Original articleExecutive function deficits in pediatric cerebellar tumor survivors
Introduction
Almost half of all pediatric brain tumors arise in the posterior fossa.1 The most common cerebellar low-grade tumor, pilocytic astrocytoma (PA), is treated with surgical resection only. In contrast high-grade medulloblastoma (MB) patients further require craniospinal irradiation, a local boost and chemotherapy.2 Treatment of infratentorial ependymomas (EP) consists in resection followed by local irradiation in case of WHO grade II or III histology.3
In view of improved survival rates, long-term cognitive, behavioral, and affective sequelae have received considerable interest in cerebellar tumor survivors.4, 5 Poor intellectual outcome has been consistently documented in MB patients. Especially in the acquisition of new skills and knowledge MB survivors lag behind healthy peers.6 This dysfunction is considered to be due to inferior working memory, attention and processing speed.6, 7, 8 The deficits of higher mental function in MB patients have been primarily attributed to the neurotoxic effect of craniospinal irradiation and secondly to the interplay with chemotherapy.9, 10 In children with cerebellar PA intelligence seems to be generally spared with the exception of inferior verbal intelligence.11 Impairments of attention, parts of executive function, and information processing speed were also reported in PA survivors.5, 11, 12, 13 Planning abilities were previously investigated using multiple function tests that cover a broad spectrum of executive functions, such as the Wisconsin Card Sorting Test (WCST).8, 11, 14 These studies have reported discordant findings concerning planning abilities of pediatric cerebellar tumor survivors, with PA survivors performing within versus below the norm variation. Imaging, neuropsychological and animal studies15, 16 strengthen the role of the cerebellum (CB) as a modulator of prefrontal cortex (PFC) functions. The PFC is dedicated to temporal integration and planning of behavior and actions, inhibitory control of responses, regulation of emotions, direction of attention, and working memory.17, 18 Reciprocal neural loops connecting the CB with the PFC are the underpinnings of this regulatory system.4, 19 Myelination of these white matter pathways proceeds from childhood to adolescence.20 In parallel, maturation of different cognitive abilities follows a stepwise process. Planning, processing speed, goal setting and cognitive flexibility are thought to evolve until mid-adolescence whereas attention, self-regulation and inhibition mechanisms develop rapidly in early childhood.21, 22 Thus, lesions to the developing cerebro-cerebellar neural network orchestrating higher mental functions by cerebellar tumor disease and its treatment render patients highly vulnerable for suffering from deficits of these functions.23
The present study focused on profiling executive functioning of children and adolescents that suffered from low- or high-grade cerebellar tumors and were exposed to different treatment associated neurotoxic effects. In this setting we tested certain aspects of the theorized executive function system such as planning (formulation, evaluation and selection of a sequence of representation of information and executive actions to achieve a desired goal), working memory (maintaining as well as manipulation/monitoring of representation of information in its absence and the control of activation of these representations, here visuospatial information), inhibition of prepotent responses (i.e. responses with immediate reinforcement available or previously associated) and task flexibility (switching between or continuous monitoring of diverse stimulus–response associations (attentional sets)).24 We sought to distinguish quality and quantity of cognitive deficits caused by confined local damage to the cerebellar structures (present in the low-grade tumor group) from the aggravating effects of the global impact of adjuvant treatment (additionally present in the high-grade tumor group). To this purpose, in addition to the clinical assessment of ataxia applying the International cooperative ataxia rating scale (ICARS) we used a battery of neurocognitive assessments, i.e. the Hamburg Wechsler Intelligence Test (HAWIK/HAWIE), the Amsterdam Neuropsychological Tasks (ANT) program25 and the Tower of London (ToL).26 In contrast to multiple function tests, the ANT program allows to precisely evaluate speed and accuracy of specific aspects of executive function, such as working memory processes, cognitive flexibility and inhibition. This is the first study using this approach in pediatric cerebellar tumor survivors. We hypothesized that both patient groups would perform worse when compared to healthy peers due to loss of cerebellar function. In addition, children who received adjuvant treatment were predicted to exhibit greater deficits of executive function when compared to those treated with resection only due to irradiation and chemotherapy associated neurotoxicity.
Section snippets
Material and methods
42 children and adolescents diagnosed with a posterior fossa tumor were recruited at the Department of Pediatric Oncology and Hematology of Charité-Universitätsmedizin Berlin. All subjects and their parents gave written informed consent. The institutional ethics committee approved the study.
16 patients had a PA, 23 were diagnosed with a MB and three suffered from an EP. Patients were allocated to two groups: a low-grade cerebellar tumor cohort (LGCT), i.e. sixteen PA and one EP patients and a
Tower of London (ToL)
The German version of the Tower of London task was administered to assess forward thinking ability in 32 out of 42 patients (11 LGCT, 21 HGCT). The test has been repeatedly applied to assess patients with frontal lesions.28, 29 It consists of a wooden board with three vertical rods of descending lengths onto which three differently colored beads are placed. The initial configuration was presented to patients. The task was to change the placement of the beads on the vertical rods in a way that a
Planning (ToL)
No differences between both patient groups were found in the total number of solved problems (LGCT: mean percentile rank 50.33, SD 29.59; HGCT: mean percentile rank 29.29, SD 37.18; unpaired t-test, p = 0.398), the number of intermissions during the performance of the task (LGCT: mean 1.78, SD 1.09; HGCT: mean 1.47, SD 1.35; unpaired M–W-test, p = 0.414) and the preplanning time (repeated measures GLM model: F(1,30) = 0.245, p = 0.624; Fig. 1). When comparing the age-corrected number of solved
Discussion
The present study demonstrates that sequelae concerning executive functions are evident in both low- and high-grade cerebellar tumor survivors. When comparing cognitive performance between groups, only working memory of HGCT patients was significantly weaker than in LGCT patients. When comparisons to healthy children were drawn, loss of executive functions became apparent in both groups. Survivors of the LGCT group manifested deficits in inhibition mechanisms and mental flexibility reflected in
Conflict of interest
There are no known conflicts of interest.
Acknowledgments
We gratefully thank “KINDerLEBEN e.V.” for supporting E. Koustenis and the “Kind-Philipp-Foundation” for supporting SM Rueckriegel.
References (81)
- et al.
Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study
Lancet Oncol
(2009) - et al.
Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing
Cortex
(2010) - et al.
Late neurocognitive sequelae in survivors of brain tumours in childhood
Lancet Oncol
(2004) The prefrontal cortex – an update: time is of the essence
Neuron
(2001)- et al.
The cerebrocerebellar system
Int Rev Neurobiol
(1997) - et al.
Executive function following focal frontal lobe lesions: impact of timing of lesion on outcome
Cortex
(2007) - et al.
Increased intra-individual reaction time variability in attention-deficit/hyperactivity disorder across response inhibition tasks with different cognitive demands
Neuropsychologia
(2009) - et al.
Information processing characteristics in subtypes of multiple sclerosis
Neuropsychologia
(2002) - et al.
Planning and problem solving: from neuropsychology to functional neuroimaging
J Physiol Paris
(2006) - et al.
Acute effects of irradiation on cognition: changes in attention on a computerized continuous performance test during radiotherapy in pediatric patients with localized primary brain tumors
Int J Radiat Oncol Biol Phys
(2002)
Cerebello-thalamo-cerebral connections in pediatric brain tumor patients: impact on working memory
Neuroimage
Differences in supratentorial damage of white matter in pediatric survivors of posterior fossa tumors with and without adjuvant treatment as detected by magnetic resonance diffusion tensor imaging
Int J Radiat Oncol Biol Phys
Supratentorial neurometabolic alterations in pediatric survivors of posterior fossa tumors
Int J Radiat Oncol Biol Phys
Relevance of the cerebellar hemispheres for executive functions
Pediatr Neurol
Cerebellar neurocognition: insights into the bottom of the brain
Clin Neurol Neurosurg
The spectrum of neurobehavioural deficits in the posterior fossa syndrome in children after cerebellar tumour surgery
Cortex
A hybrid neural network analysis of subtle brain volume differences in children surviving brain tumors
Magn Reson Imaging
Quality of survival assessment in European childhood brain tumour trials, for children aged 5 years and over
Eur J Paediatr Neurol Off J Eur Paediatr Neurol Soc
Population-based epidemiologic data on brain tumors in German children
Cancer
Multidisciplinary management of childhood brain tumors: a review of outcomes, recent advances, and challenges
J Neurosurg Pediatr
Neuropsychological long-term sequelae after posterior fossa tumour resection during childhood
Brain
Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis
J Clin Oncol
Understanding the cognitive impact on children who are treated for medulloblastoma
J Pediatr Psychol
Differential prefrontal-like deficit in children after cerebellar astrocytoma and medulloblastoma tumor
Behav Brain Funct
Reduction of health status 7 years after addition of chemotherapy to craniospinal irradiation for medulloblastoma: a follow-up study in PNET 3 trial survivors on behalf of the CCLG (formerly UKCCSG)
J Clin Oncol
Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood
J Clin Oncol
Long-term sequelae in children after cerebellar astrocytoma surgery
Neurology
The effects of treatment for posterior fossa brain tumors on selective attention
J Int Neuropsychol Soc
The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours
Brain
Cross-modal and cross-temporal association in neurons of frontal cortex
Nature
Cerebellar projections to the prefrontal cortex of the primate
J Neurosci
Frontal lobe and cognitive development
J Neurocytol
Concepts of myelin and myelination in neuroradiology
Am J Neuroradiol
Planning and problem solving skills following focal frontal brain lesions in childhood: analysis using the Tower of London
Child Neuropsychol
Tower of London procedure: a standard method and developmental data
J Clin Exp Neuropsychol
Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome
J Neuropsychiatry Clin Neurosci
Inhibition of prepotent responding and attentional flexibility in treated phenylketonuria
Dev Neuropsychol
Critical risk factors for intellectual impairment in children with posterior fossa tumors: the role of cerebellar damage
J Neurosurg
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2022, CortexCitation Excerpt :Despite improvements in treatment protocols, pediatric brain tumor survivors (PBTS) experience structural and functional damage leading to cognitive dysfunction – particularly in information processing speed and controlled attention (Dockstader et al., 2013, 2014; Mabbott et al., 2009; Moore, 2005; Palmer et al., 2007; Wolfe et al., 2012). Radiation results in more diffuse insult (King et al., 2015; Makola et al., 2017) and cognitive dysfunction than surgery alone (Koustenis et al., 2016; Vaquero et al., 2008). Younger age at diagnosis also increases risk of injury and poorer cognitive outcomes (Palmer et al., 2003).
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2022, Radiotherapy and OncologyCitation Excerpt :Studies reported few prognostic factors of memory impairment. Radiotherapy is undoubtedly the main prognostic factor for secondary memory impairment as shown in the previous section [18,23–26,28,30,33,35]. A younger age at the time of treatment was linked with a poor memory prognosis in the medulloblastoma group, as shown by a comparison between children treated before 8 years old and those treated after in most of the studies [37,53].
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2021, Clinical Neurology and NeurosurgeryCitation Excerpt :VOIs related to impaired performances showed a maximum overlap both on the enlargement of the left lateral ventricles and in the left vermis lesion for all selected tasks, except for impaired narrative fluency, which showed a higher relation to the left lateral ventricle enlargement and narrative memory which showed a correlation with the right vermis and the enlarged fourth ventricle (see Fig. 2, Table 5). Previous studies investigating neuropsychological outcome in children with PFT suggested that cerebellar damage may result in decreased intelligence and neuropsychological impairments, including disturbances of executive functions, memory, spatial cognition, and language, as well as personality changes [1,2,5,6,10,20,21,26,32,37,38,41,44,50,51,55,56,58,64,65]. To date, such studies have not evaluated the complexity of neuropsychological functions and processes through multidimensional batteries.
Neuropsychological consequences of childhood medulloblastoma and possible interventions: A review
2021, NeurochirurgieCitation Excerpt :More interestingly, Edelstein et al., 2011 showed that—despite stable IQ scores 20–40 years after diagnosis—working memory was the only index that continued to decline over the long-term. Other types of cognitive impairments also often emerge during these children's subsequent development in a number of neuropsychological areas, such as executive functions, fluency, problem solving, planning [25,26], episodic memory [22,27–29] or control and identification of emotions [30]. Some of these difficulties emerge very early after disease onset, while others emerge much later (several years), as deficits become evident when environmental demands increase, and cognitive functions fail to develop at the expected rate.
The role of cerebellum in the child neuropsychological functioning
2020, Handbook of Clinical NeurologyCitation Excerpt :Impairments in sustained attention, processing speed, and working memory have been most often identified (Reeves et al., 2005; Mabbott et al., 2009; Palmer et al., 2010, 2013; Droit-Volet, 2013; Yock et al., 2016; Wegenschimmel et al., 2017; Szentes et al., 2018; Heitzer et al., 2019). In addition, deficits have been documented in a variety of cognitive functions, including executive functions (Levisohn et al., 2000; Spiegler et al., 2004; Vaquero et al., 2008; Koustenis et al., 2016), speech and language (Levisohn et al., 2000; Riva and Giorgi, 2000; Huber et al., 2007; Morgan et al., 2011), learning and memory (Maddrey et al., 2005; Ribi et al., 2005), and visuospatial functions and visual–motor integration (Levisohn et al., 2000; Riva and Giorgi, 2000; Scott et al., 2001; Spiegler et al., 2004; Khajuria et al., 2015). Identified factors associated with unfavorable cognitive outcome are numerous: young age at diagnosis (Johnson et al., 1994; Rønning et al., 2005; Edelstein et al., 2011; Ris et al., 2013; Khalil et al., 2019), presence and dose of supratentorial radiation (Mulhern et al., 1998; Copeland et al., 1999; Grill et al., 1999; Kieffer-Renaux et al., 2000; Palmer et al., 2003; Lafay-Cousin et al., 2009; Brinkman et al., 2018), white matter integrity (Mulhern et al., 1999, 2001; Mabbott et al., 2006; Brinkman et al., 2012b; Perreault et al., 2014; Law et al., 2017; Moxon-Emre et al., 2016), history of postoperative CMS (Palmer et al., 2010; Kieffer et al., 2019), hydrocephalus (Hardy et al., 2008; Moxon-Emre et al., 2014), adverse perioperative medical events and postsurgical complications (Kao et al., 1994; Mabbott et al., 2008; Roncadin et al., 2008), hearing loss (Paulino et al., 2010; King et al., 2017; Orgel et al., 2016), molecular subgroup (Schwalbe et al., 2017; Oyefiade et al., 2019), female gender (Ris et al., 2001), low level of parent education (Kieffer et al., 2019).
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Elisabeth Koustenis and Pablo Hernáiz Driever equally contributed to this manuscript.