Pku neuro psych webinar

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Pku neuro psych webinar

  1. 1. Understanding and Managing the Neurocognitive and Psychiatric Issues Associated with PKU
  2. 2. Key Points <ul><li>Awareness </li></ul><ul><ul><li>Even patients following dietary restrictions can experience PKU-related neurocognitive and psychiatric issues </li></ul></ul><ul><li>Assessment </li></ul><ul><ul><li>Patient assessment is the first step in the management process </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Strategies for improving patient functioning exist </li></ul></ul><ul><ul><li>Control blood phe levels </li></ul></ul><ul><ul><li>Address comorbid conditions </li></ul></ul>
  3. 3. Learning Objectives <ul><li>Understand the susceptibility of patients with PKU to neurocognitive and psychiatric complications. </li></ul><ul><li>Be aware of the neurocognitive testing used to gauge neurocognitive function in patients with PKU. </li></ul><ul><li>Recognize patients with neurocognitive impairment and participate in referral to a psychologist. </li></ul><ul><li>Determine if a patient’s history or clinical presentation is consistent with a comorbid psychiatric condition. </li></ul><ul><li>Recognize patients with psychiatric comorbidity and participate in referral to a psychologist or psychiatrist. </li></ul>
  4. 4. Lecture Overview <ul><li>Review of PKU </li></ul><ul><li>Neurocognitive complications </li></ul><ul><li>Psychiatric issues </li></ul><ul><li>Management of neurocognitive and psychiatric issues </li></ul>
  5. 5. Review of PKU <ul><li>Rare, chronic, metabolic disorder </li></ul><ul><li>Approximately 1 of every 15,000 infants in US is born with PKU </li></ul><ul><li>Deficiency of liver enzyme phenylalanine hydroxylase (PAH); therefore, phenylalanine (phe) accumulates in blood and body tissues </li></ul><ul><li>Autosomal recessive disease caused by mutations in the PAH gene </li></ul><ul><li>Wide genetic variability -> wide clinical variability </li></ul>NIH Consensus Development Panel. Pediatrics . 2001;108(4):972-82. Blau, et al. Mol Genet Metabol . 2009;96(4):158-63. Phenylalanine Tyrosine PAH
  6. 6. Dietary Compliance and Blood Phe Levels in Patients with PKU Over Time % Patients Above Recommended Blood Phe Level Walter, et al. Lancet . 2002;360:55-7. N = 178 N = 137 N = 98 N = 77
  7. 7. Lecture Overview <ul><li>Review of PKU </li></ul><ul><li>Neurocognitive complications </li></ul><ul><ul><li>Pathophysiology </li></ul></ul><ul><ul><li>Intelligence / IQ </li></ul></ul><ul><ul><li>Executive function </li></ul></ul><ul><ul><li>Academic performance </li></ul></ul><ul><ul><li>Maternal PKU </li></ul></ul><ul><ul><li>Neurocognitive testing </li></ul></ul><ul><li>Psychiatric issues </li></ul><ul><li>Management of neurocognitive and psychiatric issues </li></ul>
  8. 8. Possible Mechanisms of Neurotoxicity <ul><li>Dopamine depletion </li></ul><ul><ul><li>Dopamine </li></ul></ul><ul><ul><ul><li>Precursor to norepinephrine, epinephrine </li></ul></ul></ul><ul><ul><ul><li>Neurotransmitter essential to executive function </li></ul></ul></ul><ul><li>White matter pathology and disruptions in the interconnectivity between brain regions </li></ul><ul><ul><li>White matter </li></ul></ul><ul><ul><ul><li>Myelin insulates nerve fibers found in white matter which increases speed of transmission of nerve signals (mental processing speed) </li></ul></ul></ul><ul><ul><ul><li>Excess phe is believed to damage myelin </li></ul></ul></ul>Anderson, et al. Mol Genet Metabol . 2010;99(S1):3-9. Christ, et al. Mol Genet Metabol . 2010;99(S1):22-32. De Groot, et al. Mol Genet Metabol . 2010;99(S1):86-9.
  9. 9. Prefrontal Cortex <ul><li>Area of the brain that supports various neurocognitive activities, including executive function </li></ul><ul><li>PKU-associated dopamine dysregulation -> </li></ul><ul><ul><li>Disruption of prefrontal cortex (PFC) function </li></ul></ul><ul><ul><li>Poor performance on measures of executive function </li></ul></ul>De Sonneville, et al. Mol Genet Metabol . 2010;99(S1):10-17. Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.
  10. 10. Vulnerable Neurocognitive Domains Moyle, et al. Neuropsychol Rev . 2007;17(2):91-101. Motor Skills Information Processing Speed Inhibitory Control Working Memory Attention IQ PKU
  11. 11. Intelligence / IQ <ul><li>Robust relationship between blood phe levels and IQ </li></ul><ul><li>Early-treated children experience loss of IQ if diet is discontinued </li></ul><ul><li>Those who continue diet are more likely to achieve greater IQ / academic success </li></ul>Brumm, et al. Mol Genet Metabol . 2010;99(S1):18-21.
  12. 12. IQ in Patients with PKU Comparison to Peer Group 1 Comparison to Siblings 2 P < 0.0001 P < 0.001 N = 21 N = 55 N = 55 N = 26 IQ (Wechsler Intelligence Scale) 1) Gassio, et al. Pediatr Neurol . 2005;33(4):267-71. 2) Koch, et al. J Inherit Metab Dis . 1984;7(2):86-90.
  13. 13. Impact of Blood Phe Levels on IQ N = 3361 Waisbren, et al. Mol Genet Metabol . 2007;92:63-70. Observation Period Blood Phe Levels ( μ mol/L) Lifetime IQ Loss for Each 100 μ mol/L ↑ in Blood Phe 0 - 12 years old 423 - 750 1.3 - 3.1 points Lifetime 394 - 666 1.9 - 4.1 points
  14. 14. Impact of Blood Phe Variability on IQ <ul><li>Study design </li></ul><ul><ul><li>Retrospective review </li></ul></ul><ul><ul><li>N = 46 children under dietary control </li></ul></ul><ul><li>Study results </li></ul><ul><ul><li>Inverse relationship between FSIQ and blood phe levels </li></ul></ul><ul><ul><li>FSIQ ↓ 4.3 points for every 1 point ↑ in standard deviation of blood phe levels </li></ul></ul><ul><ul><li>Patient (7 y.o. female) with low blood phe variability -> IQ = 116 </li></ul></ul><ul><ul><li>Patient (6 y.o. male) with high blood phe variability -> IQ = 92 </li></ul></ul><ul><ul><li>Stability of blood phe levels may have a greater impact on cognitive functioning than total exposure to phe in well-treated children. </li></ul></ul>Anastasoaie, et al. Mol Genet Metab . 2008;95:17-20.
  15. 15. Executive Function <ul><li>Higher-order cognitive abilities </li></ul><ul><li>Working memory </li></ul><ul><li>Inhibitory control </li></ul><ul><li>Cognitive flexibility </li></ul><ul><li>Decision making </li></ul><ul><li>Problem solving </li></ul><ul><li>Abstract reasoning </li></ul><ul><li>Planning / organization </li></ul><ul><li>Strategic planning </li></ul>De Sonneville, et al. Mol Genet Metabol . 2010;99(S1):10-17. Christ, et al. Mol Genet Metabol . 2010;99(S1):22-32. Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.
  16. 16. Role of Executive Function in Self-Management Executive Task Plan diet Maintain supplies of formula and supplements Record phe intake Resist restricted foods (inhibitory control) Take blood phe levels Adjust diet based on blood phe levels
  17. 17. PKU Adult Collaborative Study Preliminary Review <ul><li>Study design </li></ul><ul><ul><li>Neurocognitive testing in early-treated adults (N = 24) </li></ul></ul><ul><li>Study results </li></ul><ul><ul><li>Intelligence – IQ scores in normal range </li></ul></ul><ul><ul><li>Neurocognitive deficits </li></ul></ul><ul><ul><ul><li>Executive function, attention, verbal memory, verbal fluency, expressive naming </li></ul></ul></ul><ul><ul><ul><li>Deficits were more pronounced in patients with high blood phe levels (> 1000 μ mol/L) </li></ul></ul></ul><ul><ul><ul><li>Greater correlation between deficits and blood phe level during childhood compared to current blood phe level </li></ul></ul></ul>Brumm, et al. J Inherit Metab Dis . 2004(27):549-566.
  18. 18. Neurocognitive Outcomes in Early-Treated PKU <ul><li>Study design </li></ul><ul><ul><li>Meta-analysis of 33 primary studies with 200 patient outcomes (time period: 1980-2004) </li></ul></ul><ul><li>Study results </li></ul><ul><ul><li>Intelligence – moderately lower IQ scores </li></ul></ul><ul><ul><li>Neurocognitive deficits </li></ul></ul><ul><ul><ul><li>Significantly impaired executive functions – working memory, inhibitory control, cognitive flexibility, planning </li></ul></ul></ul>DeRoche, et al. Dev Neuropsychol . 2008;33(4):474-504.
  19. 19. Executive Function in Patients with PKU vs. Control Group Leuzzi, et al. J Inherit Metab Dis . 2004;27(2):115-25. P < 0.001 P < 0.05
  20. 20. Working Memory in Patients with PKU vs. Control Group P < 0.05 (all domains) Mean Span White, et al. J Int Neuropsychol Soc . 2002;8:1-11.
  21. 21. Inhibitory Control in Patients with PKU vs. Control Group * P < 0.05 vs. control * Number of Errors Christ, et al. Dev Neuropsychol . 2006;30(3):845-64.
  22. 22. Strategic Planning in Patients with PKU vs. Normative Data P < 0.05 vs. normative data * * N = 15 VanZutphen, et al. Clin Genet . 2007;72(1):13-8. Test Score
  23. 23. Information Processing Speed in Patients with PKU vs. Control Group Anderson, et al. Dev Neuropsychol . 2007;32(2):645-68. Test Score Time to Rapid Retrieval P < 0.01 vs. control (all domains)
  24. 24. Memory and Learning Impairments in Patients with PKU White, et al. Neuropsychol . 2001;15(2):221-9. Words Recalled * P < 0.05 vs. control * California Verbal Learning Test Patients up to 11 y.o. Patients ≥ 11 y.o.
  25. 25. Motor Issues and Perception <ul><li>Motor skills </li></ul><ul><ul><li>Dexterity; hand-wrist steadiness and speed </li></ul></ul><ul><li>Perception and visual-spatial difficulties </li></ul><ul><ul><li>Sensitivity to visual contrast </li></ul></ul>Janzen, et al. Mol Genet Metabol . 2010;99(S1):47-51.
  26. 26. Preserved Functional Areas <ul><li>Developmental milestones </li></ul><ul><li>Language </li></ul><ul><ul><li>Expressive and receptive language skills </li></ul></ul><ul><li>Gross motor coordination </li></ul>Janzen, et al. Mol Genet Metabol . 2010;99(S1):47-51.
  27. 27. Academic Performance <ul><li>Academic difficulties due to: </li></ul><ul><li>Executive functioning deficits </li></ul><ul><li>Information processing speed deficits </li></ul><ul><li>ADHD </li></ul>Antshel, et al. Mol Genet Metabol . 2010;99(S1):52-8.
  28. 28. Academic Difficulties in Patients with PKU vs. Control Group * P < 0.05 vs. control * % Students Gassio, et al. Pediatr Neurol . 2005;33(4):267-71.
  29. 29. Maternal PKU <ul><li>Risks to children born to women with untreated maternal PKU: </li></ul><ul><li>Mental retardation (92% risk) </li></ul><ul><li>Microcephaly </li></ul><ul><li>Congenital heart disease </li></ul><ul><li>Low birth weight </li></ul><ul><li>Other issues: </li></ul><ul><li>Postnatal growth retardation </li></ul><ul><li>Mild craniofacial dysmorphism </li></ul><ul><li>Neurological abnormalities </li></ul><ul><li>Behavioral problems </li></ul><ul><li>M etabolic control must be achieved early and consistently </li></ul><ul><li>throughout the pregnancy to prevent or minimize complications </li></ul>Brumm, et al. Mol Genet Metabol . 2010;99(S1):18-21. Koch, et al. Mol Genet Metabol. 2010;99 (S1):68-74.
  30. 30. Neurocognitive Testing * BRIEF-P (preschool version) is available for children aged 2-5 years old. Christ, et al. Mol Genet Metabol . 2010;99(S1):22-32. Janzen, et al. Mol Genet Metabol . 2010;99(S1):47-51. Neurocognitive Domain Test / Assessment Intelligence / IQ Wechsler intelligence scale Executive function • Working memory, attention • Inhibitory control, cognitive flexibility • Planning / organization Behavior rating inventory of executive function (BRIEF*) • Digit span; self-ordered pointing test; trail making test • Stroop color-word test; Wisconsin card sorting test; tower tasks; test of everyday attention for children • Rey-Osterreith complex figure test; tower tasks Non-executive function • Information processing speed • Motor skills • Memory and learning • Symbol digit coding; finger tapping test; trail making test • Purdue test; Peabody developmental motor scales • California verbal learning test; Rey learning tests Academic performance Teacher/parent reports; academic testing Social-emotional adjustment Quality of life questionnaires
  31. 31. Lecture Overview <ul><li>Review of PKU </li></ul><ul><li>Neurocognitive complications </li></ul><ul><li>Psychiatric issues </li></ul><ul><ul><li>Psychosocial impact of neurocognitive impairment </li></ul></ul><ul><ul><li>Psychiatric and psychological comorbidities </li></ul></ul><ul><ul><li>Psychiatric symptoms </li></ul></ul><ul><ul><li>ADHD </li></ul></ul><ul><ul><li>Psychiatric evaluation </li></ul></ul><ul><ul><li>Patient referral and management </li></ul></ul><ul><li>Management of neurocognitive and psychiatric issues </li></ul>
  32. 32. Psychosocial Impact of PKU-Related Neurocognitive Impairment <ul><li>Self-esteem </li></ul><ul><li>Interpersonal skills </li></ul><ul><li>Social competence </li></ul><ul><li>Relationships </li></ul><ul><li>Academic difficulties </li></ul><ul><li>Quality of life </li></ul>Gentile, et al. Mol Genet Metabol . 2010;99(S1):64-67. Feillet, et al. Mol Genet Metabol . 2010;99(S1):79-85.
  33. 33. Common Psychiatric and Psychological Comorbidities <ul><li>ADHD </li></ul><ul><li>Depression </li></ul><ul><li>Anxiety and phobias </li></ul><ul><li>Other: </li></ul><ul><li>Behavior problems, social dysfunction </li></ul>Antshel, et al. Mol Genet Metabol . 2010;99(S1):52-8. Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63.
  34. 34. Psychiatric Symptoms in PKU ↓ Positive Emotions Less joy, happiness, confidence, autonomy, social competence ↑ Negative Emotions More depression, anxiety, phobias, social isolation Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Feillet, et al. Mol Genet Metabol . 2010;99(S1):79-85.
  35. 35. Psychiatric Symptoms in PKU Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Untreated Individual Early-Treated Child Early-Treated Adult Aggression Attention problems Decreased positive emotions Anxiety Decreased autonomy Depression Autistic behaviors Decreased social competence Generalized anxiety Depression Less achievement motivation Lack of autonomy Hyperactivity Low self-esteem Low self-esteem Impaired social skills School problems Phobias Psychotic symptoms Social isolation/withdrawal Social withdrawal Social maturity deficits
  36. 36. Psychiatric Symptoms in Patients with PKU vs. Control Group Pietz, et al. Pediatrics . 1997;99(3):345-50. Percent of Adult Patients Reporting Symptom P < 0.05 vs. control (all domains) % % % % % % % % % %
  37. 37. ADHD <ul><li>ADHD and PKU are theoretically linked by low levels of dopamine in the PFC </li></ul><ul><li>Academic underachievement </li></ul><ul><li>Difficulties with math skills </li></ul>Antshel, et al. Mol Genet Metabol . 2010;99(S1):52-8.
  38. 38. Stimulant Use for ADHD in Patients with PKU vs. Control Group Control group = patients with diabetes mellitus Arnold, et al. J Inherit Metab Dis . 2004;27(2)137-43. Control Group (N = 76) PKU (N = 38) Percent of patients using stimulants for ADHD ( P < 0.006) ADHD symptoms were associated with higher blood phe levels
  39. 39. Psychological Issues in Patients with PKU <ul><li>“ The prevalence and severity of problems generally correlates with the timing and degree of exposure to elevated blood phe levels.” </li></ul>Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63.
  40. 40. Psychological Issues in Patients with PKU: Clinical Features and Presentation <ul><li>Stress of chronic illness </li></ul><ul><li>Burden of dietary restrictions </li></ul><ul><li>Symptom overlap vs. independent condition </li></ul><ul><li>Diagnostic overshadowing* </li></ul><ul><ul><li>Symptoms are misattributed to one condition without consideration of a second comorbid condition </li></ul></ul><ul><li>Delayed diagnosis, misdiagnosis </li></ul>* Antshel, et al. Mol Genet Metabol . 2010;99(S1):52-8.
  41. 41. Psychiatric Evaluation <ul><li>Monitor the emotional and behavioral well-being of patients with PKU </li></ul><ul><li>Intervene and refer before psychiatric symptoms and counterproductive behaviors initiate a vicious cycle of poor dietary control, elevated blood phe levels, and worsening symptoms </li></ul>Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Poor dietary control Elevated blood phe levels Psychiatric symptoms
  42. 42. Assessment by Non-Psychologists Psychological Realm Test / Assessment Adaptive functioning Adaptive behavior assessment system (ABAS-II) Behavior Behavior assessment system for children (BASC-II) Executive function Behavior rating inventory of executive function (BRIEF) (BRIEF-P = preschool version for children aged 2-5 years old)
  43. 43. Patient Referral and Management <ul><li>Referral to: </li></ul><ul><ul><li>Psychologist </li></ul></ul><ul><ul><li>School psychologist (children) </li></ul></ul><ul><ul><li>Psychiatrist </li></ul></ul><ul><ul><li>Other mental health professional (e.g. social worker, licensed professional counselor) </li></ul></ul><ul><li>Management plan </li></ul>Schmidt, et al. J Clin Exp Neuropsychol . 1994;16(5):681-8. Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Reintroduction of strict dietary control is recommended for patients displaying neurocognitive or psychiatric symptoms
  44. 44. Lecture Overview <ul><li>Review of PKU </li></ul><ul><li>Neurocognitive complications </li></ul><ul><li>Psychiatric issues </li></ul><ul><li>Management of neurocognitive and psychiatric issues </li></ul>
  45. 45. Management of Neurocognitive and Psychiatric Issues <ul><li>Recognition </li></ul><ul><li>Dietary restrictions have improved patient outcomes, but often this intervention alone is not enough. </li></ul>
  46. 46. Management of Neurocognitive and Psychiatric Issues <ul><li>Empowerment </li></ul><ul><li>All healthcare professionals can take action to screen patients for problems, to help patients be more compliant with dietary restrictions, and to refer patients to a psychologist or psychiatrist. </li></ul>
  47. 47. Management of Neurocognitive and Psychiatric Issues <ul><li>Continuation </li></ul><ul><li>Early and ongoing monitoring and intervention helps break the cycle of suboptimal performance. Life-long observation, management and support of patients is critical. </li></ul>
  48. 48. Summary of Key Points <ul><li>Awareness </li></ul><ul><ul><li>Even patients following dietary restrictions can experience PKU-related neurocognitive and psychiatric issues </li></ul></ul><ul><li>Assessment </li></ul><ul><ul><li>Patient assessment is the first step in the management process </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Strategies for improving patient functioning exist </li></ul></ul><ul><ul><li>Control blood phe levels </li></ul></ul><ul><ul><li>Address comorbid conditions </li></ul></ul>

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