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3/8/2010
DISCLAIMER
PANDAS:
A Case Discussion
NEITHER THE PUBLISHER NOR
THE AUTHORS ASSUME ANY
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Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcus
Suzanne Collier, MD
ETSU Psychiatry Resident PGY-III
March 5, 2010
Case Study: CJ

7 year old Caucasian male

One month prior to admission, would repeat himself
compulsively, i.e. “I love you Mom, okay, okay, okay,
okay, okay” etc.

More “clingy”
clingy than normal

One week prior to admission began praying incessantly.
Cannot answer questions without interrupting himself in
order to pray. God is talking to him.

Sleep disturbance

Would not step on certain colored tiles on the floor

Odd hand gestures
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Further collateral information
reveals:



No clear precipitant to worsening of symptoms
in last one week
Started an allergy medication in October that
made him more agitated
One month prior to presentation, difficulty
hearing
 FP noted enlarged tonsils
 ENT referral – PE tubes and tonsillectomy
scheduled
 No Strep screen, no antibiotics initiated
Let’s review


Rheumatic Fever – Requires 2 major criteria or 1 major
and 2 minor criteria
Major criteria:
 Migratory polyarthritis (usually starts in legs and
migrates upward)
 Carditis
 Subcutaneous nodules (painless collagen nodules on
back of wrist, outside elbow, and front of knees)
 Erythema marginatum
 Sydenham’s chorea (a.k.a. St. Vitus’ dance,
characteristic series of rapid, purposeless movements
of face and arms)
Differential Diagnosis
OCD, possibly related to medical
reason, r/o PANDAS
 Psychosis NOS
 Bipolar disorder with psychotic
features
 Tic disorder, Tourette’s syndrome
 Anxiety disorder
 Psychosis NOS
 Sydenham’s chorea (rheumatic fever)

Rheumatic fever, continued

Minor criteria
 Fever
 Arthralgia
 Laboratory abnormalities (increased ESR, C reactive
protein,, leukocytosis)
p
y
)
 Electrocardiogram abnormalities (prolonged PR
interval)
 Evidence of Group A streptococcal infection
(elevated or rising titers of Antistreptolysin O titre, or
DNAase, though by clinical illness onset cultures for
streptococci will be negative)
 Previous rheumatic fever or inactive heart disease
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“So what’s your point?”

Basal ganglia dysfunction =
neuropsychiatric symptoms in some
cases, particularly in Sydenham’s
chorea and OCD
What’s the connection?

Observations of patients with rheumatic fever who had
Sydenham’s chorea and classic OCD symptoms




BG also anatomic target for Tourette’s
syndrome, ADHD
 SC patients often display motor and
vocal tics, OCD, and ADHD symptoms

Possible link between GABHS in subset of OCD patients
Suggested by Swedo in 1994 that there may some autoimmune
link to neuropsychiatric disorders
GABHS also implicated in development of Tourette syndrome
and autism in children
NIMH 1998 – research group to characterize a subgroup of
children with OCD and tic disorders

Defined PANDAS and diagnostic criteria
Swedo, Susan. “Sydenham’s chorea: a model for childhood autoimmune
neuropsychiatric disorders”, JAMA. 1994;272:1788-91.
PANDAS Diagnostic Criteria






Also watch for:
Presence of obsessive-compulsive disorder and/or tic disorder
Pediatric onset of symptoms (age 3 years to puberty)
Episodic course of symptom severity
Association with group A Beta-hemolytic streptococcal infection
(a positive throat culture for strep. or history of Scarlet Fever.)
Association with neurological abnormalities (motoric
hyperactivity, or adventitious movements, such as choreiform
movements)

Also now accepted that you need at least two exacerbations
after GABHS infection to meet criteria






ADHD symptoms (hyperactivity, inattention,
fidgety)
Separation anxiety (Child is "clingy" and has
difficulty separating from his/her caregivers.)
Mood changes (irritability
(irritability, sadness
sadness, emotional
lability)
Sleep disturbance
Night- time bed wetting and/or day- time urinary
frequency
Fine/gross motor changes (e.g. changes in
handwriting)
Joint pains
Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections: clinical description of the first
50 cases [published correction appears in Am J Psychiatry. 1998;155(4):578]. Am
J Psychiatry. 1998;155 (2):264 –271
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Psychiatric comorbidity
“Saving Sammy”
ADHD – 40%
 Affective disorders – 42%
 Anxiety
y disorders – 32%
“Today” show September 24, 2009

Today Show Video Clip
Swedo, Susan E., et al. Am J Psychiatry 155:2, February 1998
Clinical Controversy
o Age of onset criteria
o 1-3% of children have OCD
o 10-25% school age children have tics
o 75% Tourette’s
Tourette s patients have onset prior to
11 y/o
o Increases possibility that association
between GABHS and psych symptoms is
coincidence
Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infection (PANDAS) etiology for tics and
obsessive-compulsive symptoms: hypothesis or entity? Practical
considerations for the clinician. Pediatrics. 2004;113 (4):883 –886
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Controversy, continued
Controversy, continued
o Abrupt exacerbation criteria
o GABHS infection criteria
o Neurological symptom exacerbation
could be due to stress from infections
in general, not just GABHS
o Longitudinal history of GABHS
infection and OCD or tic symptoms
can be difficult to establish
o Since tics are either present or not,
onset could always seem abrupt
o Patients with tics often seem to have
sudden worsening of tics even without
meeting PANDAS criteria
o Family reports subject to recall bias
Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms:
hypothesis or entity? Practical considerations for the clinician. Pediatrics. 2004;113
(4):883 –886
Fig 1. Model of pathogenesis for PANDAS
Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms:
hypothesis or entity? Practical considerations for the clinician. Pediatrics. 2004;113
(4):883 –886
Proposed Theory of
Pathogenesis
Immune-mediated model of molecular
mimicry
 Autoimmune attack on tissues such
as joints,
j i
h
heart valves,
l
b
brain
i
 Antibodies cross-react with neuronal
tissue of the CNS (basal ganglia)


BG is responsible for movement and
behavior
Swedo, S. E. et al. Pediatrics 2004;113:907-911
Copyright ©2004 American Academy of Pediatrics
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Pathogenesis, continued
Pathogenesis, continued
o Yet another theory: immune-mediated altered neuronal
signaling

o Involves the dominant epitope of GABHS
o Monoclonal antibodies reacted with lysoganglioside GM1
o This lysoganglioside influences neuronal signal transduction
o Also found an autoantibodyy that induces CaM kinase II activity
y
o CaM kinase II could be an intracellular mediator of behavioral
and motor manifestations in some neuropsychiatric disorders
o CaM kinase II activation at low levels: non-PANDAS OCD
o CaM kinase II activation at high levels : rheumatic chorea
Kirvan, CA, Swedo, SE. Antibody-mediated neuronal cell signaling in behavior
and movement disorders. J Neuroimmunology. 2006;179:173-179.

Peripheral markers
Trait marker D8/17 that has been associated with
rheumatic fever can also be used to identify children
with PANDAS
 This is a non-HLA B-cell marker
 D8/17 found on subset of DR+ cells in peripheral
circulation
 Frequency of D8/17 positive individuals:
• Sydenham's chorea – 89%
• PANDAS – 85%
• Healthy volunteers - 17%
Swedo, Susan E., et al. “Identification of Children with Pediatric Autoimmune Neuropsychiatric Disorders Associated
with Streptococcal infections by a Marker Associated with Rheumatic Fever”, Am J Psychiatry 1997; 154:110-112.
A Recent Example –
“Sneezing Girl”
Lauren Johnson, 12 year old
“Today” show November 11, 2009 and again on December
11, 2009
Today Show Lauren Johnson Video Clip
Today Show Update Video Clip
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Diagnostic studies
Check for Strep!
 Two tests available:

ASO titer: rises 3-6 weeks postinfection
 Anti DNAase-B titer: rises 6-8 weeks
post-infection
 If negative, get throat culture

Back to our Case Study, CJ:
Initial rapid Strep test was negative
(this was at least one month postinfection)
 Throat
Th
culture
l
was negative
i ((patient
i
was uncooperative with obtaining
culture, likely inadequate culture)
 Further titers not obtained due to
expense of tests and also results
would not have changed treatment

Therapeutic Strategies – To
use antibiotics or not?
o Prospective longitudinal study of 12 children with
PANDAS
o 5 were given penicillin or amoxicillin
o 1 was given amoxicillin and clavulanate (Augmentin)
o 6 were given
i
cephalosporin
h l
i
o In all patients, resolution of OCD, anxiety symptoms,
and tics within average 14 days
Murphy ML, Pichichero ME. Prospective identification and treatment of children
with pediatric autoimmune neuropsychiatric disorder associated with group
A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med.
2002;156:356–61.
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Antibiotics or not?
Antibiotics or not?
o First controlled trial on antibiotic prophylaxis for PANDAS
o Were Garvey’s negative results due to inefficacious prophylaxis
against GABHS infection or lack of association between
GABHS infection and neuropsychiatric symptoms?
o Snider compared penicillin (“active placebo”) with azithromycin
o 23 patients - continued meds for 12 months
o In contrast to previous studies, both effectively decreased
GABHS infections and neuropsychiatric exacerbations.
o They concluded that antibiotic prophylaxis may be useful in the
management of children with PANDAS
o Others later pointed out limitations of study
o 37 children with PANDAS were randomized to 4 months
of penicillin V (250mg PO BID) followed by 4 months of
placebo, or placebo followed by penicillin
o Oral penicillin failed to provide adequate prophylaxis for
GABHS and subsequently for neuropsychiatric symptom
exacerbations
Garvey MA, Perlmutter SJ, et al. A pilot study of penicillin prophylaxis for
neuropsychiatric exacerbations triggered by streptococcal infections. Biol
Psychiatry. 1999;45:1564-1571.
Snider LA, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhoodonset neuropsychiatric disorders. Biol Psychiatry. 2005;57:788-792.
Treatment Plan
CJ's Treatment:




Treat any suspected active Strep infection with
antibiotics!
 Accepted standard of care for Strep – but there are no
set guidelines for if/how long to continue antibiotics as
prophylaxis for PANDAS
 More research needed
OCD, anxiety: SSRIs
Tic disorders/Tourette's: typical and atypical antipsychotic
meds
Option for severely ill patients is IVIG or plasma
exchange
Erythromycin 250mg PO QID x 7 days
 Risperdal
 Cogentin
g
 Gradual improvement during
hospitalization
 Strongly considered SSRI (Zoloft) for
anxiety


Nicolson R, Swedo SE, et al. An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without
poststreptococcal exacerbations. J Am Acad Child Adolesc Psychiatry. 2000;39:1313-1315.
Not clear if anxiety secondary to
PANDAS or innate anxiety disorder
Perlmutter, Susan J., et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin for Obsessive Compulsive
Disorders and Tic Disorders in Childhood. The Lancet 1999;345 (9185):1153-58.
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Special Thanks:
Dr. Jill McCarleyy
References
References
Ashbar, FR, et al. “Obsessive-compulsive and related symptoms in children and adolescents
with rheumatic fever with and without chorea: a prospective 6-month study.” Am J
Psychiatry. 1998;155:1122-1124.
Pavone, P, et al. Anti-brain antibodies in PANDAS versus uncomplicated streptococcal
infection. Pediatric Neurology. 2004;30:107-10.
Gabbay V, Coffey BJ, Babb JS, et al. Pediatric autoimmune neuropsychiatric disorders
associated with streptococcus: comparison of diagnosis and treatment in the community
and at a specialty clinic. Pediatrics. 2008;122 (2):273 –278
Perlmutter, Susan J., et al. Therapeutic Plasma Exchange and Intravenous Immunoglobulin
for Obsessive Compulsive Disorders and Tic Disorders in Childhood. The Lancet 1999,
345 (9185):1153-58
Garvey MA, Perlmutter SJ, et al. A pilot study of penicillin prophylaxis for neuropsychiatric
exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;45:1564-1571.
Geidd JN, Rapoport JS, Garvey MA, Perlmutter S, Swedo SE. MRI assessment of children with
obsessive-compulsive disorder or tics associated with streptococcal Am J Psychiatry.
2000;157:281–283.
Kirvan, CA, Swedo, SE. Antibody-mediated neuronal cell signaling in behavior and movement
disorders. J Neuroimmunology. 2006;179:173-179.
Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms:
hypothesis or entity? Practical considerations for the clinician. Pediatrics. 2004;113
(4):883 –886
Snider LA, et al. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset
neuropsychiatric disorders. Biol Psychiatry. 2005;57:788-792.
Swedo, Susan. “Sydenham’s chorea: a model for childhood autoimmune neuropsychiatric
disorders”, JAMA. 1994;272:1788-91.
Swedo, Susan E., et al. “Identification of Children with Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal infections by a Marker
Associated with Rheumatic Fever”, Am J Psychiatry 1997; 154:110-112.
Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection
and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective
blinded cohort study. Pediatrics. 2008;121 (6):1188 –1197
Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infections: clinical description of the first 50 cases
[published correction appears in Am J Psychiatry. 1998;155(4):578]. Am J Psychiatry.
1998;155 (2):264 –271
Nicolson R, Swedo SE, et al. An open trial of plasma exchange in childhood-onset obsessivecompulsive disorder without poststreptococcal exacerbations. J Am Acad Child Adolesc
Psychiatry. 2000;39:1313-1315.
Swedo SE, Leonard HL, Rapoport JL. The pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction.
Pediatrics. 2004;113 (4):907 –911
Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric
autoimmune neuropsychiatric disorder associated with group A streptococcal infection
(PANDAS). Arch Pediatr Adolesc Med. 2002;156:356–61.
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