childhood-onset obsessive compulsive disorder (ocd) and the pandas subgroup are contamination fears...
TRANSCRIPT
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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
OBSESSIONSConcerns about:
ContaminationSafetyRight/wrong
Intrusive thoughts:CountingNumbers/wordsViolent images
COMPULSIONSOrdering/arrangingSymmetryHoarding/collectingRepeating rituals:
Cleaning/WashingCheckingRe-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
Ventral Prefrontal Cortex Basal Ganglia Thalamus Hippocampus
R L
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 modelFrom: Rapoport & others
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Pediatric
Autoimmune
Neuropsychiatric
Disorders
Associated with
Streptococcal 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 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
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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 DisorderII. Prepubertal onsetIII. Episodic course of symptom severityIV. Association with neurological
abnormalitiesV. 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
SusceptibleHost
AbnormalImmune Response
CNS & Clinical Manifestations
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Model of Pathogenesis for PANDAS
GABHS
SusceptibleHost
AbnormalImmune 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
0
2
4
6
8
10
12
NOV DEC J AN FEB MAR APR MAY J UN
Month Observed
TICS
BEHAVIOR
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0
5
10
15
20
25
1 2 3 4 5 6 7 8 9 10 11Time (Months)
Sym
ptom
Sev
erity
0100200300400500600700800
ASO
Tite
rs
NON-PANDAS
0
5
10
15
20
25
30
1 2 3 4 5 6 7 8 9 10 11
0
200
400
600
800
ASO
Tite
rs
Sym
ptom
Sev
erity
PANDAS
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 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
N = 22
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PENICILLIN AZITHROMYCIN
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Model of Pathogenesis for PANDAS
GABHS
SusceptibleHost
AbnormalImmune 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 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)
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Host Susceptibility
VULNERABLE CHILD
IMMUNOLOGIC
NEUROLOGICGENETICS
TYPES OF EXPOSURES
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Model of Pathogenesis for PANDAS
GABHS
SusceptibleHost
AbnormalImmune 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
PANDAS
Controls
SC
SC
Control
PANDAS
Controls
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Induced CaM kinase II Activity
SC PANDAS Non-PANDAS 405060708090
100110120130140150160170180190200210220230240250
CaM
Kin
ase
II a
ctiv
atio
n (
% a
bo
ve b
asal
rat
e)
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Immunomodulatory Treatment TrialPlasma Exchange vs. IVIG vs. Placebo
Pla sm a Excha ngeN = 10
IV IGN = 9
SH AM IV IGN = 10
RANDOMIZATION
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Change in OCD Severity 1 Month Following Treatment With IVIG, Placebo, or Plasma Exchange
0
5
10
15
20
25
30
35
40
45
Baseline 1 Month Baseline 1 Month Baseline 1 Month IVIG Placebo Plasma Exchange
YBO
CS
Rating
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Response to Immunomodulatory Therapy with IVIG (n=9) or Plasmapheresis (n=8)
0
20
40
60
80
Sum
YB
OC
S+
TS
UR
S
IVIGPlasma Exchange
Baseline 1 mo 1 yr 1 yr Baseline 1 mo
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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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