Table 1.
Clinical trials targeting cognitive and behavioral outcomes in children with neurofibromatosis type 1
| Reference | Intervention (design) | N (Mean, SD)2 | Key selection criteria | Treatment weeks | Primary outcomes | Secondary outcomes | Findings |
|---|---|---|---|---|---|---|---|
| 5 | Lovastatin (randomized, parallel group, placebo‐controlled, double‐blind) | 146 (11.6, 2.1) | Impaired performance on primary outcome(s); FSIQ ≥ 70 | 16 | CANTAB (PAL); TEA‐Ch (Score) | CANTAB (SST, SWM, SOC); TEA‐Ch (Sky Search, Creature Counting; Sky Search DT); CPT‐II; COWAT; OA; BRIEF‐P; JLO; BASC‐2‐P; BASC‐2‐SR; PedsQL‐P; PedsQL‐SR | Lovastatin did not improve visuospatial learning or attention |
| 6 | Simvastatin (randomized, parallel‐group, placebo‐controlled, double‐blind) | 62 (12.4, 10.4‐14.4)3 | Nil | 12 | RCFT‐recall; Cancellation test; prism adaption; MRI ADC | RCFT‐copy; Stroop CWT; BD and OA; Beery VMI; JLO | No significant effect of simvastatin except for improvement on OA |
| 7 | Simvastatin (randomized, parallel‐group, placebo‐controlled, double‐blind) | 84 (11.2, 7.9‐16.0)3 | No stimulant medication | 52 | CBCL‐P; FSIQ | RCFT, Stroop CWI; Grooved Pegboard; CHQ; CBCL4 | No significant improvement in cognitive deficits or behavioral problems on simvastatin |
| 12 | Methylphenidate (single arm, open‐label) | 201 (10.7, 2.2) | Diagnosed with comorbid ADHD | 52 | TOVA | CBCL‐P; CBCL‐T | Methylphenidate improved cognitive and behavioral attention; decline in aggressive behavior and social problems |
| 13 | Lovastatin (single arm, open‐label, phase 1 escalation trial) | 23 (13.0, 2.4) | History of learning disability; FSIQ > 80 | 12 | TEA‐Ch; CVLT; WRAML‐2 | JLO; Grooved Pegboard; BRIEF‐P; BRIEF‐SR; BASC‐2‐P; WASI | Some improvements in verbal and nonverbal memory after lovastatin use, but not in attention or vigilance |
| 14 | Simvastatin (randomized, parallel group, placebo‐controlled, triple‐blind) | 30 (8.1, 1.8) | Diagnosed with comorbid ASD; T > 60 on SRS | 12 | ABC; CGI‐S; Conners3; Resting state fMRI, MRI MRS (GABA, Glx), ADC, ASL, peripheral MAPK assay | Nil | Possible effect of simvastatin in brain regions associated with NF1 pathophysiology and social brain network |
| 15 | Lovastatin (randomized, parallel group, placebo‐controlled, double‐blind) | 44 (25.7, 11.6) | FSIQ ≥ 70 | 14 | BVMT‐R; LNS | HVLT; Cancellation test; OA; CBCL‐P; CBCL‐SR; fMRI | Significant improvement on nonverbal declarative memory, working memory, and categorical verbal generation; significant improvement in internalizing symptoms for adult patients |
| 16 | Methylphenidate (randomized, crossover, placebo‐controlled) | 39 (9.3, 1.8) | FSIQ between 80‐120; attention problems, school problems | 9 | SCRS‐P | CRS‐T; CDRS; CDI; STAI‐C | Methylphenidate improved parent rated ADHD symptoms |
Abbreviations: ABC, Aberrant Behavior Checklist; ADC, apparent diffusion coefficient; ADHD, attention deficit/hyperactivity disorder; ASD, autism spectrum disorder; ASL, arterial spin labelling; BASC‐2‐P, Behavior Assessment System for Children, Second Edition, Parent Form; BD, Wechsler Block Design; Beery‐VMI, Beery Developmental Test of Visual Motor Integration; BRIEF‐P; Behavior Rating Inventory of Executive Function, Parent Report; BRIEF‐SR, Behavior Rating Inventory of Executive Function, Self‐Report; BVMT, Brief Visuospatial Memory Test Revised; CANTAB, Cambridge Neuropsychological Test Automated Battery; CBCL‐P, Child Behavioral Checklist, Parent Report; CBCL‐SR, Child Behavioral Checklist, Self‐Report; CBCL‐T, Child Behavioral Checklist, Teacher Report; CDI, Children’s Depression Inventory; CDRS, Children’s Depression Rating Scale; CGI‐S, Clinical Global Impression Scale; COWAT, Controlled Oral Word Association Test; CPT‐II, Continuous Performance Test, Second Edition; CRS‐T, Conners’ Teacher Rating Scale; CVLT, California Verbal Learning Test; CWT, Color Word Interference test; fMRI, functional magnetic resonance imaging; FSIQ, Full Scale Intelligence Quotient; GABA, gamma‐aminobutyric acid; Glx, glutamate + glutamine; JLO, Judgement of Line Orientation; LNS, Wechsler Letter Numer Sequencing; MAPK, Mitogen‐activated protein kinase; NF1, neurofibromatosis type 1; OA, Wechsler Object Assembly test; PAL, Paired Associative Learning; PedsQL‐P, Pediatric Quality of Life Inventory, Parent; PedsQL‐SR, Pediatric Quality of Life Inventory, Self Report; RCFT, Rey Complex Figure Test; SCRS‐P, simplified Conners’ Parent Rating Scale; SOC, Stockings of Cambridge; SRS, Social Responsiveness Scale; SST, Stop Signal Task; STAI‐C, State‐Trait Anxiety Inventory for Children; SWM, Spatial Working Memory; TEA‐Ch, Test of Everyday Attention for Children; TOVA, Test of Variables of Attention; WRAML‐2, Wide Range Assessment of Memory and Learning, Second Edition.
1NF1 participants only.
2Years of age.
3Median (interquartile range).
4Teacher and youth self‐report.