Transcript Section on Behavioral Pediatrics Susan E. Swedo, M.D.

TWO PANDAS
Edward L. Goodman, MD, FACP, FIDSA,
with the assistance of Susan Swedo, MD
NIMH/NIH
July 6, 2005
A Case of PANDAS
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.
nd
2
Case Presentation
• ZZN 10 year old boy has the acute onset of
acute obsessive compulsive disorder
– Can’t stop looking at a sore on skin
• Has mother photograph daily
– Intense separation anxiety makes going to
school very difficult
– States to mother: “I wish I wasn’t so attached to
inaminate objects.”
• Hoards items like candy wrappers
Past History
• Migraine Headaches
– Normal MRI head previous year
• Extremely picky eater
• Normal developmental milestones
• Normal weight and height
– Recently has lost weight
Presentation
• Physical exam normal
• Psych exam reveals
– Mild tic like movements of arms/shoulders and
eye blinking
– Normal mental state
– Anxiety
– Aware that he “feels crazy”
Presentation
• Routine Lab normal
• Anti –streptococcal antibody very high
– No history of pharyngitis
– Poor oral intake for several days
• Throat culture + for Group A Streptococcus
Management
• Cefadroxil once daily
– Did well immediately with resolution of symptoms
– Then mild relapse on 9th day of therapy
• Was being given suboptimal dosage of drug
• Strept Screen was negative at the time
• Psychiatry follow up
• Whole family (6) had throat cultures: only sister
age 7 had GAS
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
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
PANDAS
800
Symptom
Severity
600
400
200
ASO Titers
30
25
20
15
10
5
0
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 --
“Prospective Identification and Treatment of
Children with PANDAS”
M. Murphy & M. Pichichero
• 12 patients identified over 3 years period
• 7 boys & 5 girls presented with neuropsychiatric
symptoms related to GABHS infections
– 100% with OCD (3/4’s were germ-related) and
emotional lability
– 58% (7/12) with urinary frequency or enuresis
– 42% (5/12) with acute separation anxiety
– 33% (4/12) with tics or handwriting changes
• Antibiotic treatment of GABHS infections
reduced symptom severity in 5 – 21 days
Arch Ped Adolesc Med 2002;156:356-361
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%
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
Snider et al, Pediatrics
Postulates of PANDAS Prophylaxis
IF
• OCD/Tics are sequelae of GABHS infections
(similar to Sydenham chorea)
THEN
• Penicillin prophylaxis should be effective in
reducing exacerbations of OCD/Tics
PCN
PCN
4 months
PLA
4 months
PLA
Penicillin/Placebo Trial - Results
39 Children completed the 8 months long trial
35 Documented GABHS infections occurred
14 during penicillin, 21 during placebo
Depression & anxiety were significantly better
during penicillin phase than placebo phase
But, no difference in OCD or tics severity
M. Garvey et al., Biol Psychiatry
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.
Antibiotics Prophylaxis Trial – Study Design
• Double-blind, parallel-design study of
azithromycin (500 mg q week) and
penicillin (250 mg po bid)
(Note – All Children receive antibiotics)
• One year long trial with monthly visits for
throat culture, titers and symptom ratings
• Comparison of symptom course year prior
to study, with course during prophylaxis.
• Assessment of GABHS infections via titers
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
2.0/ subject
.74/ subject
*T >5.25; p< 0.01 for both
Snider et al., Biol Psych 2005
PCN
ZITH
Effectiveness of Antibiotic Prophylaxis
Year Prior to Study
Year on Antibiotics
Penicillin Prophylaxis
Discontinuation Study
• Currently recruiting 5 – 12 yrs old children
who meet criteria for PANDAS subgroup
• 6-months long study, but only two clinic
visits are required
• All children receive penicillin prophylaxis
and 50% are randomized to continue, and
50% to switch to placebo
• If a child relapses, open-label penicillin is
restarted.
Model of Pathogenesis for PANDAS
Susceptible
Host
GABHS
Abnormal
Immune
Response
Clinical
Manifestations
Host Susceptibility
NEUROLOGIC
GENETICS
VULNERABLE
CHILD
IMMUNOLOGIC
TYPES OF
EXPOSURES
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
(Lougee et al, 2000)
• 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
• D8/17 prevalence significantly greater among patients
with OCD/tics or rheumatic fever than controls
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; appears
to affect cell signaling
Immunomodulatory Treatment Trial
Plasma Exchange vs. IVIG vs. Placebo
RANDOMIZATION
Plasma Exchange
N = 10
IVIG
N=9
SHAM IVIG
N = 10
Perlmutter et al., Lancet
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
IVIG
1 yr
Baseline
1 mo
Plasma Exchange
1 yr
Caudate Size in 14 y.o. Patient with OCD
Summary - Future Directions
GABHS
• Identify pathogenic factors
• Prevent symptom onset/worsening
Vulnerable Host • Identify susceptible hosts
• Protect at-risk individuals
Altered Immune • Determine nature of local, regional
and systemic autoimmunity
Response
• Develop new immunologic therapies
PANDAS
• Identify unique clinical characteristics
• Identify CNS basis of OCD/tics
Implications:
• Is this only the first of many to be
discovered biologic bases of behavioral
disorders?
Thanks to the following
• Susan Swedo, MD NIMH/NIH who
provided references and many slides
• Beverly Dickson, MD, who authorized the
follow up throat cultures
• Sharon Williamson, MT(ASCP), who
assisted with the throat cultures
Bibliography
Thanks to Susan Swedo, MD of the NIMH,
Beverly Dickson, MD and Sharon
Williamson, MT (ASCP) for their help in
preparing this presentation.