The Child Advocate
The Child Advocate
Home What'sNew Subjects Contents Feedback Search
Introduction:
There has
been a subset of young children who have been noted to abruptly develop
Obsessive Compulsive Disorder (OCD) and/or tic disorders, such as Tourette’s
Disorder, in association to a recently documented Group A Beta-hemolytic
Streptococcal (GABHS) infection. It
was found that these children have a condition termed Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS),
which has unique criteria and characteristics differentiating it from classic
childhood OCD or tic disorders.
PANDAS as a separate
identity:
The working
criteria for the diagnosis of PANDAS was modified through a study which
identified the first 50 cases of PANDAS:
“Pediatric
Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections:
Clinical Description of the First 50 Cases” by Susan E. Swedo et al Am J
Psychiatry 155:2, Feb 1998.
The five
criteria established are as follows:
1.
Presence of OCD and/or tic disorder – the patient must meet lifetime diagnostic
criteria (DSM V) for OCD or tic disorder
2.
Pediatric onset – symptoms first evident between ages 3 and beginning of puberty
3.
Episodic course of symptom severity – clinical course consists of abrupt onset
psychiatric symptoms or dramatic symptom exacerbation
4.
Association with GABHS infection – lifetime pattern of symptom exacerbation must be
temporally related to GABHS infection (diagnosed via throat culture or rise in
antibody titers)
5.
Association with neurological abnormalities
– abnormal neurological exam (i.e. – choreiform movements or tics) during
exacerbation
In
this report, children were recruited that met the above criteria for PANDAS.
These
50 children were then systematically evaluated clinically to further evaluate
any unique characteristics of PANDAS.
Evaluation consisted of medical and psychiatric assessment, including
structured psychiatric interview, standard neurological exam, and baseline labs.
Results
of clinical investigation revealed the following:
·
The
average age of onset of PANDAS is much earlier than classic childhood OCD or tic
disorder. Mean age PANDAS subset of
OCD 7.5 years (SD = 2.7), and mean age PANDAS subset of tic disorder 6.3 years
(SD = 2.7); these mean ages are nearly 3 years younger than previous groups of
childhood onset OCD or tic disorders.
·
The
PANDAS children were evenly divided between those with a primary tic disorder
(52%) and primary OCD (48%)
·
Demographic
data showed males outnumbered females with PANDAS, 2.6:1
·
PANDAS
clinical course: acute and dramatic relapsing and remitting course (parents
could pin-point date neuropyschiatric symptoms erupted) with significant
comorbidity accompanying the exacerbations: emotional lability, separation
anxiety, nighttime fears, cognitive defects, oppositional behaviors
·
Frequent
association with motoric hyperactivity, impulsivity, and distractibility.
Several patients met criteria for ADHD, except the onset of symptoms
frequently occurred after age 6 years.
·
Each
child had at least one symptom exacerbation that was preceded (within 6 weeks)
by a documented GABHS infection. Though,
of the total 144 neuropsychiatric -exacerbations of the 50 children it was noted
that 23 % (33 cases) were not associated with any sign of GABHS infection within
the preceding month.
Author’s
conclusion:
The working diagnostic criteria appear to accurately characterize a homogeneous
patient group in which psychiatric symptom exacerbations are triggered by GABHS
infections. The identification of
such a subgroup will allow for testing of models of pathogenesis, as well as
development of novel treatment and prevention strategies.
PANDAS as a separate
identity based on pathophysiology:
The proposed
theory of the pathophysiology of PANDAS is an immune-mediated model of molecular
mimicry, the same mechanism suggested for rheumatic fever. After exposure to antigens on the surface of Group A
beta-hemolytic streptococcus during a streptococcal infection, the body develops
antibodies to combat the bacteria. In
susceptible individuals, the antigenic area of the bacteria is similar
enough to endogenous host tissue, causing a cross-reaction of the
antibody to the host; therefore, formulating an autoimmune attack on it’s own
tissue. This causes a local immune
reaction to the targeted tissue; i.e. – brain, joints, heart valves.
In rheumatic fever, this causes heart valve damage, arthritis, and
abnormal neurological movements termed Sydenham’s chorea.
In PANDAS the antibodies are thought to cross-react with neuronal tissue
of the CNS, in particular the basal ganglia of the brain, which is
responsible for movement and behavior – resulting in tics and/or OCD.
Studies supporting this theory:
1. “Identification of Children with
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal
infections by a Marker Associated with Rheumatic Fever”, by Susan E. Swedo et
al Am J Psychiatry 1997; 154:110-112.
In this
article, a highly specific and sensitive trait marker used to identify patients
susceptible to rheumatic fever, D8/17 (found on subset of DR+ cells in the
peripheral circulation), was found to also identify children susceptible to
PANDAS accurately.
There were 70 children enrolled, separated into three groups: 9 children
with Sydenham’s chorea served as the positive comparison group,
24 healthy children served as the negative comparison group, and 27
meeting PANDAS criteria served as the experimental group.
Results: The frequency of D8/17- positive individuals was significantly
higher in both patient groups, Sydenham’s chorea at 89 % and PANDAS at 85 %,
than healthy volunteers at 17 %. Also,
the mean number of D 8/17 + cells in the serum samples from the patient groups
were significantly higher than the healthy volunteer group.
These results suggest that the PANDAS subgroup of children with OCD and
Tourette’s disorder are susceptible to a post-streptococcal autoimmune
phenomenon, similar to that of Sydenham’s chorea (the neurological
manifestation of rheumatic fever). A
trait marker, D8/17, that has been associated with rheumatic fever can now be
used to identify children with PANDAS.
2. “MRI
Assessment of Children with Obsessive-Compulsive Disorders and Tics Associated
with Streptococcal Infection”, by Jay N. Giedd et al Am J Psychiatric
Association: 157(2); 281-283
Since the basal ganglia is perceived to be the target of the autoimmune
cross-reactivity in PANDAS, a study was designed to compare brain MRIs of
children with PANDAS associated OCD and tics to healthy comparison children
(matched for age and sex) to determine if there was a significant difference in
the size of basal ganglia, reflecting inflammation.
It was found that the average sizes of the caudate, putamen, and globus
pallidus, but not the thalamus or total cerebrum, were significantly greater in
the group of children with streptococcal-associated OCD and/or tics than in
healthy children. The differences
were similar to those found in previous studies of subjects with Sydenham’s
chorea compared to normal subjects. There
was no direct correlation of increase in basal ganglia size to severity of OCD
and/or tics.
The findings of significant enlargement of the basal ganglia in children
with PANDAS, similar to those found in children with Sydenham’s chorea,
suggest that an inflammatory processes is occurring, most likely secondary to a
post-streptococcal cross-reactive autoimmune reaction.
This inflammation of the basal ganglia is likely to be the physical
factor causing of the neurologic symptoms of OCD and tic disorders.
Treatment of PANDAS
based on pathogenesis of post-streptococcal autoimmunity
The autoimmune pathophysiology proposed for PANDAS and Sydenham’s
chorea, would support the use of immuno-modulation as possible therapy for
children with PANDAS, such as plasma exchange, IV immunoglobulin, or
corticosteriods. Corticosteriods
are an unfavorable treatment modality because they worsen OCD and tic behavior. Therefore, plasma exchange (which filters out the antibodies)
and IVIG (which binds receptors with pooled antibodies) were studied compared to
placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms in the
following study:
“Therapeutic Plasma Exchange and Intravenous
Immunoglobulin for Obsessive Compulsive Disorders and Tic Disorders in
Childhood”, by Susan J. Perlmutter et al, The Lancet 1999, 345
(9185):1153-58.
In this
partial double-blind randomized trial, 30 children with severe
infection-triggered exacerbations of OCD or tic disorders were randomly assigned
treatment with plasma exchange (5 single volume exchanges over 2 weeks), IVIG (1
g/kg daily on 2 consecutive days), or placebo (IV saline solution over 2 days). Psychiatric symptom severity was rated at baseline, at 1
month, and at 1 year after treatment by standard assessment scales for OCD, tic
disorder, anxiety, depression, and global function.
{Randomized by randomization chart}
{Investigators and study participants were
blinded to whether the child received IVIG or placebo, but were obviously aware
of who received plasma exchange}
After symptom ratings at 1 month were completed the IVIG/placebo masking
was broken, and open treatment to IVIG and plasmapheresis was available for
those not improving on saline (all of the subjects), therefore, there was no
more placebo 1 year follow-up ratings.
Results:
·
29
children completed the trial:10
received plasma exchange, 9 received IVIG, and ten placebo
o
at
baseline, the three study groups were similar in age, primary diagnosis,
duration of exacerbation, use of psychotropic medications, presence of
antistreptococcal titers.
·
1
month follow up: striking improvements seen in plasma exchange and IVIG groups
concerning obsessive-compulsive symptoms, anxiety, depression, emotional
liability and global functioning.
o
Global
change scores for children in the plasma exchange and IVIG groups improved by
48% and 41 % respectively, in contrast to placebo which showed no change in
overall symptom severity
o
Improvement
in obsessive-compulsive symptoms, rated by Yale-Brown OCD scale, seen in plasma
exchange (33% improvement) and IVIG (35% improvement) groups
o
Anxiety
improvement, as rated by the NIMH anxiety scale, significant in plasma exchange
and IVIG groups, 31 % and 47% improvement respectively
o
Plasma
exchange group showed significant improvement in tic severity over placebo, but
IVIG did not
·
1 year
follow up: psychiatric symptoms remained improved from baseline on all
measures.
o
The most
clinically meaningful improvements occurred in obsessive-compulsive symptoms (58
% and 70 % improvement from baseline; IVIG and plasmapheresis respectively), tic
severity (53 % improvement plasmapheresis), and global measures of symptom
severity (26 % and 45 % improvement) and psychological functioning (26 % and 47
% improvement).
o
The
symptoms ratings and clinical impression of treatment of OCD favored
plasmapheresis over IVIG
o
Parents
report “ my child’s back to their old self again”, and children reported
“things are a lot easier now”. Kids
went from “symptom impairments in several social areas” to now “good
functioning in all areas”.
Conclusion:
Both plasma exchange and IVIG were effective in significantly reducing the
symptom severity of OCD and tic disorder for children with PANDAS.
Possible mechanisms would be through blocking (via IVIG) or removing (via
plasma exchange) the antistreptococcal antibodies that were cross-reacting to
the neuronal tissue. Supporting the
idea that PANDAS is a separate subgroup of OCD/tic disorder and may require a
unique treatment plan.
Also separating
PANDAS from classic childhood onset OCD is the remission of symptoms after a
single course of IVIG or plasma exchange. Typically, patients with OCD will have
response to SSRIs and/or behavioral modification; however, the response is only
partial and relapse is common after medication is discontinued.
Further studies:
Trials with more selective and specific immunomodulatory agents for children
with PANDAS.
Further Observations
of treatment
It has been
documented in several case studies and a prospective study at a community
pediatric practice that children with PANDAS respond readily to antibiotic
treatment. The prospective study:
“Prospective identification and
treatment of children with pediatric autoimmune neuropsychiatric disorder
associated with group A streptococcal infection (PANDAS)”, by Marie L. Murphy
et al, Archives of Pediatric and Adolescent Medicine 156(4):356-61.
Though this
study only had a sample population of 12, all cases had documented active GABHS
infections (by throat swab or culture, and/or rise GABHS Ab titers) associated
with the initial episode of neuropsychiatric symptoms, and these
neuropsychiatric symptoms (OCD, anxiety, ADHA, tic disorder) disappeared during
antibiotic treatment for streptococcal-infected throat.
The recurrences of neuropsychiatric behavioral symptoms were directly
related to the recurrence of streptococcal throat infections, which again
resolved with appropriate antibiotic treatment (amoxicillin or cephalosporin).
There were no instances of new recurrence of OCD in the absence of
new GABHS infection (throat cultures were also taken after initial treatment of
antibiotics, when symptom free, and were negative).
This study supports the linkage of GABHS infection to acute
neuropsychiatric disorders, as described in the PANDAS sub-category; however, it
slightly undermines the theory that PANDAS is caused by an autoimmune
cross-reactivity to brain tissue, because rapid treament (within 2-14 days) with
antibiotics does not target antibodies designed against GABHS/brain tissue.
This leads one to believe there are several components to the
pathophysiology of PANDAS, including genetic susceptibility of the host, an
autoimmune reaction, and possibly a reaction to the toxins of the bacteria
themselves or a certain strain of GABHS.
Each of the delineated points can be the focus
of diagnostic testing and therapeutic intervention.
Currently, the NIMH is investigating the role of antibiotic prophylaxis
against GABHS and its affects on the recurrence of neuropsychiatric symptoms in
children with PANDAS.
Resources:
Garvey
MA, Perlmutter S, Allen AJ, et al: “A Pilot of Penicillin Prophylaxis for
Neuropsychiatric Exacerbations Triggered by Streptococcal Infections” Society
of Biological Psychiatry 1999, 45: 1564-71
Giedd, JN et al: “MRI
Assessment of Children with Obsessive-Compulsive Disorders and Tics Associated
with Streptococcal Infection”, Am J Psychiatric Association: 157(2);
281-283
Murphy, ML et al. “Prospective
identification and treatment of children with pediatric autoimmune
neuropsychiatric disorder associated with group A streptococcal infection
(PANDAS)”, Archives of Pediatric and Adolescent Medicine 156(4):356-61.
Perlmutter SJ, Leitman SF,
Swedo SE, et al: “A Case of Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcal Infection”, Am J Psychiatry 1998 : 155
(11) 1592-98
Perlmutter SJ, Leitman SF,
Swedo SE, et al: “Therapeutic Plasma Exchange and Intravenous Immunoglobulin
for Obsessive- Compulsive Disorder and Tic Disorder in Childhood”. The
Lancet 1999, 354(9185): 1153-58
Snyder LA, Swedo SE: Pediatric
Obsessive-Compulsive Disorder JAMA 2000, 284(24): 3104-06
Swedo
SE, Leonard H, Garvey MA, et. al: Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal Infections: Clinical Descriptions of
First 50 Cases Am J Psychiatry 1998, 155(2): 264-71
Swedo, SE 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
Home What'sNew Subjects Contents Feedback Search
The Child Advocate PANDAS
Treatment Page.
Copyright © 2003-2013 The Child Advocate All rights reserved.
Revised: January 01, 2013
.