A Systematic Review of Host Genomic Variation and Neuropsychological Outcomes for Pediatric Cancer Survivors.

Pediatric survivors of brain tumors and acute lymphoblastic leukemia (ALL) are at risk for long-term deficits in their neuropsychological functioning. Researchers have begun examining associations between germline single nucleotide polymorphisms (SNPs), which interact with cancer treatment, and neuropsychological outcomes. This review synthesizes the impact of treatment-related toxicity from germline SNPs by neuropsychological domain (i.e., working memory, processing speed, psychological functioning) in pediatric survivors. By focusing on specific neuropsychological domains, this review will examine outcome measurement and critique methodology. Fourteen studies were identified and included in this review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All studies were published in peer-reviewed journals in English by November 24th, 2021. Reviewed studies were not of sufficient quality for a meta-analysis due to varying measurement strategies, gaps in reported descriptive variables, and low power. All neuropsychological domains evaluated in this review had associations with SNPs, except fine motor and visual integration abilities. Only five SNPs had consistent neuropsychological findings in more than one study or cohort. Future research and replication studies should use validated measures of discrete skills that are central to empirically validated models of survivors' long-term outcomes (i.e., attention, working memory, processing speed). Researchers should examine SNPs across pathophysiological pathways to investigate additive genetic risk in pediatric cancer survivors. Two SNPs were identified that confer resiliency in neuropsychological functioning, and future work should investigate resiliency genotypes and their underlying biological mechanisms.

Quantifying and reporting outcome measures in pediatric epilepsy surgery: A systematic review.

Several instruments and outcomes measures have been reported in pediatric patients undergoing epilepsy surgery. The objective of this systematic review is to summarize, evaluate, and quantify outcome metrics for the surgical treatment of pediatric epilepsy that address seizure frequency, neuropsychological, and health-related quality of life (HRQL). We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify publications between 2010 and June 2021 from PubMed, Embase, and the Cochrane Database of Systematic Reviews that report clinical outcomes in pediatric epilepsy surgery. Eighty-one articles were included for review. Overall, rates of postoperative seizure frequency were the most common metric reported (n = 78 studies, 96%). Among the seizure frequency metrics, the Engel Epilepsy Surgery Outcome Scale (n = 48 studies, 59%) was most commonly reported. Neuropsychological outcomes, performed in 32 studies (40%) were assessed using 36 different named metrics. HRQL outcomes were performed in 16 studies (20%) using 13 different metrics. Forty-six studies (57%) reported postoperative changes in antiepileptic drug (AED) regimen, and time-to-event analysis was performed in 15 (19%) studies. Only 13 outcomes metrics (1/5 seizure frequency, 6/13 HRQL, 6/36 neuropsychological) have been validated for use in pediatric patients with epilepsy and only 13 have been assessed through reliability studies (4/5 seizure frequency, 6/13 HRQL, and 3/36 neuropsychological). Of the 81 included studies, 17 (21%) used at least one validated metric. Outcome variable metrics in pediatric epilepsy surgery are highly variable. Although nearly all studies report seizure frequency, there is considerable variation in reporting. HRQL and neuropsychological outcomes are less frequently and much more heterogeneously reported. Reliable and validated outcomes metrics should be used to increase standardization and accuracy of reporting outcomes in pediatric patients undergoing epilepsy surgery.

A comparison study assessing neuropsychological outcome of patients with post-operative pediatric cerebellar mutism syndrome and matched controls after proton radiation therapy.

PURPOSE: Post-operative pediatric cerebellar mutism syndrome (CMS), characterized by mutism, ataxia/hypotonia, and emotional lability, can result in long-term deficits following resection of posterior fossa (PF) tumors. This longitudinal study compared neuropsychological outcomes of pediatric patients with post-operative CMS to a matched control patient group without CMS. METHODS: Fifty-eight PF tumor patients received post-surgical proton radiation therapy (PRT) and testing at baseline and at ≥ 1-year post-PRT over a 10-year period. Of these, 18 (31%) had post-operative CMS with baseline and follow-up neuropsychological test data. Those participants were matched to 18 controls by tumor location, age, gender, and handedness; no significant group differences were found at baseline for clinical/demographic variables. Total mean age at baseline was 7.26 years (SD = 4.42); mean follow-up interval was 3.26 years (SD = 2.24). Areas assessed: overall intelligence, expressive and receptive vocabulary, visuomotor integration, fine motor speed, inhibition, emotional control, depression, and anxiety. RESULTS: Patients were 52% male; 86% medulloblastoma/14% ependymoma; 86% craniospinal irradiation/14% focal radiation; and 86% chemotherapy. No group differences were found between most mean baseline scores; expressive vocabulary and fine motor speed were significantly lower in the post-operative CMS group (p < 0.05). Mean change scores revealed no significant differences for the sample; scores were within the normal range except fine motor skills were impaired for both groups. CONCLUSIONS: Longitudinal neuropsychological outcomes for post-operative pediatric CMS patients did not differ significantly from matched controls without this condition. Patients were in the normal range in all areas except fine motor speed, which was impaired for both groups independent of CMS diagnosis.

Neuropsychological attributes of urea cycle disorders: A systematic review of the literature.

Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35 000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in six disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the seven UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness.

A Neuropsychological Profile for Agenesis of the Corpus Callosum? Cognitive, Academic, Executive, Social, and Behavioral Functioning in School-Age Children.

OBJECTIVES: Agenesis of the corpus callosum (AgCC), characterized by developmental absence of the corpus callosum, is one of the most common congenital brain malformations. To date, there are limited data on the neuropsychological consequences of AgCC and factors that modulate different outcomes, especially in children. This study aimed to describe general intellectual, academic, executive, social and behavioral functioning in a cohort of school-aged children presenting for clinical services to a hospital and diagnosed with AgCC. The influences of age, social risk and neurological factors were examined. METHODS: Twenty-eight school-aged children (8 to 17 years) diagnosed with AgCC completed tests of general intelligence (IQ) and academic functioning. Executive, social and behavioral functioning in daily life, and social risk, were estimated from parent and teacher rated questionnaires. MRI findings reviewed by a pediatric neurologist confirmed diagnosis and identified brain characteristics. Clinical details including the presence of epilepsy and diagnosed genetic condition were obtained from medical records. RESULTS: In our cohort, ~50% of children experienced general intellectual, academic, executive, social and/or behavioral difficulties and ~20% were functioning at a level comparable to typically developing children. Social risk was important for understanding variability in neuropsychological outcomes. Brain anomalies and complete AgCC were associated with lower mathematics performance and poorer executive functioning. CONCLUSIONS: This is the first comprehensive report of general intellectual, academic, executive social and behavioral consequences of AgCC in school-aged children. The findings have important clinical implications, suggesting that support to families and targeted intervention could promote positive neuropsychological functioning in children with AgCC who come to clinical attention. (JINS, 2018, 24, 445-455).

The Efficacy of Cognitive Intervention in Mild Cognitive Impairment (MCI): a Meta-Analysis of Outcomes on Neuropsychological Measures.

Cognitive training in MCI may stimulate pre-existing neural reserves or recruit neural circuitry as "compensatory scaffolding" prompting neuroplastic reorganization to meet task demands (Reuter-Lorenz & Park, 2014). However, existing systematic reviews and meta-analytic studies exploring the benefits of cognitive interventions in MCI have been mixed. An updated examination regarding the efficacy of cognitive intervention in MCI is needed given improvements in adherence to MCI diagnostic criteria in subject selection, better defined interventions and strategies applied, increased use of neuropsychological measures pre- and post-intervention, as well as identification of moderator variables which may influence treatment. As such, this meta-analytic review was conducted to examine the efficacy of cognitive intervention in individuals diagnosed with mild cognitive impairment (MCI) versus MCI controls based on performance of neuropsychological outcome measures in randomized controlled trials (RCT). RCT studies published from January 1995 to June 2017 were obtained through source databases of MEDLINE-R, PubMed, Healthstar, Global Health, PSYCH-INFO, and Health and Psychological Instruments using search parameters for MCI diagnostic category (mild cognitive impairment, MCI, pre-Alzheimer's disease, early cognitive decline, early onset Alzheimer's disease, and preclinical Alzheimer's disease) and the intervention or training conducted (intervention, training, stimulation, rehabilitation, or treatment). Other inclusion and exclusion criteria included subject selection based on established MCI criteria, RCT design in an outpatient setting, MCI controls (active or passive), and outcomes based on objective neuropsychological measures. From the 1199 abstracts identified, 26 articles met inclusion criteria for the meta-analyses completed across eleven (11) countries; 92.31% of which have been published within the past 7 years. A series of meta-analyses were performed to examine the effects of cognitive intervention by cognitive domain, type of training, and intervention content (cognitive domain targeted). We found significant, moderate effects for multicomponent training (Hedges' g observed = 0.398; CI [0.164, 0.631]; Z = 3.337; p = 0.001; Q = 55.511; df = 15; p = 0.000; I 2 = 72.978%; τ 2 = 0.146) as well as multidomain-focused strategies (Hedges' g = 0.230; 95% CI [0.108, 0.352]; Z = 3.692; p < 0.001; Q = 12.713; df = 12; p = 0.390; I 2 = 5.612; τ 2 = 0.003). The effects for other interventions explored by cognitive domain, training type, or intervention content were indeterminate due to concerns for heterogeneity, bias, and small cell sizes. In addition, subgroup and meta-regression analyses were conducted with the moderators of MCI category, mode of intervention, training type, intervention content, program duration (total hours), type of control group (active or passive), post-intervention follow-up assessment period, and control for repeat administration. We found significant overall effects for intervention content with memory focused interventions appearing to be more effective than multidomain approaches. There was no evidence of an influence on outcomes for the other covariates examined. Overall, these findings suggest individuals with MCI who received multicomponent training or interventions targeting multiple domains (including lifestyle changes) were apt to display an improvement on outcome measures of cognition post-intervention. As such, multicomponent and multidomain forms of intervention may prompt recruitment of alternate neural processes as well as support primary networks to meet task demands simultaneously. In addition, interventions with memory and multidomain forms of content appear to be particularly helpful, with memory-based approaches possibly being more effective than multidomain methods. Other factors, such as program duration, appear to have less of an influence on intervention outcomes. Given this, although the creation of new primary network paths appears strained in MCI, interventions with memory-based or multidomain forms of content may facilitate partial activation of compensatory scaffolding and neuroplastic reorganization. The positive benefit of memory-based strategies may also reflect transfer effects indicative of compensatory network activation and the multiple-pathways involved in memory processes. Limitations of this review are similar to other meta-analysis in MCI, including a modest number studies, small sample sizes, multiple forms of interventions and types of training applied (some overlapping), and, while greatly improved in our view, a large diversity of instruments used to measure outcome. This is apt to have contributed to the presence of heterogeneity and publication bias precluding a more definitive determination of the outcomes observed.

Neuropsychological outcomes from constant current deep brain stimulation for Parkinson's disease.

OBJECTIVE: The aim of this study was to evaluate the neurobehavioral safety of constant-current subthalamic deep brain stimulation and to compare the neuropsychological effects of stimulation versus electrode placement alone. METHODS: A total of 136 patients with Parkinson's disease underwent bilateral subthalamic device implantation in this randomized trial. Patients received stimulation either immediately after device implantation (n = 101; active stimulation) or beginning 3 months after surgery (n = 35; delayed activation control). Patients were administered neuropsychological tests before, 3, and 12 months after device implantation. RESULTS: Neuropsychological change in stimulation and control groups were comparable. Within-group analyses revealed declines in category and switching verbal fluency in both groups, but only the stimulation group had letter verbal fluency and Stroop task declines. Depression symptom improvements occurred in both groups, but more often in the stimulation group. Letter fluency declines were associated with worse Parkinson's Disease Questionnaire Communication subscale scores. Baseline and 12-month comparisons (in the combined group) revealed gains in verbal and visual delayed recall scores and improvement in depression symptoms, but decrements in verbal fluency and Stroop scores. CONCLUSIONS: Constant-current bilateral subthalamic stimulation had a good cognitive safety profile except for decrements in verbal fluency and on the Stroop task. These abnormalities are related to device implantation, but stimulation likely had an additive effect. One year after surgery, the cognitive changes did not exert a detrimental effect on quality of life, although letter fluency declines were associated with communication dissatisfaction at 12 months. Improvement in depressive symptom severity appears dependent on stimulation and not placebo or lesion effects. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Neuropsychological findings associated with Panayiotopoulos syndrome in three children.

Panayiotopoulos syndrome is a common idiopathic benign epilepsy that has a peak age of onset in early childhood. The syndrome is multifocal and shows significant electroencephalogram (EEG) variability, with occipital predominance. Although a benign syndrome often refers to the absence of neurological and neuropsychological deficits, the syndrome has recently been associated with cognitive impairments. Also, despite frequent occipital EEG abnormalities, research regarding the visual functioning of patients is less reported and often contradictory. The purpose of this study was to gain additional knowledge regarding the neurocognitive functioning of patients with Panayiotopoulos syndrome and specifically to address any visual processing deficits associated with the syndrome. Following diagnosis of the syndrome based on typical clinical and electrophysiological criteria, three patients, aged 5, 8, and 10years were referred by epileptologists for neuropsychological evaluation. Neuropsychological findings suggest that the patients had notable impairments on visual memory tasks, especially in comparison with verbal memory. Further, they demonstrated increased difficulty on picture memory suggesting difficulty retaining information from a crowded visual field. Two of the three patients showed weakness in visual processing speed, which may account for weaker retention of complex visual stimuli. Abilities involving attention were normal for all patients, suggesting that inattention is not responsible for these visual deficits. Academically, the patients were weak in numerical operations and spelling, which both rely partially on visual memory and may affect achievement in these areas. Overall, the results suggest that patients with Panayiotopoulos syndrome may have visual processing and visual memory problems that could potentially affect their academic capabilities. Identifying such difficulties may be helpful in creating educational and remedial assistance programs for children with this syndrome, as well as developing appropriate presentation of information to these children in school.

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

UNLABELLED: The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Neuropsychological functioning of children treated for acute lymphoblastic leukemia: impact of whole brain radiation therapy.

OBJECTIVES: To provide one of the first prospective reports examining neuropsychological outcomes for children treated with 1800 cGy whole brain radiotherapy (WBRT) and prophylactic chemotherapy versus prophylactic chemotherapy alone for acute lymphoblastic leukemia (ALL). Acute and long-term neuropsychological toxicities associated with WBRT are compared. METHODS: This multisite study included 188 children, ages 4-21 years at enrollment, who were assessed with standardized neuropsychological tests at 9, 21, and 48 months after diagnosis with intermediate risk ALL. All participating children were receiving treatment on a parent study CCG105. RESULTS: Verbal intelligence (VIQ) scores for children receiving WBRT was significantly lower than VIQ for prophylactic chemotherapy at the 48-month time point (p < 0.05). A significant cross-level interaction between time since diagnosis and treatment condition was observed (p < 0.05). WBRT did not result in differences in PIQ; both groups of children demonstrated comparable increases in PIQ. Neuropsychological findings at 48 months after diagnosis indicated diminished performance in neuromotor, visual-motor coordination, and executive functioning for children receiving WBRT. Academic achievement was unaffected by WBRT at 4 years after diagnosis. CONCLUSIONS: The measurement of verbal and performance IQ as a primary endpoint in ALL clinical trials is critical to characterizing neuropsychological late effects. A trajectory of decline in neuropsychological functioning, specifically verbal IQ, was observed. Missing data within the trial occurred at random and did not impact results observed. The impact of WBRT becomes evident at 48 months after diagnosis, suggesting the need for long-term follow-up beyond the time frame typically used in Phase III trials.

A systematic review of neuropsychological outcomes following posterior fossa tumor surgery in children.

PURPOSE: Central nervous system tumors are the most common solid tumors in the pediatric population. As children with central nervous system (CNS) tumors are surviving into adolescence and adulthood, more research is being focused on the long-term cognitive outcomes of the survivors. This review examines the literature on different cognitive outcomes of survivors of different childhood posterior fossa CNS tumor types. METHODS: The authors reviewed the literature for articles published from 2000 to 2012 about long-term neuropsychological outcomes of children diagnosed with posterior fossa brain tumors before the age of 18, which distinguished between histological tumor types, and had a minimum follow-up of 3 years. RESULTS: The literature search returned 13 articles, and a descriptive analysis was performed comparing intelligence quotient (IQ), attention/executive function, and memory components of 456 survivors of childhood posterior fossa tumors. Four articles directly compared astrocytoma and medulloblastoma survivors and showed medulloblastoma survivors fared worse in IQ, attention/executive function, and memory measurements. Five articles reporting medulloblastomas found IQ, attention, and memory scores to be significantly below the standardized means. Articles examining astrocytoma survivors found IQ scores within the normal range for the population. Survivors of ependymomas reported 2/23 survivors impaired on IQ scores, while a second study reported a significant number of ependymoma survivors lower than the expected population norm. CONCLUSIONS: Tumor histopathology and the type of postoperative adjuvant therapy seem to have a significant impact on the long-term neuropsychological complications of pediatric posterior fossa CNS tumor survivors. Age at diagnosis and treatment factors are important variables that affect the outcomes of the survivors.

Neuropsychological outcomes following HSCT in MS: A systematic review.

BACKGROUND: Autologous haematopoietic stem cell transplant (HSCT) is considered an effective treatment for highly active multiple sclerosis (MS). To date, most research has focused primarily on disease outcome measures, despite the significant impact of neuropsychological symptoms on MS patients' quality of life. The current systematic review aimed to examine whether HSCT for MS impacts neuropsychological outcome measures such as cognition, fatigue, mood, and quality of life. METHODS: The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42023474214). Systematic searches were carried out in six databases (PsycINFO, PubMed, Embase, Scopus, CINAHL and Web of Science) based on the following inclusion criteria: (i) published in peer-reviewed journals in English; (ii) longitudinal studies of adults with MS (iii) at least one neuropsychological outcome was assessed pre- and post-HSCT using standardised measures. Risk of bias was assessed using the National Heart, Lung and Blood Institute (NHLBI) quality assessment tools. A narrative synthesis was used to present results. RESULTS: Eleven studies were included in the review. Long-term improvements in quality of life post-HSCT were identified. In terms of cognition and fatigue, the evidence was mixed, with some post-HSCT improvements identified. Decline in cognitive performance in the short-term post-HSCT was observed. No changes in mood were identified post-HSCT. Arguments for interpreting these results with caution are presented based on risk of bias. Arguments for interpreting these results with caution are presented based on risk of bias. Limitations of the evidence are discussed, such confounding variables and lack of statistical power. CONCLUSION: The evidence base for the impact of HSCT for MS on neuropsychological outcomes is limited. Further research is required to progress understanding to facilitate clinician and patient understanding of HSCT treatment for MS.

Neuropsychological and biopsychosocial evolution, therapeutic adherence and unmet care needs during paediatric transplantation: study protocol of a mixed-methods design (observational cohort study and focus groups) - the TransplantKIDS mental health project.

The present article describes the protocol of a mixed-methods study (an observational cohort design and focus groups), aimed to examine neuropsychological functioning and other biopsychosocial outcomes, therapeutic adherence and unmet care needs in paediatric population undergoing solid organ or allogeneic hematopoietic transplant during the pre- and post-transplant phases. Following a multi-method/multi-source approach, neuropsychological domains will be comprehensively measured with objective tests (SDMT, K-CPT 2/CPT 3, TAVECI/TAVEC, WISC-V/WAIS-IV Vocabulary and Digit Span subtests, Verbal Fluency tests, Stroop, ROCF, and TONI-4); ecological executive functioning, affective and behavioral domains, pain intensity/interference, sleep quality and therapeutic adherence will be assessed through questionnaires (parent/legal guardians-reported: BRIEF-2 and BASC-3; and self-reported: BASC-3, BPI, PROMIS, AIQ and SMAQ); and blood levels of prescribed drugs will be taken from each patient's medical history. These outcomes will be measured at pre-transplant and at 4-weeks and 6-months post-transplant phases. The estimated sample size was 60 patients (any type of transplant, solid organ, or hematopoietic) from La Paz University Hospital (Madrid, Spain). Finally, three focus group sessions will be organized with patients, parents/guardians, and transplant clinicians (n = 15, with 5 participants per group), in order to qualitatively identify unmet care needs during the pre-, and post-transplant stages of the process. The study protocol was registered at ClinicalTrials.gov (NCT05441436).

Neuropsychiatric Symptoms of Moyamoya Disease: Considerations for the Clinician.

Neurocognitive impairment in moyamoya disease is common, under recognized, and potentially devastating. The purpose of this paper is to provide an updated overview on this topic for the practicing clinician. We searched PubMed for keywords including cognitive impairment, neurocognitive dysfunction, and neuropsychological recovery in moyamoya disease. We summarized the literature to provide a concise review of the treatment and management of neuropsychiatric symptoms associated with moyamoya disease. Neuropsychiatric sequelae have conventionally been attributed to chronic cerebral hypoperfusion and/or stroke. Cognitive dysfunction in adults with moyamoya disease is most commonly in the form of impaired executive function, whereas intelligence is the predominant impairment in children with moyamoya disease. Pharmacotherapy for treatment of the neuropsychiatric symptoms associated with moyamoya disease is appropriate and can improve quality of life; however, careful consideration is needed to avoid adverse cerebrovascular events. It remains unclear as to whether surgical revascularization improves or stabilizes cognitive performance and outcomes. Additional prospective studies are warranted to better understand the long-term impact of revascularization on cognitive functioning in moyamoya disease.

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

Neuropsychological Outcomes of Children Treated for Brain Tumors.

Central nervous system (CNS) neoplasms are the most common solid tumors diagnosed in children. CNS tumors represent the leading cause of cancer death and cancer-related morbidity for children less than 20 years of age, although there has been a moderate increase in survival rates over the past several decades. The average survival at 5 years now nearly reaches 75%, and for some, non-malignant histology approximates 97% at 20 years from diagnosis. Neurological, cognitive, and neuropsychological deficits are the most disabling long-term effects of brain tumors in children. Childhood is a time of extreme brain sensitivity and the time of life in which most brain development occurs. Thus, the long-term toxicities that children treated for CNS tumors experience can affect multiple developmental domains and day-to-day functioning, ultimately leading to a poor quality of survival (QoS). We reviewed literature focusing on the risk factors for cognitive and neuropsychological impairment in pediatric patients treated for brain tumors with the aim of better understanding who is at major risk and what the best strategies for monitoring these patients are.

Implications of age at lesion onset for neuropsychological outcomes: A systematic review focusing on focal brain lesions.

Theories of the relation between age at lesion onset and outcomes posit different views of the young brain: resilient and plastic (i.e., the so-called "Kennard Principle"), or vulnerable (i.e., the Early Vulnerability Hypothesis). There is support for both perspectives in previous research and questions about the "best" or "worst" times to sustain brain injury remain. Here, we present a systematic review investigating the influence of age at focal brain lesion onset on cognitive functioning. This systematic review identifies and qualitatively synthesizes empirical studies from 1985 to 2021 that investigated age at lesion onset as a variable of interest associated with neuropsychological outcomes. A total of 45 studies were identified from PubMed, PsycINFO, and CINAHL databases. Almost all studies indicated that brain injury earlier in the developmental period predicts worse cognitive outcomes when compared to onset either later in the developmental period or in adulthood. More specifically, the overwhelming majority of studies support an "earlier is worse" model for domains of intellect, processing speed, attention and working memory, visuospatial and perceptual skills, and learning and memory. Relatively more variability in outcomes exists for domains of language and executive functioning. Outcomes for all domains are influenced by various other age and injury variables (e.g., lesion size, lesion laterality, chronicity, a history of epilepsy). Continued interdisciplinary understanding and communication about the influence of age at lesion onset on neuropsychological outcomes will aid in promoting the best possible outcomes for patients.

Neurocognitive and Psychological Outcomes among Children and Adolescents with Brain Tumors: Development of an Observational and Longitudinal Prospective Study Protocol.

Children and adolescents affected by brain tumors are at risk for neuropsychological sequelae that need to be evaluated in order to plan adequate rehabilitation programs, and to support their development and recovery. This work aims to describe an innovative prospective observational study protocol for the early evaluation and monitoring over time of neuropsychological outcomes in this pediatric population. Pediatric patients aged 3-17 with a brain tumor diagnosis will be assessed through the use of a battery of Italian standardized neuropsychological tests, with good psychometric properties and age-appropiate, at three different time points of their clinical course: at diagnosis and before surgery (T0), after surgical removal and before the start of potential adjuvant therapies (T1), and at the one-year follow-up after potential adjuvant therapies (T2). This study will allow clinicians to support the neuropsychological development of these children by promoting appropriate and timely rehabilitation and educational programs from the early phases of their clinical course.

Responsive Neurostimulation of the Anterior Thalamic Nuclei in Refractory Genetic Generalized Epilepsy: A Case Series.

Genetic generalized epilepsies (GGEs) are thought to represent disorders of thalamocortical networks. There are currently no well-established non-pharmacologic treatment options for patients with drug-resistant GGE. NeuroPace's Responsive Neurostimulation (RNS) System was approved by the United States Food and Drug Administration to treat focal seizures with up to two ictal foci. We report on three adults with drug-resistant GGE who were treated with thalamic RNS. Given the severity of their epilepsies and the potential ictogenic role of the thalamus in the pathophysiology of GGE, the RNS System was palliatively implanted with leads in the bilateral anterior thalamic nuclei (ANT) of these patients. The ANT was selected because it was demonstrated to be a safe target. We retrospectively evaluated metrics including seizure frequency over 18-32 months. One patient required explantation due to infection. The other two patients were clinical responders. By the end of the observation period reported here, one patient was seizure-free for over 9 months. All three self-reported an improved quality of life. The clinical response observed in these patients provides 'proof-of-principle' that GGE may be treatable with responsive thalamic stimulation. Our results support proceeding to a larger study investigating the efficacy and safety of thalamic RNS in drug-resistant GGE.