreased in the TLE group. Furthermore, the patients with abnormal electroencephalograms (EEGs) showed significantly increased activation bilaterally in the temporal structures, basal ganglia and thalamus relative to those with normal EEGs. The patients with normal interictal EEGs had a significantly stronger deactivation than those with abnormal EEGs or the controls, the differences being located outside the temporal structures. CONCLUSIONS: Our results suggest that TLE entails a widespread disruption of brain networks. This needs to be taken into consideration when evaluating learning abilities in patients with TLE. The thalamus seems to play an active role in TLE. The changes in deactivation may reflect neuronal inhibition.

Neuropsychological performance in children with temporal lobe epilepsy having normal MRI findings.

BACKGROUND AND AIMS: Most information on the neuropsychological performance of pediatric patients with temporal lobe epilepsy (TLE) is derived from selected surgical series. Non-lesional pediatric TLE patients were studied here at the population level in order to investigate the extent to which neuropsychological deficits predisposing to learning difficulties exist in this more common group. METHODS: Language, memory and executive functions were measured in children aged 8-15 years with non-lesional TLE and of normal intelligence (n = 21), and their performance was compared with that of healthy age and gender-matched children (n = 21). The effects of clinical epilepsy variables on performance were examined. RESULTS: Although neuropsychological performance did not differ between the TLE patients and the healthy controls, female gender, early onset, longer duration and abnormal interictal EEG had a negative effect on neuropsychological performance. CONCLUSIONS: Children with early-onset epilepsy should be assessed carefully for neuropsychological impairment using sufficiently broad batteries of tests in order to detect even slight deficits. Our sample size was small and these findings should be interpreted as preliminary results and need to be confirmed in larger studies.

Connectivity disruptions in resting-state functional brain networks in children with temporal lobe epilepsy.

Functional resting-state connectivity has been shown to be altered in certain adult epilepsy populations, but few connectivity studies have been performed on pediatric epilepsy patients. Here functional connectivity was measured in pediatric, non-lesional temporal lobe epilepsy patients with normal intelligence and compared with that in age and gender-matched healthy controls using the independent component analysis method. We hypothesized that children with non-lesional temporal lobe epilepsy have disrupted functional connectivity within resting-state networks. Significant differences were demonstrated between the two groups, pointing to a decrease in connectivity. When the results were analyzed according to the interictal electroencephalogram findings, however, the connectivity disruptions were seen in different networks. In addition, increased connectivity and abnormally anti-correlated thalamic activity was detected only in the patients with abnormal electroencephalograms. In summary, connectivity disruptions are already to be seen at an early stage of epilepsy, and epileptiform activity seems to affect connectivity differently. The results indicate that interictal epileptiform activity may lead to reorganization of the resting-state brain networks, but further studies would be needed in order to understand the pathophysiology behind this phenomenon.

Low depressive symptom and mental distress scores in adult long-term survivors of childhood acute lymphoblastic leukemia.

Childhood cancer survivors are thought to be at risk of psychological difficulties. We examined the prevalence of depressive symptoms and mental well-being in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) at a mean age of 20 years after the cessation of therapy. Depressive symptoms were assessed with Beck Depression Inventory (BDI-21) and mental distress with General Health Questionnaire (GHQ-12) among 73 ALL survivors and 146 healthy controls. The ALL survivors obtained significantly lower BDI scores (P=0.046) compared with the controls, indicating less depressive symptoms among the ALL survivors. BDI scores indicated a significantly less frequent moderate or severe depression in the ALL survivors compared with the controls (P=0.039). BDI scores indicated no depression in 80.8% of the ALL survivors and 73.3% of the control group. The female ALL survivors obtained lower BDI scores than did the female controls (P=0.005). No difference was found in GHQ-12 scores between the survivors and the controls. Survivors of ALL reported fewer depressive symptoms and equal mental well-being compared with healthy controls. Our findings support the idea that childhood leukemia survivors' subjective experience of well-being is possibly affected by repressive adaptive style.

Alterations in regional homogeneity of baseline brain activity in pediatric temporal lobe epilepsy.

Recent findings on intracortical EEG measurements show that the synchrony of localized neuronal networks is altered in epileptogenesis, leading to generalized seizure activity via connector hubs in the neuronal networks. Regional homogeneity (ReHo) analysis of blood oxygen level-dependent (BOLD) signals has demonstrated localized signal synchrony and disease-related alterations in a number of instances. We wanted to find out whether the ReHo of resting-state activity can be used to detect regional signal synchrony alterations in children with non-lesional temporal lobe epilepsy (TLE). Twenty-one TLE patients were compared with age and gender-matched healthy controls. Significantly increased ReHo was discovered in the posterior cingulate gyrus and the right medial temporal lobe of the patients, and they also had significantly decreased ReHo in the cerebellum compared with the healthy controls. However, the alterations in ReHo differed between the patients with normal and abnormal interictal EEGs, the latter showing significantly increased ReHo in the right fusiform gyrus and significantly decreased ReHo in the right medial frontal gyrus relative to the controls, while those with normal EEGs had significantly increased ReHo in the right inferior temporal gyrus and the left posterior cingulate gyrus. We conclude that altered BOLD signal synchrony can be detected in the cerebral and cerebellar cortices of children with TLE even in the absence of interictal EEG abnormalities.

High health-related quality of life among long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Health-related quality of life (HRQoL) was assessed in a cohort of long-term childhood acute lymphoblastic leukemia (ALL) survivors. PROCEDURE: Rand-36-Item health Survey (RAND-36) was used to assess subjective HRQoL in 74 survivors of ALL an average of 20 years after the diagnosis. Cranial irradiation had been administered to 46 of the survivors, while 28 survivors had solely been treated with chemotherapy. The control group consisted of 146 healthy young adults selected from local population registry. Survivors were examined by a physician and late effects were graded using the Common Terminology Criteria for Adverse Events (CTCAEv3). RESULTS: ALL survivors achieved significantly higher scores than the controls on three of the eight HRQoL subscales; role limitations due to emotional problems (P = 0.030), mental health (P = 0.030) and vitality (P = 0.004). In comparison to controls, survivors with a follow-up of more than 20 years had significantly higher scores on vitality (P = 0.006) and mental health (P = 0.011). Survivors with severe (grade 3 and 4) late effects scored significantly better than controls on vitality (P = 0.043) and mental health (P = 0.040). Patients who had been treated for an ALL relapse and had received the most intensive chemo- and radiotherapy had significantly higher scores on mental health (P = 0.004) and vitality (P = 0.004) than the controls. CONCLUSIONS: Long-term survivors of childhood ALL reported equal or better HRQoL in RAND-36. Higher HRQoL scores were associated with more severe late effects and intensive therapy. Our findings support the idea of response bias.

Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Despite the extensive literature on neuropsychological sequelae after treatment of childhood acute lymphoblastic leukemia (ALL), the very-long-term neurocognitive outcome of the survivors is poorly studied. We assessed neuropsychological functioning in a population-based cohort of young adult childhood ALL survivors. PROCEDURE: Neuropsychological testing was performed on 64 survivors an average of 20 years after the diagnosis. The test battery included verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ), memory function, orientation and attention as well as motor performance. Cranial irradiation had been administered to 44 survivors as part of ALL treatment, whereas 20 survivors had been treated solely with chemotherapy. A control group consisted of 45 healthy young adults. Earlier neuropsychological test results of 45 of the survivors were available for comparison. RESULTS: The ALL survivors attained significantly lower test scores than the controls in all the neuropsychological function areas. The mean VIQ test scores were 91, 100, and 109 (P < 0.001), and the mean PIQ test scores 100, 111, and 118 (P < 0.001) for the irradiated survivors, non-irradiated survivors and controls, respectively. Memory and motor functions were impaired among the irradiated survivor group compared with the controls. A significant decline in PIQ and VIQ test scores was observed in the irradiated survivor group during the follow-up period, but only in VIQ in the non-irradiated group. CONCLUSIONS: Survivors of childhood ALL suffer from long-lasting progressive neuropsychological impairment, especially when treatment includes cranial irradiation.

Radiation-induced meningiomas: a shadow in the success story of childhood leukemia.

While the prognosis of acute childhood leukemia has improved, long-term survivors are increasingly experiencing late effects of the treatment. Cranially irradiated survivors are predisposed to the development of CNS tumors. Our aim was to describe the incidence of secondary brain tumors and to define the significance of treatment-related risk factors and host characteristics in a cohort of childhood leukemia survivors. Our cohort consisted of 60 consecutive cranially irradiated adult survivors of childhood leukemia treated in Oulu University Hospital (Oulu, Finland); MRI of the brain was performed on 49. The sites of the tumors, their histology, and details of the leukemia treatment were determined. Of the 49 patients, 11 (22%) 1-8 years of age at the time of diagnosis developed meningioma later in life, while no other brain tumors were seen. In this cohort, the development of meningioma seemed to show undisputable linkage with long latency periods (mean, 25 years; range, 14-34 years) and an increasing incidence 20 years after the treatment (47%). Three patients had multiple meningiomas, two had recurrent disease, and one had an atypical meningioma. Age at the time of irradiation, gender, or cumulative doses of chemotherapeutic agents showed no significant association with the development of meningiomas. The high incidence of meningiomas in this study was associated with long follow-up periods. Although the cohort is small, it seems probable that the increasing incidence of meningioma will shadow the future of cranially irradiated leukemia survivors. Systematic brain imaging after the treatment is therefore justifiable.