1 / 70

Brain and Cognitive Correlates in Neurofibromatosis, type 1

Brain and Cognitive Correlates in Neurofibromatosis, type 1. Bart Moore, Ph.D. Children’s Cancer Hospital Univ. Texas M. D. Anderson Cancer Center Houston, Texas. Background. History of NF1 First Description Recognized for centuries Friedrich von Recklinghausen 1882

kimberly
Download Presentation

Brain and Cognitive Correlates in Neurofibromatosis, type 1

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Brain and Cognitive Correlates in Neurofibromatosis, type 1 Bart Moore, Ph.D. Children’s Cancer Hospital Univ. Texas M. D. Anderson Cancer Center Houston, Texas

  2. Background • History of NF1 • First Description • Recognized for centuries • Friedrich von Recklinghausen • 1882 • Genetic nature noted in early 1900s • Causative gene identified 1990

  3. Background • Genetics • Autosomal dominant disorder • Fully penetrant, variably expressed • Mutations in NF1 gene • Located on chromosome 17q11. 3 • Produces neurofibromin

  4. Background • Mortality • Phenotypic features increase with age • Shortened life-span • Childhood deaths • Intracranial tumors • MPNST, Leukemia, or embryonal tumors • Adult Deaths • MPNST, and sarcomas • GI bleeding, severe seizures, hydrocepahlus, and hypertension

  5. General Features of Neurofibromatosis, type 1 (NF) • Autosomal dominant genetic disorder resulting from a mutation on chromosome 17 • Has an incidence of about 1 in 3500 • One-half of new cases are spontaneous mutations (50% are inherited) • Offspring of a parent with NF have about a 50-50 chance of inheriting the disorder • Clinical manifestations are quite variable, but generally become more severe with age • Often mistaken for the “Elephant-Man” syndrome (Proteus syndrome) • Currently, there is no cure or effective treatment

  6. Clinical Features of NF • Cutaneous café-au-lait spots • Axillary freckling • Subcutaneous neurofibromas • Plexiform neurofibromas • Brain tumors, primarily optic glioma • Orthopedic malformations (eg., scoliosis) • Family history • Macrocephaly • Learning disability and behavioral problems A diagnosis of NF requires two of the above criteria

  7. What makes NF-1 so interesting from a neuropsychological standpoint • 40-50% incidence of learning disability, specific cognitive impairments (eg., visual spatial abilities), and ADHD • 60-70% incidence of brain “hyperintensities” in cortical and subcortical white matter (UBOs) in children but not adults • Cognitive profile similar to traumatic brain injury (language deficits are also common). • 15-20% incidence of brain tumors • 30-40% incidence of macrocephaly • Could there be a neuroanatomical basis for the cognitive and behavioral features of NF-1?

  8. Neurological Factors Cognitive Impairments Learning Disability Brain tumors Behavioral Factors Macrocephaly UBOs White matter? Corpus Callosum?? Cognitive, Learning, Behavioral, and Neuroanatomical Features of NF-1: Is There a Connection?

  9. Intelligence in Children and Adolescents with NF: A Meta Analysis (From North, et al, 1997)

  10. Math Performance Proportion with scores at least 1 SD below average

  11. Academic Profile • It is commonly reported that 40% have a cognitive or learning disability • 50% are described by parents as having “school problems” • One-third have repeated a grade • One-half are in a special class

  12. (N=90) Pediatric Research, 1994,35:25 (abstract)

  13. Longitudinal research using individual growth curve statistical methodology • In general, growth in math and overall IQ is positive and comparable to normal, but lower. • But growth in Verbal IQ declines with age • Presence of UBOs resulted in faster growth in Performance IQ Long,Swank, Slopis, Moore (2000). Cognitive profile and academic achievement of children with neurofibromatosis: a longitudinal study using individual growth curves. J Intl Neuropsychological Soc,6(2):165.

  14. What could cause these problems? • Cranial tumors • Brain “hyperintensities” • Macrocephaly • Abnormalities of cortical development • Abnormalities of cortical function

  15. CNS Tumors in NF 1 • In patients referred for non-ophthalmologic reasons to NF clinic: • 15% had optic gliomas • <20% with gliomas were symptomatic Listernick et al. J Pediatr 1989;114:788-92

  16. Optic Nerve & Pathway Gliomas

  17. COG A9952CHEMOTHERAPY FOR PROGRESSIVE LOW GRADE ASTROCYTOMA IN CHILDREN LESS THAN TEN YEARS OLD A Phase III Intergroup COG Study PRIMARY GOALS To compare the event-free survival as a result of treatment with either carboplatin and vincristine (CV*) or a combination of thioguanine, procarbazine, CCNU, and vincristine (TPCV). SECONDARY GOALS: To estimate tumor response, toxicity, and QOL to each regimen of chemotherapy. To investigate biological and clinical factors which may predict tumor response To investigate factors contributing to neuropsychological and endocrine status * NF-1 patients non-randomly assigned to CV regimen

  18. Eligibility for COG 9952 • Residual tumor after surgery or radiographic diagnosis • Further resection would cause unacceptable morbidity • Age less than 10 years old to delay radiation Evidence of tumor progression • Objective growth on MRI - Required for NF • Progressive symptoms prior to diagnosis

  19. Brain Tumors in Children with Neurofibromatosis: Additional Neuropsychological Morbidity?De Winter AE, Moore BD, Slopis JM, Ater JL, Copeland DR, (2000). Neuro Oncology, 1(4):275-281.

  20. De Winter, Moore, Slopis, Ater, & Copeland (1999) Neuro Oncology 1(4);275-281.

  21. NF MRI Hyperintensities, orUBOs (“unidentified bright objects”)

  22. If UBOs diminish with age, does that mean learning disabilities will also?

  23. MRI of 41 year old man with optic glioma and pheochromocytoma, but not NF-1

  24. Neuropsychological Comparisons

  25. School performance for those with and without hyperintensities

  26. So, the mere presence of UBOs does not seem to explain the neurocognitive deficits of children with NF-1 What about their location???

  27. Thalamus Basal Brainstem Cerebral Cerebe - Optic Ganglia Cortex llum paths Moore BD, et al. (1996) . Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis. Neurology, 46 , 1660-8.

  28. Visual Spatial and Visual Motor Tasks are a diagnostic predictor of NF-1 The multivariate combination of visual-spatial/motor tasks proved to be a strong confirmatory test of NF1 diagnosis in that it correctly identified 90% of individuals with clinically identified NF1 (p = .0007) Schrimsher GW, Billingsley RL, Slopis JM, Moore BD (2003). Visual-Spatial performance deficits in children with neurofibromatosis type-1. Am J Med Gen. 120A(3):326-30

  29. In the general population ADHD is more frequently diagnosed in boys than girls Girls more frequently receive the diagnosis of ADD while boys are mostly ADHD or combined What is the pattern of ADHD in children with NF-1?

  30. ADHD Incidence, Subtypes, and Sex Ratios for 91 Children with NF-1

  31. Children in the general population with ADHD are reported to have abnormalities in the morphology of the corpus callosum It is commonly reported that children with NF-1 have a high incidence (40-50%) of ADHD

  32. Corpus Callosum, NF, & ADHD De Winter, et.al., 1999 Related Studies: ADHD vs. controls • Filipek et al. (1997): decreased volumes for subjects with ADHD • Hynd et al. (1991): smaller regional areas for ADHD group • Semrud-Clikeman et al. (1994): smaller splenium measurements for ADHD group • Giedd et al. (1994): smaller rostral and rostral body areas for ADHD group

  33. Corpus Callosum Morphology

  34. Brain Volume in Children with Neurofibromatosis, Type 1:Relation to Neuropsychological Status Moore BD, Slopis JM, Jackson EF, De Winter A, Leeds NE, (2000). Neurology,2000,54:914-920.

  35. Moore, et.al., 2000 Brain Size The BIG MAC hypothesis “This law of proportion of course governs the brain, as well as all else in Nature. …..Large brains must be, and are, more efficient than small ones, when the quality of both is alike…..” Fowler OS. Human Science, or Phrenology. New York, Fowler & Wells, 1873 Washington, DC: 164-165.

  36. Bilateral Basal Ganglia Hyperintensities

  37. Moore, et.al., In Press Brain Volumes (Cm3) from MRI Segmentation

  38. Moore, et.al., In Press R=0.73 p<0.001

  39. Moore, et.al., 2000, Neurology, 54:914-920 Gray/White Matter Ratios Relationship with Age 2.50 NF: r = - 0.62, P= 0.0001 NF Controls: r = - 0.20, P = 0.45 2.00 patients Gray/White Matter volume Control 1.50 Subjects 1.00 0.50 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Age in years

More Related