Table 1.
Extraction table including study design, level of evidence (Joanna Briggs Institute levels of evidence), sample characteristics, objectives and results of the studies that addressed cognitive and behavior in children with neurofibromatosis type 1 (NF1).
| Reference | Study design | Level of evidence | Sample | Objectives | Results |
|---|---|---|---|---|---|
| Allen et al. (27) | Case–control study | 3d | 23 NF1 23 Controls Age: 8–16 |
Identify possible relations between neurocognitive ability, facial expression recognition, and social functioning in NF1 children compared with typically developing peers | Children with NF1 had significantly lower parent- and child-rated social functioning per the Pediatric Quality of Life Inventory and greater social problems according to the Child Behavior Checklist. Children with NF1 also had significantly weaker recognition of child faces and adult faces on low intensity conditions |
| Aydin et al. (36) | Case–control study | 3d | 37 NF1 Mean age: 10.12 ± 3.82 31 Controls Mean age: 9.83 ± 3.76 |
Evaluate the association between the microstructural integrity of CC and neurocognitive disabilities, based on apparent diffusion coefficient and fractional anisotropy values in NF1 children compared with healthy controls | Children with NF1 showed a significantly larger total CC area than healthy controls. Apparent diffusion coefficient values obtained from the CC genu were significantly higher in NF1 children than in healthy controls. There was a negative correlation between the apparent diffusion coefficient values of the CC genu and arithmetic and digit span scores (verbal IQ and performance IQ scores), and between the fractional anisotropy values of the genu and coding scores (verbal IQ and performance IQ scores) in children with NF1 |
| Barquero et al. (11) | Clinical trial | lc | 49 NF1 + Reading deficits 17 Idiopathic reading deficit Two control groups: 14 wait list idiopathic reading deficit, 26 typically developing readers Age: 8–14 |
Determine the effect of remedial reading programs in children with NF1 and reading deficits | Children with NF1 and reading deficiencies responded better to the kinesthetic reading program than the one requiring visual-spatial demands. Similar distribution of reading scores in children with NF1 were found regardless of whether the Conners Parent Rating scores indicated low (T score <50), medium (T score = 50–65), or high risk (T score >65) of ADHD |
| Champion et al. (17) | Case–control study | 3d | 46 NF1 Age: 7–17 Not comparison group, normative data was used |
Determine the relations between motor impairment, gait variables, and cognitive function in children with NF1 | Normalized scores on the Bruininks-Oseretsky Test of Motor Proficiency, for an NF1 cohort were significantly lower than age-matched normative reference values. Compared with normative data, children with NF1 demonstrated significantly decreased performance on gait parameters. Poorer balance skills were significantly associated with reduced perceptual reasoning and working memory |
| Cosyns et al. (8) | Descriptive | 3e | 43 NF1: 14 children, age: 7.4–16; 29, adults, age: 17.9–53.5 | Evaluate the articulation skills of NF1 school children and adults | Children’s phonetic inventory was incomplete for their age: realizations of the sibilants/R/and/or/a/were not totally correct. Distortions were the predominant phonetic error type and rhotacismus non vibrans were frequently observed. There were also substitution and syllable structure errors, particularly deletion of the final consonant of words. Girls tended to display more articulation errors than boys |
| Debrabant et al. (18) | Case–control study | 3d | 20 NF1 20 controls Age: 8–12 |
Evaluate visual-motor reaction time and its association to the impairment of fine visual-motor skills in children with NF1 | Children with NF1 responded more slowly and with fewer anticipatory responses to predictive stimuli, after controlling for IQ and processing speed. Predictive reaction time performance did not differ from reaction time to unpredicted stimuli, indicating an inability to adopt rhythmic stimuli. All children with NF1 scored below the normal range (percentile 16) on the Movement Assessment Battery for Children, Second edition. Finally, the NF1 group demonstrated a significantly poorer performance on the Beery-Buktenica Developmental Test of Visual-Motor Integration copy test, showing reduced visual-motor integration and tracing outcomes (eye–hand coordination) |
| Galasso et al. (21) | Case–control study | 3d | 18 NF1 Mean age: 11.00 ± 2.87 18 ADHD Mean age: 11.17 ± 2.92 18 controls Mean age: 11.22 ± 2.80 |
Evaluate specific planning deficits in children with NF1 in relation to ADHD comorbidity | They found no correlation between Tower of London test scores and Conners ratings scale for parents’ scores in children with NF1. The authors concluded that planning and problem-solving deficits are not directly related to inattention level |
| Gilboa et al. (19, 23) | Case–control study | 3d | 30 NF1 Age: 8–16.6 30 controls Age: 8.4–16.3 |
Evaluate NF1 children performance in lower and higher processes required for intact writing; and to identify predictors of the written product’s spatial arrangement and content | Children with NF1 performed significantly poorer on higher-level processes, evaluated using the Rey Complex Figure Test for cognitive planning skills and the Hebrew version of the Wechsler Intelligence Scale for Children for verbal intelligence. Cognitive planning skills predicted the written product’s spatial arrangement and verbal intelligence scores predicted the written content level |
| Gilboa et al. (19, 23) | Case–control study | 3d | 29 NF1 Mean age: 12.3 ± 2.6 27 controls Mean age: 12.4 ± 2.5 |
Identify a possible relation between executive function and academic skills in children with NF1 | Children with NF1 performed significantly lower on four of the BRIEF scales (initiate, working memory, plan/organize, and organization of materials) and two subtests of the BADS-C (water and key search). Significant correlations were shown between BADS-C subtest scores and ACES scale scores: children who scored higher (better performance) on the BADS-C received higher scores (better performance) from their teachers on the ACES. In addition, children who received higher scores (performed better) on the ACES received lower scores from their parents (performed better) on the BRIEF |
| Huijbregts et al. (37) | Case–control study | 3d | 15 NF1 Mean age: 12.9 ± 2.6 18 controls Mean age: 13.8 ± 3.6 |
Evaluate volumetric measures of cortical and subcortical brain regions in children with NF1 and its possible association with social skills, attention problems and executive dysfunction | Larger left putamen volume, larger total white matter volume, and smaller precentral gyrus gray matter density in children with NF1 were associated with more social problems (evaluated using Child Behavior Checklist parent ratings). Larger right amygdala volume in children with NF1 was associated with autistic mannerisms (evaluated using Social Responsiveness Scale parent ratings) |
| Isenberg et al. (12) | Case–control study | 3d | 55 NF1 Mean age: 9.71 ± 2.63 No control group, normative data was used |
Evaluate attention skills in children with NF1 using measures of visual and sustained auditory attention, divided normative attention, selective attention, and response inhibition | Deficits in sustained visual and auditory attention, and deficits in divided attention and response inhibition were identified in Children with NF1 |
| Lehtonen et al. (13) | Case–control study | 3d | 49 NF1 Mean age: 11.75 ± 3.16 19 healthy siblings Mean age: 12.58 ± 2.58 29 healthy children-community Mean age: 11 ± 2.58 |
Evaluate cognitive skills in children with NF1 | Children with NF1 had significantly lower Full-scale IQs and lower academic achievement than their siblings. Compared with their siblings, they also had significantly poorer visuospatial processing, visual associate learning, non-verbal working memory, and executive function |
| Lidzba et al. (44) | Retrospective case–control study | 3d | 43 NF1: 16 without ADHD, 27 with ADHD (13 medicated) Age range: Tl, 6–14 years; T2, 7–16 years; mean interval, 49.09 months |
Evaluate possible benefits of methylphenidate in cognitive functioning in children with NF1 and comorbid ADHD | Medicated children with NF1 improved significantly in full-scale IQ between two periods of time, this effect was not evident for the other groups. With attention measures as covariates, the effect remained marginally significant. |
| Lidzba et al. (25) | Retrospective Case–control study | 3d | 111 NF1: 36 without ADHD, 62 ADD, 13 ADHD. Age range: 6–16 | Evaluation of the influence of ADHD symptoms on the intellectual profile of patients with NF1 | Patients with ADHD symptoms performed significantly worse than those without ADHD symptoms on all intelligence measures (main effects for Full-scale, Verbal, and Performance IQ). Subtests typically impaired in patients with NF1 (visuospatial skills and arithmetic) were not specifically influenced by ADHD symptoms. There were no differences between ADHD subtypes |
| Lion-Francois etal (45) | Randomized, double blind, placebo controlled, and crossover trial | lc | 39 NF1 (80 < IQ > 120) Age: 7.9–12.9 | Evaluate possible benefits of methylphenidate in cognitive functioning in children with NF1 and comorbid ADHD | The Simplified Conners’ Parent Rating Scale scores decreased by 3.9 points in medicated children |
| Loitfelder et al. (38) | Cross-sectional study | 4b | 14 NF1 Mean age: 12.49 ± 2.65 30 controls Mean age: 12.30 ± 2.94 |
Evaluation of functional connectivity in relation to the cognitive profile of children with NF1 | Associations of increased frontofrontal and functional connectivity with cognitive, social, and behavioral deficits were found. Children and adults with NF1 showed deficient activation of the low-level visual cortex and specific impairment of the magnocellular visual pathway |
| Michael et al. (15) | Case–control study | 3d | 20 NF1 20 controls Age: 7–13 |
Evaluation of reactivity to visual signals in children with NF1 and its alteration as a possible cause of attention instability | The NF1 group exhibited slower global responses on measures of response time and weakened resistance to interference, leading to difficulties in the ability to continuously focus on a primary task |
| Orraca-Castillo et al. (9) | Case–control study | 3d | 32 NF1 Age: 7–14 No control group, normative sample was used |
Evaluate children with NF1 through neurocognitive tests dedicated to assess basic capacities which are involved in reading and mathematical achievement | Core numeric capacities do not seem to be responsible for calculation dysfluency in NF1 children. Word decoding deficits and poor number facts retrieval seem to be good predictors of dyslexia and dyscalculia, respectively. A high prevalence of developmental dyslexia was identified |
| Payne et al. (22) | Case–control study | 3d | 49 NF1 Mean age: 11 ± 2.3 35 NF1 + ADHD Mean age: 10.6 ± 2.3 30 controls Mean age: 10 ± 2.6 |
Evaluate if executive dysfunction is exacerbated by comorbid diagnosis of ADHD in children with NF1 | Compared with typically developing children, children with NF1 with or without comorbid ADHD demonstrated significant impairment of both spatial working memory (SWM) and inhibitory control. There were no differences between the two NF1 groups in SWM or response inhibition |
| Payne et al. (14) | Case–control study | 3d | 71 NF1 Median age: 10.5 29 controls Median age: 10 |
Identify interrelationships between visuospatial learning and other cognitive abilities that may influence performance, such as intelligence, attention and visuospatial function in children with NF1 | Children with NF1 displayed significant impairments in visuospatial learning, with reduced initial retention and poorer learning across repeated trials. Visuospatial learning was inferior in NF1 even after accounting for group differences in intelligence, sustained attention and visuospatial abilities |
| Payne et al. (33) | Prospective cohort study | 3c | 18 NF1 Age: 8–16.8 5 controls Age: 8.9–15.2 |
Determine the natural history of cognitive function and T2H from childhood to adulthood and to examine if the presence of discrete T2H in childhood can predict cognitive performance in adulthood | Longitudinal analyses revealed a significant increase in general cognitive function in patients with NF1 over the study period. Improvements were limited to individuals with discrete T2H in childhood. Patients without lesions in childhood exhibited a stable profile. The number of T2H decreased over time, particularly discrete lesions. Lesions located within the cerebral hemispheres and deep white matter were primarily stable, whereas those located in the basal ganglia, thalamus and brainstem tended to resolve |
| Piscitelli et al. (35) | Case–control study | 3d | 49 NF1: 32 withT2H in cerebellum, 18 without T2H. Age: 6–16.9 | Evaluate the neuropsychological profile in order to establish the clinical meaning of T2H in the cerebellum of children with NF1 | Patients with T2H in the cerebellum showed a lower IQ than those without. T2H-positive patients showed clinical impairment more frequently than T2H-negative patients, although the group differences were not statistically significant |
| Pride et al. (24) | Restrospective case–control study | 3d | 132 NF1 60 NF1 + ADHD 52 unaffected controls Age: 6–16 |
Determine if cognitive and academic functioning are affected by comorbid ADHD in patients with NF1 | Children with NF1 and ADHD performed significantly worse on measures of mathematical reasoning, receptive language, sustained attention, reading, and spelling compared with children with NF1 only. Children with NF1 and ADHD were also rated more severely by parents and teachers on the BRIEF than the NF1 only group |
| Ribeiro et al. (16) | Case–control study | 3d | 17 NF1 19 controls Age: 8–17 |
Investigate the neural mechanisms underlying the visual deficits of children with NF1 by using visual evoked potentials and brain oscillations during visual stimulation and rest periods | Abnormal long-latency visual evoked potentials may be related to deficits in high-level processing of visual stimuli; a specific enhancement of alpha brain oscillations related to problems in attention allocation |
| Roy et al. (34) | Case–control study | 3d | 36 NF1 36 controls Age: 7–12.9 years |
Compare executive functioning profile with characteristics of T2H i children with NF1 | Executive dysfunction in children with NF1 was not significantly influenced by T2H presence, number, size, and location (whole brain or specific areas) |
| Roy et al. (26) | Case–control study | 3d | 30 NF1 60 controls Age: 7–12 |
Investigate spontaneous versus reactive cognitive flexibility in children with NF1 and their comorbidity with ADHD | NF1 children performed worse than healthy children on both spontaneous and reactive cognitive flexibility tasks, even when intelligence and basic skills were partially excluded. However, ADHD symptomatology did not adversely affect performance |
| Van der Vaart et al. (42) | Randomized, double-masked, placebo-controlled trial | lc | 84 NF1: 43 simvastatin, 41 placebo Age: 8–16 |
Assess the use of simvastatin for the improvement of cognitive and behavioral deficits in children with NF1 for 12 months | Simvastatin for 12 months had no effect on full-scale intelligence, attention, and internalizing behavioral problems |
| Violante et al. (39) | Case–control study | 3d | 15 NF1 24 controls Age: 7–17 |
Investigate the activation pattern of high-level visual and non visual regions modulated by the different stimuli to examine possible functional consequences of low-level visual impairments | Children and adults with NF1 showed deficient activation of the low-level visual cortex, indicating that low-level visual processing deficits do not ameliorate with age. There was specific impairment of the magnocellular visual pathway in early visual processing associated with a deficient deactivation of the default mode network |
| Walsh et al. (30) | Retrospective, cross-sectional study | 4b | 66 NF1 Age: 6–12 |
Evaluate systematically, symptoms of autism spectrum disorder in children with NF1 | Forty percent of the NF1 sample showed symptom levels that reached clinical significance on the Social Responsiveness Scale, and 14% showed levels consistent with those seen in children with autism spectrum disorder (ASD). These raised symptom levels were not explained by NF1 disease severity or externalizing and internalizing behavioral disorders. There was a statistically significant relationship between symptoms of ADHD and ASD |
| Wessel et al. (10) | Longitudinal cohort study | 3c | 124 NF1 Age: 0–8 |
Determine the age of presentation for specific areas of delay in children with NF1 and the time-dependent progression of these deficits | School-age children exhibited significantly more areas of delay than infants or preschool-age children. Delays in math, reading, gross motor, fine motor, and self-help development were observed more frequently in older than younger children. Analysis of 43 subjects for whom longitudinal assessments were available revealed that children often migrated between delayed and nondelayed groups in all areas except gross motor development |
ACES, Academic Competence Evaluation Scales; BADS-C, Behavioral Assessment of the Dysexecutive Syndrome in Children; BRIEF, Behavior Rating Inventory of Executive Function; CC, Corpus Callosum; ADD, Attention-Deficit Disorder; ADHD, attention-deficit/hyperactivity disorder; JLO, Judgment of Line Orientation; NF1, Neurofibromatosis type 1; T2H, T2-hyperintensities.