Beyond Survival - Cognition after Pediatric Brain Tumor

Background: Pediatric Brain Tumor (PBT) survivors suffer from cognitive sequelae, especially within the areas of cognitive tempo, attention, executive function and memory. The cognitive difficulties are often accentuated over the years, but knowledge about the long term trajectory is still scarce. Aim: The aim of this thesis was to examine cognitive sequelae after Pediatric Brain Tumor (PBT); risk factors, common difficulties, development and neuroimaging correlates. Methods: In study I, data from medical logs were used to examine characteristics of the patients who got access to neuropsychological services, compared to those who did not. In study II, data from 70 neuropsychological assessments were used to describe common cognitive impairments and to find risk factors. In study III, patients were invited to a follow-up study 10-13 years after diagnosis. Neuropsychological and neuroimaging data were collected and the two were compared. In study IV, longitudinal cognitive data from 173 patients were analyzed in order to describe development over time and to find risk factors for a negative development. Results: Study I: There were few differences between referred and non-referred patients. Study II: Patients had generally suppressed IQ and difficulties with executive function, memory, cognitive processing speed and attention. Risk factors were Whole-Brain Radiation Therapy (WBRT), large tumors, young age at diagnosis and male sex. Study III: Radiated as well as non-radiated patients had white matter abnormalities. Correlation between neuroimaging and cognition was low when group based statistics were used, but increased when a personalized method was used. Study IV: Most cognitive abilities showed a decline in age related scores over time unconsidered treatment given. Risk factors for impaired cognitive function at diagnosis were: male sex, WBRT, supratentorial lateral tumor, young age at diagnosis, larger tumor size and treatment with chemotherapy. Conclusions: A systematic neuropsychological follow-up is important. Risk factors for cognitive impairment and IQ decline are WBRT, large tumors, young age at diagnosis, male sex, supratentorial lateral tumor, and treatment with chemotherapy. A decline in IQ after PBT is common, unconsidered treatment given. Personalized methods of research would contribute significantly to our understanding of cognitive sequelae after PBT and its relation to neuroimaging

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa

Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.Peer reviewe

Auditory hypersensitivity and attention in survivors of paediatric brain tumours

Objective: Both auditory and visual hypersensitivity are clinical features of mental fatigue after acquired brain damage or in neurological disorders. Both types of hypersensitivity are also associated with attention deficits, especially in neurodevelopmental syndromes. The aim of this study was to examine auditory and visual hypersensitivity, and associations to attention, in a group of children and adolescents treated for paediatric brain tumours (PBTs).Participants and Methods: Included in the study were 34 survivors of PBTs, 8–18 years of age (M: 13.6, SD: 3.0). Eighteen participants were female and 16 were male. Mean time since diagnosis was 4.2 years (SD: 2.2). Auditory and visual hypersensitivity were assessed using two items from the questionnaire Mental Fatigue Scale (MFS), scored on a 7-point Likert scale from 0 – 3. Scores above 1 indicate hypersensitivity. Attention was assessed using Conners Continuous Performance Test 3 (detectability, commissions, variability), and T-scores above 60 were considered impaired. Spearman correlations were conducted between the performance-based and self-report measures.Results: Results from the MFS revealed that 53% of the survivors experienced auditory and 18% visual hypersensitivity as a sequela. Regarding attention, elevated scores were more common for detectability (18%) and variability (21%) than commissions (8%). Visual hypersensitivity was not significantly associated with any of the attention measures, whereas auditory hypersensitivity was significantly associated with detectability (r=.42, p=0.013) and variability (r=.57, p<0.001).Conclusions: These results suggest that auditory hypersensitivity is common after treatment for PBT, and that it is associated with decreased attention. This relationship should be taken into consideration when assessing survivors of PBTs

Pretreatment Cognition in Patients Diagnosed With Pediatric Brain Tumors

Background: There is a large body of literature identifying risk factors for the long-term cognitive alterations found in survivors of pediatric brain tumors. Less is known about baseline cognitive functioning in this population, but studies suggest that cognitive dysfunctions are often present at the time of diagnosis. This study aimed to identify potential risk factors for lower cognitive function at the time of pediatric brain tumor diagnosis. Methods: Participants were children and adolescents (n = 101) diagnosed with a pediatric brain tumor between 2006 and 2015, who underwent a pretreatment neuropsychologic assessment. Multivariate regression models were used to estimate the association between gender, age at diagnosis, tumor size and location, increased intracranial pressure, epilepsy, and six different indicators of cognitive functioning. Results: Overall, cognitive performance was relatively intact, with results close to norm means, but impairments were found in memory and cognitive processing speed. Male gender, older age, epilepsy, increased intracranial pressure, and larger tumors were all associated with lower cognitive function at the time of brain tumor diagnosis; whereas tumor location was not. Conclusions: Pretreatment neuropsychologic assessments, with some adjustments, can be carried out with children and adolescents with brain tumors. Our study adds to a small but growing body of literature documenting cognitive impairments at the time of diagnosis; these impairments may partly explain the longer-term deficits that commonly occur in pediatric brain tumor survivors. Consistent with previous research, pretreatment impairments were more common among boys, older children, and those with increased intracranial pressure, epilepsy, and larger tumors. The relationship between baseline and longer-term cognitive deficits requires further examination

Cognitive fatigue in relation to depressive symptoms after treatment for childhood cancer

BACKGROUND: Cognitive fatigue after childhood cancer is frequently overlooked despite guidelines recommending follow-up, and might be mistaken for depression due to overlapping symptoms. Our objectives were: 1) to examine ratings of fatigue in survivors of paediatric brain tumours (BT) and acute lymphoblastic leukaemia (ALL) compared to healthy controls, 2) to examine the relationship between symptoms of depression and cognitive fatigue, and 3) to evaluate parent-child concordance in ratings of cognitive fatigue.METHODS: Survivors of BT (n = 30), survivors of ALL (n = 30), and healthy controls (n = 60) aged 8-18 years completed the Pediatric Quality of Life Multidimensional Fatigue Scale and the Beck Youth Inventories. Associations between cognitive fatigue, diagnosis and depression were assessed with general linear modelling. Group differences were analysed using the Kruskal-Wallis test. Parent-child concordance was investigated with internal consistency reliability.RESULTS: Cognitive fatigue was prevalent in 70% of survivors of BT survivors and in 30% of survivors of ALL. Diagnosis was the main predictor of cognitive fatigue (p < .001, ηp2 = 0.178), followed by depression (p = .010, ηp2 = 0.080). Survivors of BT reported significantly more fatigue than healthy controls on all fatigue subscales. While they also expressed more symptoms of depression, we found no evidence for an interaction effect. Parent-child concordance was moderate to good among survivors, but poor for controls.CONCLUSIONS: Survivors of BT and ALL suffer from cognitive fatigue, with survivors of BT expressing more problems. Cognitive fatigue and depression should be assessed in survivors of childhood cancer using both self-rated and proxy-rated measures, and appropriate interventions offered

Cognitive Fatigue and Processing Speed in Children Treated for Brain Tumours

Objective:The relationship between fatigue and cognition has not been fully elucidated in children and adolescent survivors of brain tumours. The aim of the present study was to investigate the potential relationship between fatigue and cognitive impairments in these survivors, as this group is at risk for both types of deficits.Methods:Survivors of paediatric brain tumours (n = 45) underwent a neuropsychological testing on average 4 years after diagnosis. Mean age at follow-up was 13.41 years. Cognition was assessed with neuropsychological tests, and fatigue with the Pediatric Quality of Life (PedsQL™) Multidimensional Fatigue Scale. Regression analysis, adjusted for cranial radiotherapy and age at diagnosis, was used to investigate the associations between cognitive variables and fatigue subscales. Cognitive variables associated with fatigue were subsequently exploratively assessed.Results:Significant associations were found for cognitive fatigue and measures of cognitive processing speed; Coding: p = .003, r = .583, 95% CI [9.61; 22.83] and Symbol Search: p = .001, r = .585, 95% CI [10.54; 24.87]. Slower processing speed was associated with poorer results for cognitive fatigue. Survivors with the largest decrease in processing speed from baseline to follow-up also experienced the most cognitive fatigue. Survivors expressed more cognitive fatigue compared to other types of fatigue.Conclusions:The association between cognitive fatigue and cognitive processing speed in children and adolescents treated for brain tumours is in concordance with the results previously reported in adults. Some survivors experience fatigue without impairment in processing speed, indicating the need for comprehensive assessments. Moreover, the study supports that fatigue is a multidimensional concept which should be measured accordingly

Sex differences in strategy and performance on computerized neuropsychological tests as related to gender identity and age at puberty

Neuropsychological sex differences have since long been under debate. Support for the relation between behavioral differences and biological variables like hormone influence is, however, emerging. Sixteen men and sixteen women, all university students, were tested with computerized neuropsychological tests (APT), the Bem Sexual Role Inventory, and asked about pubertal age. The results were in line with earlier findings of sex differences in neuropsychological tests, men being faster and women more cautious. The assumption that women tend to use left-hemispheric, verbal/serial strategies also in spatial tasks was also partly supported. In women, late onset of puberty was related to better spatial performance, and there were also more intercorrelations between verbal and spatial tests in the female than in the male group, indicating that women use less specific strategies (more g-factor intelligence) in problem solving, or that aptitudes are less compartmentalized in women than in men