Transcript Section on Behavioral Pediatrics Susan E. Swedo, MD

Childhood-onset Obsessive Compulsive
Disorder (OCD) and the PANDAS Subgroup
Are Contamination Fears Justified?
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 timeconsuming, and/or significantly interfere with
normal routine, work/school functioning, and/or
social relationships
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”)
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
fMRI scan of the OrbitofrontalStriatal-Thalamocortical Circuit
R
Ventral Prefrontal Cortex
Basal Ganglia
Thalamus
Casey et al. , 2002
Dysfunction
in Striatum
Dysfunction
in GPi
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
Pediatric
Autoimmune
Neuropsychiatric
Disorders
Associated with
Streptococcal infections
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
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.
Criteria for PANDAS
I.
II.
III.
IV.
V.
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
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%
Dysfunction
in Striatum
Dysfunction
in GPi
Neuropsychological Tests of
Executive Function
BJ Casey et al, 2002
Structural MRI
Giedd et al, 2000
Model of Pathogenesis for PANDAS
Susceptible
Host
GABHS
Abnormal
Immune
Response
CNS & Clinical
Manifestations
Model of Pathogenesis for PANDAS
Susceptible
Host
GABHS
Abnormal
Immune
Response
CNS & Clinical
Manifestations
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
Epidemiological Evidence of a Relationship
Between GABHS and Rheumatic Fever
Point Prevalences for Tics & Behavioral Problems in a
Virginia Elementary School Population
30
25
20
800
15
10
5
0
400
600
200
ASO Titers
Symptom Severity
PANDAS
Y-BOCS ---
0
1
2
3
4
5
6
7
8
9
10
11
NON-PANDAS
800
700
600
500
400
300
200
100
0
20
15
10
5
0
1
2
3
4
5
6
7
Time (Months)
8
9
10
11
ASO TITER --Y-BOCS --ASO Titers
25
Symptom Severity
ASO TITER --
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.
Penicillin (PCN) vs. Azithromycin (Zith)
N = 22
• Streptococcal Infections*
– Year Prior to Study
– Study Year
2.0/ subject
0.0/ subject
• Exacerbations*
– Year Prior to Study
– Study Year
*T >5.25; p< 0.01 for both
2.0/ subject
.74/ subject
PENICILLIN
AZITHROMYCIN
Model of Pathogenesis for PANDAS
Susceptible
Host
GABHS
Abnormal
Immune
Response
Clinical
Manifestations
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)
Host Susceptibility
NEUROLOGIC
GENETICS
VULNERABLE
CHILD
IMMUNOLOGIC
TYPES OF
EXPOSURES
Model of Pathogenesis for PANDAS
Susceptible
Host
GABHS
Abnormal
Immune
Response
Clinical
Manifestations
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
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.
Reactivity with Neurons and Caudate/Putamen
PANDAS
SC
Control
PANDAS
PANDAS
SC
Controls
Controls
CaM Kinase II activation (% above basal rate)
Induced CaM kinase II Activity
250
240
230
220
210
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
SC
PANDAS
Non-PANDAS
Immunomodulatory Treatment Trial
Plasma Exchange vs. IVIG vs. Placebo
RANDOMIZATION
Plasma Exchange
N = 10
IVIG
N=9
SHAM IVIG
N = 10
45
Change in OCD Severity 1 Month Following Treatment With
IVIG, Placebo, or Plasma Exchange
40
35
YBOCS Rating
30
25
20
15
10
5
0
Baseline
IVIG
1 Month
Baseline
1 Month
Placebo
Baseline
1 Month
Plasma Exchange
Response to Immunomodulatory Therapy
with IVIG (n=9) or Plasmapheresis (n=8)
Sum YBOCS+TSURS
80
60
40
20
0
Baseline
1 mo
IV IG
1 yr
Baseline
1 mo
Plasma Exchange
1 yr
Caudate Size in 14 y.o. Patient with OCD
Childhood-onset Obsessive Compulsive
Disorder (OCD) and PANDAS
Are Contamination Fears Justified?