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Identification of children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections by a marker associated with rheumatic fever

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  • Lilly (retired)
Article

Identification of children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections by a marker associated with rheumatic fever

Abstract

The authors' goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). Blood samples obtained from 27 children with PANDAS, nine children with Sydenham's chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham's chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette's syndrome, rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity.
Am J Psychiatry 154:1, January 1997
Brief Reports
BRIEF REPORTSBRIEF REPORTS
Identification of Children With Pediatric Autoimmune
Neuropsychiatric Disorders Associated With Streptococcal
Infections by a Marker Associated With Rheumatic Fever
Susan E. Swedo, M.D., Henrietta L. Leonard, M.D., Barbara B. Mittleman, M.D.,
Albert J. Allen, M.D., Ph.D., Judith L. Rapoport, M.D., Sara P. Dow,
Melissa E. Kanter, Floresta Chapman, and John Zabriskie, M.D.
Objective: The authors’ goal was to determine whether a trait marker of rheumatic fever
susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychi-
atric disorders (obsessive-compulsive disorder and tic disorders) associated with strepto-
coccal infections (PANDAS).
Method: Blood samples obtained from 27 children with PAN-
DAS, nine children with Sydenham’s chorea, and 24 healthy children were evaluated for D8/17
reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells.
Results: The frequency of D8/17-positive individuals was significantly higher in both patient
groups than it was among the healthy volunteers: 85% of the children with PANDAS and
89% of the children with Sydenham’s chorea, compared with 17% of the healthy children,
were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient
groups and was significantly higher in these groups than in the group of healthy children.
Conclusions: These results suggest that there may be a subgroup of D8/17-positive children
who present with clinical symptoms of obsessive-compulsive disorder and Tourette’s syn-
drome, rather than Sydenham’s chorea, but who have similar poststreptococcal autoimmunity.
(Am J Psychiatry 1997; 154:110–112)
C
hildhood-onset obsessive-compulsive disorder,
once considered a psychological disorder or neu-
rosis, is now known to be a neurobiological disorder
with a variety of etiologic factors, including genetic sus-
ceptibility, neurophysiological aberrations, and re-
gional brain dysfunction (1). Poststreptococcal autoim-
munity has been postulated as another etiologic factor
(2, 3). This hypothesis is supported by data from two
parallel lines of research: studies of Sydenham’s chorea
(a variant of rheumatic fever characterized by neuro-
logical dysfunction) and investigations of childhood-
onset obsessive-compulsive disorder and Tourette’s
syndrome (2–7). Results of these studies led to the iden-
tification of a subgroup of children with obsessive-com-
pulsive disorder or Tourette’s syndrome in whom
symptom exacerbations were abrupt, dramatic, and
temporally related to group A β-hemolytic streptococ-
cal infections (4, 8). Further research has revealed a dis-
tinct subgroup of neuropsychiatrically ill children whose
tics and obsessive-compulsive symptoms appear to
arise in response to an exogenous pathogen (usually β-
hemolytic streptococcal infections) and for whom tar-
geted therapeutic and preventive strategies can be devel-
oped. This subgroup is designated by the acronym
PANDAS (pediatric autoimmune neuropsychiatric dis-
orders associated with streptococcal infections).
In this paper, we describe the association of a known
marker for susceptibility to rheumatic fever with PAN-
DAS. This marker is found on a subset of DR+ cells in
the peripheral circulation (B cells are included in this
group). The relative frequency of cells bearing this
marker is an inherited characteristic. Susceptibility to
rheumatic fever also appears to be genetically deter-
mined: familial rates of rheumatic fever are dramati-
cally high, and large family studies have suggested
Received Feb. 16, 1996; revision received July 26, 1996; accepted
Sept. 3, 1996. From the Section on Behavioral Pediatrics, Child Psy-
chiatry Branch, NIMH; the Experimental Immunology Branch, Na-
tional Cancer Institute; and Rockefeller University, New York City.
Address reprint requests to Dr. Swedo, NIMH, 10 Center Drive, MSC
1381, Bethesda, MD 20892-1381.
The authors thank Ms. Billinda Duppert, Ms. Susan Hamburger,
and Drs. Collette Parker, Kenneth Rickler, Mark Schapiro, and Gre-
gory Swedo for their contributions to the study.
110 Am J Psychiatry 154:1, January 1997
either an autosomal recessive or autosomal dominant
(with limited penetrance) pattern of inheritance (9, 10).
Individuals at risk for the development of rheumatic fe-
ver can be identified on the basis of a DR+ cell surface
marker recognized by a monoclonal antibody desig-
nated D8/17. This marker has been tested in a wide va-
riety of study groups and has been found to be both
highly specific (only 5%–15% of healthy volunteers are
D8/17 positive) and highly sensitive in identifying indi-
viduals with rheumatic fever, 90%–100% of whom are
D8/17 positive regardless of disease status (i.e., D8/17
appears to function as a trait marker) (11, 12).
METHOD
Twenty-seven children met the following diagnostic criteria and
were included in the PANDAS group: 1) presence of obsessive-com-
pulsive disorder (diagnosed according to DSM-III-R or DSM-IV) or
tic disorder, 2) symptom onset between 3 years of age and puberty,
3) episodic course of symptom severity characterized by the abrupt
onset of symptoms or frequent, dramatic symptom exacerbations,
4) symptom exacerbations associated with β-hemolytic streptococcal
infection, and 5) presence of neurological abnormalities, such as mo-
toric hyperactivity or adventitious movements, including choreiform
movements or tics (note: choreiform movements are not chorea).
The eight girls and 19 boys in the PANDAS group had a mean age of
9.9 years (SD=2.3, range=5.3–14.6). Three children met diagnostic cri-
teria for obsessive-compulsive disorder alone, five for obsessive-com-
pulsive disorder and Tourette’s syndrome, five for obsessive-compulsive
disorder and tics, six for subclinical obsessive-compulsive disorder and
Tourette’s syndrome and tics, two for tics alone, and six for Tourette’s
syndrome alone. None of the children had ever had chorea, arthritis,
carditis, or any other major criterion of rheumatic fever; therefore, there
were no “missed” cases of Sydenham’s chorea (13).
Nine children with Sydenham’s chorea (five boys and four girls
whose mean age was 9.8 years, SD=1.6) served as a positive compari-
son group (3, 4). All met the revised Jones criteria for rheumatic fever
(13). Twenty-four healthy children (seven boys and 17 girls whose
mean age was 10.3 years, SD=2.2) served as the negative comparison
group. All subjects and their parents gave written informed assent and
consent, respectively, for participation in this study.
The method of D8/17 staining and assessment has been described
in detail elsewhere (11, 12). The ratio of DR+ cells to D8/17+ cells
divided by the number of DR+ cells was multiplied by 100 to yield
the percentage of D8/17+ cells. Individuals were defined as D8/17
positive if they had 12% or more D8/17+ cells and D8/17 negative if
they had 10% or less D8/17+ cells. These cutoffs were established
from previous work that has demonstrated a bimodal curve of distri-
bution for this marker (10–12).
SAS was used for the statistical analysis, and comparisons among
the PANDAS patients, the patients with Sydenham’s chorea, and the
healthy children were analyzed by using chi-square (odds ratio) with
the dichotomous variable of D8/17 positive versus D8/17 negative.
The percentages of D8/17+ cells in each group were compared by
using analysis of variance and Duncan’s multiple range post hoc test.
RESULTS
Twenty-three of the 27 PANDAS patients and eight
of the nine patients with Sydenham’s chorea were found
to be D8/17 positive; in contrast, only four of the 24
healthy children were D8/17 positive (table 1). The fre-
quency of D8/17 positive children among the healthy
children was significantly smaller than the frequency
among both patients with Sydenham’s chorea (χ
2
=14.7,
df=1, odds ratio=40, confidence interval=10–166, p<
0.0001) and patients with PANDAS (χ
2
=23.9, df=1,
odds ratio=29, confidence interval=9–95, p<0.0001)
(table 1). The mean and median values of the percent-
ages of D8/17+ cells by group are also given in table 1.
The mean percentage of D8/17+ cells was significantly
smaller in the group of healthy children than in the
PANDAS group and in the Sydenham’s chorea group
(table 1). The patient groups did not differ significantly
from one another in their mean values. Nonparametric
analysis of these data provided the same results.
DISCUSSION
These data demonstrate that a trait marker associated
with rheumatic fever can be used to identify children
with PANDAS. The results raise questions about the
nature of the relationship between PANDAS and Sy-
denham’s chorea. Both disorders are triggered by β-
hemolytic streptococcal infections, both have neuro-
psychiatric symptoms, and both have dramatically high
rates of D8/17 positivity. However, the disorders are
distinct and separable—it is clear that PANDAS does
not merely represent “missed” cases of rheumatic fever
(as Sydenham’s chorea) because each of the children
was carefully screened by a pediatrician and a pediatric
neurologist and none of the major Jones criteria (in-
cluding chorea) was found in the PANDAS patients.
Several factors could account for the differential re-
sponse to β-hemolytic streptococcal infection seen in
TABLE 1. D8/17 Status in Children With Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PAN-
DAS) or Sydenham’s Chorea and Healthy Volunteers
Subjects
Percent D8/17+ Cells
a
D8/17-
Positive
Individuals
b
Odds Analysis
Mean SD Median Range N % Odds Ratio
c
p
Children with PANDAS (N=27) 29 20 25 0–77 23 85 28.8 <0.0001
Children with Sydenham’s chorea (N=9) 35 22 29 5–76 8 89 40.0 <0.0001
Healthy children (N=24) 8 9 5 0–34 4 17
a
Means were compared by analysis of variance and Duncan’s multiple range post hoc test. PANDAS patients and patients with Sydenham’s
chorea differed significantly from the healthy children (F=12.4, df=2, 57, p<0.001).
b
Individuals were defined as D8/17 positive if they had 12% D8/17+ cells.
c
Odds ratios were calculated in comparison with healthy children.
BRIEF REPORTS
Am J Psychiatry 154:1, January 1997 111
PANDAS and Sydenham’s chorea. These include differ-
ences in genetic vulnerability, neurodevelopmental
maturation at the time of exposure, and the specificity
of the host-microbe interaction. For example, in Syden-
ham’s chorea, cross-reactive antibodies might recognize
a different population of cells from those which cause
obsessive-compulsive symptoms or tics (14, 15).
Although the findings of this study require amplifica-
tion and replication, they raise intriguing possibilities. If
the D8/17 marker is able to identify PANDAS-suscepti-
ble individuals, not only would it be the first such marker
for a psychiatric disorder, but it would have both imme-
diate and long-term benefits. In the short-term, it would
improve research into the etiology and pathophysiology
of obsessive-compulsive disorder and Tourette’s syn-
drome by allowing us to define a more homogeneous
subgroup of patients for study; it would provide patients
and their families with more accurate descriptive and
prognostic information; and it would promote the devel-
opment of treatments designed to address the underlying
pathophysiology of the disorder, rather than mere symp-
tom palliation. Studies of the effectiveness of immuno-
modulatory therapies for reducing symptom relapses are
underway for children who have already been identified
as having PANDAS, and preliminary results are encour-
aging (8). The long-term benefit of an effective trait
marker of PANDAS susceptibility would be the ability to
screen at-risk individuals and prevent symptom onset. If
the D8/17 marker proves reliable in identifying PAN-
DAS-susceptible individuals, then it may be possible to
provide prophylaxis to at-risk individuals and prevent
the onset of some cases of obsessive-compulsive disorder
and Tourette’s syndrome. Such possibilities provide the
impetus for further investigations.
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BRIEF REPORTS
112 Am J Psychiatry 154:1, January 1997
... It is an established concept that obsessive-compulsive symptoms (OCS) may be associated with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS; [27][28][29][30]), which is proposed to be caused by an infection with group A beta-hemolytic Streptococcus pyogenes. It is assumed that reactive autoimmune phenomena can develop after infections that cause PANDAS [31]. ...
... The PANDAS consensus criteria were developed by Swedo and colleagues [27][28][29] and describe a neuropsychiatric syndrome with the presence of OCD or tic disorder and a temporal association of symptom onset with group A streptococcal infection. Up to now, reports of similar cases in adulthood are rare [64][65][66][67]. ...
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... In the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), obsessive-compulsive symptoms (OCS) may be autoimmune mediated (1). The first cases of autoimmune obsessive-compulsive disorders (OCD) in adults with well-characterized and novel neuronal autoantibodies have been described previously (2,3). ...
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We reviewed the phenomenology of obsessive-compulsive disorder (OCD) in 70 consecutive children and adolescents studied prospectively at the National Institute of Mental Health, Bethesda, Md, between 1977 and 1987. There is striking similarity between the clinical presentation of OCD in children and in adult patients. Washing, grooming, and checking rituals and/or preoccupation with disease, danger, and doubt account for the great majority of cases. Twenty-five percent of subjects had a first-degree relative with OCD. The fixed content and style of symptoms within and across subjects, and the identical presentation across a wide age range, suggest an ethological model for OCD.
Article
SELECTED CASE AN 18-YEAR-OLD high school girl from a small town in Maine was brought to a psychiatrist by her mother because of her excessive showering and dressing rituals. Showers lasted two hours; it took a half hour to dress. Each act of dressing was counted and had to be repeated precisely 17 times. These behaviors had begun gradually at age 15 years, causing chronic tardiness at school; two months of counseling with the school psychologist was not helpful. When the psychiatrist was consulted, the patient's circle of friends and activities had narrowed, and she was missing school one or two days a week.She had been an outgoing, popular girl, with average grades, who had not previously exhibited unusual concern for neatness, expressed odd thoughts or preoccupations, or presented any behavioral problems of note. When interviewed, she was embarrassed discussing her washing and counting behaviors. She said she "knew