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Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup

Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup. Are Contamination Fears Justified?. Obsessive Compulsive Disorder in DSM-IV.

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Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup

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  1. Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup Are Contamination Fears Justified?

  2. Obsessive Compulsive Disorder in DSM-IV • Presence of OBSESSIONS – repetitive, intrusive thoughts or concerns; and COMPULSIONS – mental or physical rituals performed repetitively in response to anxiety or compulsive urge • Symptoms are seen as senseless, excessive, or unreasonable • Symptoms cause marked distress, are time-consuming, and/or significantly interfere with normal routine, work/school functioning, and/or social relationships

  3. OBSESSIONS Concerns about: Contamination Safety Right/wrong Intrusive thoughts: Counting Numbers/words Violent images COMPULSIONS Ordering/arranging Symmetry Hoarding/collecting Repeating rituals: Cleaning/Washing Checking Re-reading/writing (Certain # or “just right”) OCD Symptoms in Pediatric Patients

  4. Neurobiology of OCD • PET scans demonstrate hypermetabolism of orbital frontal cortex and caudate nucleus; normalizes with response to treatment • Structural and functional MRI scans demonstrate abnormalities of cortical/basal ganglia function (subtle abnormalities only) • Neuropsychological deficits, particularly in executive functioning From: Rapoport & Wise

  5. fMRI scan of the Orbitofrontal-Striatal-Thalamocortical Circuit Casey et al. , 2002

  6. Dysfunction in Striatum Dysfunction in GPi

  7. Basal Ganglia Dysfunction in Childhood-onset OCD • CT scans demonstrate decreased caudate size in adult males with childhood-onset • Volumetric changes on structural MRI in caudate, putamen & globus pallidus • Neuropsychological testing deficits • Led to the search for a medical model From: Rapoport & others

  8. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections

  9. SYDENHAM CHOREA Sir William Osler – 1894 “perseverativeness” of behavior in choreic children Chapman, Freeman & Grimshaw – increased obsessional neurosis during episode and afterwards NIMH: 75% of SC children have OC symptoms Sao Paulo (1998): 65% have OCD at initial episode and 100% at recrudescence OCD/TIC DISORDERS Post-infectious tics described by vonEconomo & Sellinger in early 1900’s Choreiform movements present in 1/3 of children with OCD Episodic course, abrupt onset in some children with OCD Kiessling – Tic patients have antineuronal antibodies Young children with OCD/tic disorders exacerbate after streptococcal infections Background

  10. Case Example C.B. • 10 year old female awoke one morning “a changed child” • Unable to dress secondary to fears of clothing being contaminated with blood and AIDS, and simultaneous fear that she would give AIDS to others. Fears quickly generalized to anything red and she began washing excessively • Abrupt onset of motoric hyperactivity, twitches and tics, as well as handwriting deterioration • Two days later developed separation anxiety, impulsivity and difficulties with concentration.

  11. Criteria for PANDAS • Presence of OCD and/or Tic Disorder • Prepubertal onset • Episodic course of symptom severity • Association with neurological abnormalities • Temporal relationship between symptom exacerbations and streptococcal infections

  12. COMORBID DIAGNOSES ADHD – 40% ODD – 40% Depression – 36% Dysthymia – 12% Sep. Anxiety – 20% Overanxious – 28% Enuresis – 20% SYMPTOMS DURING EXACERBATIONS Choreiform movements - 95% Emotional lability – 66% School changes – 60% Personality change – 54% Bedtime fears – 50% Fidgetiness – 50% Separation fears – 40% Sensory defensiveness – 40% Irritability – 40% Impulsivity /distraction – 38% Frequency of Comorbid Symptoms in PANDAS

  13. Dysfunction in Striatum Dysfunction in GPi

  14. Neuropsychological Tests of Executive Function BJ Casey et al, 2002

  15. Structural MRI Giedd et al, 2000

  16. Model of Pathogenesis for PANDAS Susceptible Host GABHS Abnormal Immune Response CNS & Clinical Manifestations

  17. Model of Pathogenesis for PANDAS Susceptible Host GABHS Abnormal Immune Response CNS & Clinical Manifestations

  18. Documentation of Etiologic Role for GABHS in Rheumatic Fever • Direct Evidence • GABHS infection prior to rheumatic fever symptoms • Identification of “rheumatogenic” strains of GABHS • Indirect Evidence • Epidemiologic studies showed temporal relationship • Penicillin prophylaxis prevents recrudescences • Rheumatic fever rates declined after antibiotic treatment of GABHS pharyngitis became routine

  19. Epidemiological Evidence of a Relationship Between GABHS and Rheumatic Fever

  20. Point Prevalences for Tics & Behavioral Problems in a Virginia Elementary School Population

  21. ASO TITER -- Y-BOCS --- ASO TITER ---Y-BOCS ---

  22. Azithromycin & Penicillin Prophylaxis Trial GOAL OF THE INVESTIGATION: To establish that azithromycin and penicillin provide effective prophylaxis against GABHS infections for the PANDAS subgroup. HYPOTHESIS OF THE INVESTIGATION: If antibiotics prophylaxis prevents GABHS infections, then neuropsychiatric symptom exacerbations will be decreased.

  23. Penicillin (PCN) vs. Azithromycin (Zith) N = 22 • Streptococcal Infections* • Year Prior to Study 2.0/ subject • Study Year 0.0/ subject • Exacerbations* • Year Prior to Study 2.0/ subject • Study Year .74/ subject *T >5.25; p< 0.01 for both

  24. PENICILLIN AZITHROMYCIN

  25. Model of Pathogenesis for PANDAS Susceptible Host GABHS Abnormal Immune Response Clinical Manifestations

  26. PANDAS – Host Susceptibility • Increased familial rates of OCD & tics • 36/50 (67%) of PANDAS probands had an affected 1o relative • 15% of relatives had OCD • 15% of relatives had tic disorder • Increased familial rates of rheumatic fever • 5/126 (4%) PANDAS parents/grandparents affected • 6/90 (7%) of Sydenham parents/grandparents affected • 3/210 (1.4%) of controls parents/grandparents affected (Lougee et al, 2000)

  27. Host Susceptibility NEUROLOGIC GENETICS VULNERABLE CHILD TYPES OF EXPOSURES IMMUNOLOGIC

  28. Model of Pathogenesis for PANDAS Susceptible Host GABHS Abnormal Immune Response Clinical Manifestations

  29. PANDAS – Abnormal Immune Response • Local • Identification of antineuronal antibodies • Regional • Pathological reports from Sydenham chorea • Volumetric changes in basal ganglia • Systemic • Cytokine abnormalities • Effectiveness of immunomodulatory therapies

  30. Antineuronal Antibodies in OCD/Tics • Kiessling et al. – Serum antibodies recognize human caudate and neuroblastoma cell line • Singer et al. – Antibodies against human caudate & putamen; but also present in 40% controls. • Hallett et al. – Serum from patients induces stereotypies in rats infused in basal ganglia • Morshed et al. – Antibodies against striatum among patients; sera also induces stereotypies • Cunningham et al. – Cross-reactive antibodies present in sera of acutely ill SC patients; affects cell signaling • Kirvan et al – Cross-reactive antibodies in PANDAS sera are comparable to those in SC, but lower concentrations.

  31. Reactivity with Neurons and Caudate/Putamen PANDAS SC Control PANDAS PANDAS SC Controls Controls

  32. Induced CaM kinase II Activity

  33. Immunomodulatory Treatment TrialPlasma Exchange vs. IVIG vs. Placebo

  34. Response to Immunomodulatory Therapy with IVIG (n=9) or Plasmapheresis (n=8)

  35. Caudate Size in 14 y.o. Patient with OCD

  36. Childhood-onset Obsessive Compulsive Disorder (OCD) and PANDAS Are Contamination Fears Justified?

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