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

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Transcript of Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup Are Contamination Fears...

  • Slide 1
  • Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup Are Contamination Fears Justified?
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  • 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
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  • OCD Symptoms in Pediatric Patients 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)
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  • 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
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  • fMRI scan of the Orbitofrontal- Striatal-Thalamocortical Circuit Casey et al., 2002
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  • Dysfunction in Striatum Dysfunction in GPi
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  • 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
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  • P ediatric A utoimmune N europsychiatric D isorders A ssociated with S treptococcal infections
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  • Background 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 1900s 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
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  • 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.
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  • Criteria for PANDAS I.Presence of OCD and/or Tic Disorder II.Prepubertal onset III.Episodic course of symptom severity IV.Association with neurological abnormalities V.Temporal relationship between symptom exacerbations and streptococcal infections
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  • Frequency of Comorbid Symptoms in PANDAS 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%
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  • Dysfunction in Striatum Dysfunction in GPi
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  • Neuropsychological Tests of Executive Function BJ Casey et al, 2002
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  • Structural MRI Giedd et al, 2000
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  • Model of Pathogenesis for PANDAS GABHS Susceptible Host Abnormal Immune Response CNS & Clinical Manifestations
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  • Model of Pathogenesis for PANDAS GABHS Susceptible Host Abnormal Immune Response CNS & Clinical Manifestations
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  • 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
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  • Epidemiological Evidence of a Relationship Between GABHS and Rheumatic Fever
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  • Point Prevalences for Tics & Behavioral Problems in a Virginia Elementary School Population
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  • ASO TITER -- Y-BOCS --- ASO TITER --- Y-BOCS ---
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  • 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.
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  • Penicillin (PCN) vs. Azithromycin (Zith) Streptococcal Infections* Year Prior to Study2.0/ subject Study Year0.0/ subject Exacerbations* Year Prior to Study2.0/ subject Study Year.74/ subject *T >5.25; p< 0.01 for both N = 22
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  • PENICILLINAZITHROMYCIN
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  • Model of Pathogenesis for PANDAS GABHS Susceptible Host Abnormal Immune Response Clinical Manifestations
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  • PANDAS Host Susceptibility Increased familial rates of OCD & tics 36/50 (67%) of PANDAS probands had an affected 1 o 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)
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  • Host Susceptibility VULNERABLE CHILD IMMUNOLOGIC NEUROLOGIC GENETICS TYPES OF EXPOSURES
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  • Model of Pathogenesis for PANDAS GABHS Susceptible Host Abnormal Immune Response Clinical Manifestations
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  • 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
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  • 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.
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  • Reactivity with Neurons and Caudate/Putamen PANDAS Controls SC Control PANDAS Controls
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  • Induced CaM kinase II Activity
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  • Immunomodulatory Treatment Trial Plasma Exchange vs. IVIG vs. Placebo
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  • Response to Immunomodulatory Therapy with IVIG (n=9) or Plasmapheresis (n=8)
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  • Caudate Size in 14 y.o. Patient with OCD
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  • Childhood-onset Obsessive Compulsive Disorder (OCD) and PANDAS Are Contamination Fears Justified?
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