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Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases


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The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.
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Pediatric Autoimmune Neuropsychiatric Disorders
Associated With Streptococcal Infections:
Clinical Description of the First 50 Cases
Susan E. Swedo, M.D., Henrietta L. Leonard, M.D., Marjorie Garvey, M.D.,
Barbara Mittleman, M.D., Albert J. Allen, M.D., Ph.D., Susan Perlmutter, M.D.,
Lorraine Lougee, L.C.S.W., Sara Dow, B.A., Jason Zamkoff, B.A., and Billinda K. Dubbert, M.S.N.
Objective: The purpose of this study was to describe the clinical characteristics of a novel
group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as
pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A
β-hemolytic streptococcal [GABHS]) infections (PANDAS).
Method: The authors conducted
a systematic clinical evaluation of 50 children who met all of the following five working
diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, epi-
sodic course of symptom severity, association with GABHS infections, and association with
neurological abnormalities.
Results: The children’s symptom onset was acute and dramatic,
typically triggered by GABHS infections at a very early age (mean=6.3 years, SD=2.7, for tics;
mean=7.4 years, SD=2.7, for OCD). The PANDAS clinical course was characterized by a
relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying
the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals,
cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly com-
mon. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by
pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children, there
were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with docu-
mented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory in-
fection (no throat culture obtained), and six (4%) with GABHS exposure.
Conclusions: The
working diagnostic criteria appear to accurately characterize a homogeneous patient group in
which symptom exacerbations are triggered by GABHS infections. The identification of such
a subgroup will allow for testing of models of pathogenesis, as well as the development of
novel treatment and prevention strategies.
(Am J Psychiatry 1998; 155:264–271)
his is the first comprehensive report of a group of
patients with childhood-onset obsessive-compul-
sive disorder (OCD) and tic disorders. The children
have different primary diagnoses, including both OCD
and tic disorders, but share in common a clinical course
characterized by dramatic symptom exacerbations fol-
lowing group A β-hemolytic streptococcal (GABHS) in-
fections. Sir William Osler was actually the first to no-
tice such a relationship when he described “a certain
perseverativeness of behavior” in patients with Syden-
ham’s chorea, a variant of rheumatic fever (1). Aside
from a few isolated reports (2–4), the importance of his
prescient observations went unnoticed until the late
1980s, when we undertook a series of investigations di-
rected at the hypothesis that basal ganglia dysfunction
could cause a wide variety of neuropsychiatric symp-
toms depending upon the nature of both the environ-
mental trigger and the host susceptibility (5). Support
for this hypothesis had been provided by pathological
reports of basal ganglia involvement in Sydenham’s
chorea (6) and neuropsychological and neuroimaging
evidence of basal ganglia dysfunction in both Syden-
ham’s chorea and OCD (7–11), as well as demonstra-
tions of similar antineuronal antibodies in both disor-
Received Aug. 26, 1996; revision received April 8, 1997; accepted
May 12, 1997. From the Section on Behavioral Pediatrics, Child Psy-
chiatry Branch, NIMH. Address reprint requests to Dr. Swedo, Child
Psychiatry Branch, NIMH, Bldg. 10, Rm. 4N224, 9000 Rockville
Pike, Bethesda, MD 20892-1381; (e-mail).
The authors thank Ms. Madeline Ramsey, Dr. Judy Rapoport, Dr.
Colette Parker, Dr. Mark Schapiro, Ms. Marlene Clark, Ms. Melissa
Kanter, Ms. Marge Lenane, and Mr. Dan Richter; the nursing staffs
of 11East, 9West, and the Dowling Apheresis Center; and especially
the patients and their parents.
264 Am J Psychiatry 155:2, February 1998
ders (5, 12–14). Further support was generated from
longitudinal studies of children and adolescents with
OCD and from systematic evaluation of children with
Sydenham’s chorea. Studies of Sydenham’s chorea re-
vealed that obsessive-compulsive symptoms were com-
mon during the illness (present in nearly three-quarters
of children) and had their onset shortly before the cho-
rea began, suggesting that the obsessive-compulsive
symptoms were not “compensatory” for physical dis-
ability (because the children were not yet ill when they
began to experience obsessions and compulsive rituals)
(15, 16). On the basis of these observations, we postu-
lated that children might exhibit only tics or OCD if the
“dose” of a presumed etiologic agent was not sufficient
to cause frank chorea (5).
Longitudinal follow-up of a group of children and
adolescents with OCD revealed that a subgroup of the
children had an episodic course characterized by dra-
matic and acute symptom exacerbations interspersed
with periods of relative symptom quiescence (17–19).
Of particular note, these exacerbations often followed
infections with GABHS. The clinical course of a 10-
year-old boy examined early in 1991 is illustrative.
Patient A presented to the child psychiatry clinic with a 2-
week history of severe obsessive concerns about contamina-
tion from AIDS and other germs, cleaning and hoarding ritu-
als, a nearly constant spitting tic, and choreiform movements
(neurologically distinct from chorea). The symptoms had be-
gun abruptly “overnight” and had progressed over a 48-hour
period to the point where A was unable to attend school or
participate in his usual extracurricular activities. His mother,
a medical technologist, brought our attention to the fact that
he had been diagnosed with GABHS pharyngitis less than 2
weeks before the onset of these symptoms. She had noted that
her older son’s tic disorder also had an episodic pattern, with
exacerbations typically occurring a few days after he had been
ill with a streptococcal pharyngitis; she suggested that “there
had to be a connection between the two” events. At the time
of initial presentation, A’s antistreptococcal antibody titers
were markedly elevated (threefold rise), and antineuronal an-
tibody titers (12, 14) were positive. Over the next few weeks,
A’s OCD symptoms decreased in severity to a subclinical level
(occasional contamination obsessions but no spitting, hoard-
ing, or hand washing), and his antibody titers also fell. About
8 months later, after another GABHS infection, A had a dra-
matic symptom exacerbation, which was again associated with
increased antibody titers, and then, slow resolution of his symp-
toms with a concomitant diminution of titers. Over the ensu-
ing 2 years, each time A’s symptoms increased and his medi-
cation dose required an upward adjustment, he had positive
antistreptolysin O titers; during periods of remission, he was
These clinical observations led to the proposal of a
unique subgroup of patients with neuropsychiatric dis-
orders that could be identified by the following criteria:
1) presence of OCD and/or a tic disorder, 2) prepuber-
tal symptom onset, 3) episodic course of symptom se-
verity, 4) association with GABHS infection, and 5) as-
sociation with neurological abnormalities. The five
criteria appeared to reliably identify a group of children
who shared a common clinical course and were pre-
sumed to have a similar pathophysiology. The criteria
reflect an underlying hypothesis that autoimmunity me-
diates the neuropsychiatric symptoms, and so the group
was designated by the acronym PANDAS, for pediatric
autoimmune neuropsychiatric disorders associated
with streptococcal infections.
This report describes the first 50 children meeting the
working diagnostic criteria for PANDAS and, in addi-
tion, discusses the clinical implications of such a diag-
nosis and proposes a model of pathogenesis.
Establishing the Working Criteria for Diagnosis of PANDAS
Systematic clinical evaluation of children with Sydenham’s chorea
suggested that specific clinical characteristics might define a homoge-
neous subgroup of patients with OCD and tic disorders, including
Tourette’s disorder. Five working criteria were formulated (20) and
have been modified slightly, as follows:
1. Presence of OCD and/or a tic disorder: The patient must meet
lifetime diagnostic criteria (DSM-III-R or DSM-IV) for OCD or a tic
2. Pediatric onset: Symptoms of the disorder first become evident
between 3 years of age and the beginning of puberty (as is generally
true for rheumatic fever [21]).
3. Episodic course of symptom severity: Clinical course is charac-
terized by the abrupt onset of symptoms or by dramatic symptom
exacerbations. Often, the onset of a specific symptom exacerbation
can be assigned to a particular day or week, at which time the symp-
toms seemed to “explode” in severity. Symptoms usually decrease
significantly between episodes and occasionally resolve completely
between exacerbations.
4. Association with GABHS infection: Symptom exacerbations
must be temporally related to GABHS infection, i.e., associated with
positive throat culture and/or elevated anti-GABHS antibody titers.
Of note, the temporal relationship between the GABHS infection and
the symptom exacerbation may vary over the course of the illness. In
rheumatic fever, there is often a delay of 6–9 months between the last
documented GABHS infection and the appearance of symptoms of
Sydenham’s chorea; however, recrudescences follow the GABHS in-
fections at a much shorter interval, often with a time lag of only sev-
eral days to a few weeks (22). It appears that the pattern is similar for
PANDAS. It should be further noted that because fever and other
stressors of illness are known to increase symptom severity, the exac-
erbations should not occur exclusively during the period of acute ill-
ness. Furthermore, as in Sydenham’s chorea and rheumatic fever,
some symptom recurrences may not be associated with documented
GABHS infections (23), so the child’s lifetime pattern should be con-
sidered when making the diagnosis.
5. Association with neurological abnormalities: During symptom
exacerbations, patients will have abnormal results on neurological
examination. Motoric hyperactivity and adventitious movements (in-
cluding choreiform movements or tics) are particularly common. Of
note, children with primary OCD may have normal results on neuro-
logical examination, particularly during periods of remission. Fur-
ther, the presence of frank chorea would suggest a diagnosis of Sy-
denham’s chorea, rather than PANDAS. It is particularly important
to make this distinction, since Sydenham’s chorea is a known variant
of rheumatic fever and requires prophylaxis against GABHS; PAN-
DAS does not.
The diagnostic criteria were applied retrospectively to patients seen
between 1991 and 1993 and prospectively to those seen thereafter.
Each case was presented at a case conference, and consensus opinion
was used to determine whether or not the child should be included in
the PANDAS category. The assigned diagnoses were then inde-
pendently confirmed by two of us (H.L.L. and S.E.S.) by strict appli-
cation of the diagnostic criteria to case summaries; both authors were
in complete agreement about the 50 PANDAS and 32 non-PANDAS
cases reviewed.
Am J Psychiatry 155:2, February 1998 265
As a further test of the validity of the PANDAS working diagnostic
criteria, 20 screening histories (10 PANDAS and 10 non-PANDAS
cases) were selected by one of us (L.L.) and identifying information
was removed. Five raters (B.K.D., M.G., H.L.L., S.P., and S.E.S.) in-
dependently applied the diagnostic criteria to the case summaries, and
each rater correctly identified all 20 cases (kappa=1.0).
Children with an acute onset or dramatic exacerbations of obsessive-
compulsive symptoms and/or tics were sought through mailings to child
psychiatrists, pediatricians, and pediatric neurologists, as well as
through advertisements in the Tourette’s Syndrome Association na-
tional newsletter. The advertisements did not include mention of infec-
tious agents as a trigger. The local Tourette’s Syndrome Association
chapter and the national Obsessive Compulsive Foundation also served
as sources of patient referrals. In addition, referrals were sought through
presentations at national meetings and direct contact with physicians.
As might be expected, referrals were initially limited (one or two patients
per month) but increased gradually to the point where we currently
conduct four to six telephone screenings per week.
At the time of this report, 270 telephone screenings had been con-
ducted; of these, 109 subjects were invited to come to the National In-
stitute of Mental Health (NIMH) for an in-person screening evaluation.
The screening evaluation was conducted by at least two physicians
(S.E.S., H.L.L., A.J.A., M.G., and/or S.P.) and consisted of a review of
the child’s medical records and a clinical interview with the child and his
or her parents—this included a complete assessment of the history of the
OCD and/or tic disorder and emphasized the chronology of the child’s
neuropsychiatric symptoms in relationship to environmental triggers.
Children were excluded from study participation if they had a his-
tory of Sydenham’s chorea, rheumatic fever, or another autoimmune
disorder or if examination revealed cardiac abnormalities consistent
with prior rheumatic carditis (none of the children was excluded for
heart disease.) They were also excluded if they failed to meet the
working criteria for the diagnosis of PANDAS; of note, 27 children
were excluded at the time of the in-person screening because the in-
terview revealed that they did not have a clear association between
streptococcal infections and symptom exacerbations; 32 children
were excluded following baseline evaluation.
Thus, 50 children met the working diagnostic
criteria for PANDAS and are the subjects of
this report.
Depending upon their symptom acuity, the
children were enrolled in one of two proto-
cols—a placebo-controlled study of penicillin
prophylaxis or a randomized-entry controlled
study of various immunomodulatory treat-
ments (for acutely ill patients). Both studies
had appropriate institutional review board re-
view and approval. All subjects gave written
assent, and their parents written consent, to
participate in the research investigations.
At baseline, subjects completed a battery
of neuropsychological tests and a limited
number of psychological tests to assess
general intelligence level (5, 10). Parents
provided historical information about their
child (Diagnostic Interview for Children and
Adolescents, revised, parent version) (24, 25),
themselves (medical history and Schedule for
Affective Disorders and Schizophrenia [26]),
and their family members (semistructured
family history; instrument available from
Dr. Swedo upon request). The subjects un-
derwent systematic medical and psychiatric
assessment, including a structured psychiat-
ric interview (Diagnostic Interview for Chil-
dren and Adolescents, revised, child version)
(24, 25) and standardized neurological examination (unpublished
examination, available from Dr. Garvey upon request, and the
Physical Assessment of Neurologic Subtle Signs examination [27]).
Choreiform movements (small, jerky movements occurring irregu-
larly and arrhythmically in different muscles) were assessed by us-
ing a modification of the guidelines outlined by Touwen (28).
Proximal and distal movements were scored together. A score was
assigned according to the amplitude and frequency of the move-
ments over a 30-second period: 0=no movements observed; mini-
mal=occasional small-amplitude movements of fingers; moder-
ate=continuous, small-amplitude movements of fingers, wrists, and
proximal areas (arms/shoulders); marked=continuous, moderate-
amplitude movements of fingers, wrists, and proximal areas.
The child’s neuropsychiatric symptom severity was rated at
baseline by using a variety of semistructured scales, including the
TABLE 1. Demographic Characteristics of 50 Children With PANDAS
Characteristic Value
Mean SD
Age at baseline evaluation (years) 9.3 2.6
Age at onset of obsessions/compulsions (years) 7.4 2.7
Age at onset of tics (years) 6.3 2.7
DSM-III-R or DSM-IV diagnosis
Subclinical OCD with tics or OCD and tics 32 64
Tics only 8 16
OCD only 10 20
Meets DSM-IV criteria 28 56
Subclinical 14 28
None 8 16
Tic disorder 40 80
None 10 20
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections. The ratio of boys to girls was 2.6:1.
FIGURE 1. Age at Onset for Boys and Girls With PANDAS
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
266 Am J Psychiatry 155:2, February 1998
Yale-Brown Obsessive Compulsive Scale (29, 30), Shapiro tic se-
verity rating (31), Global Assessment Scale (32), and NIMH ratings
of global, OCD, depression, and anxiety symptom severity (33,
34), as well as three scales designed specifically for use with these
children: NIMH irritability, tic severity, and attention deficit hy-
peractivity disorder (ADHD) severity scales (instruments were
modified from the NIMH OCD rating scale and are also available
from Dr. Swedo upon request).
Baseline laboratory studies included CBC with WBC differential,
erythrocyte sedimentation rate, standard tests of thyroid function,
blood chemistries including osmolality and electrolytes, and an im-
munologic panel that included antinuclear antibody titer and quanti-
tative immunoglobulin levels, among others. (These laboratory stud-
ies have not yet been systematically analyzed, and results are not
presented in this article.) Each child also had a throat culture for
GABHS, antistreptolysin O titers, and antistreptococcal DNAase B
The demographic data for the 50 subjects are shown
in table 1. Of particular note is the young age of this
group and the early age at onset of both obsessive-com-
pulsive symptoms and tics. The children were evenly
divided between those with a primary diagnosis of
OCD (N=24, 48%) and those with primary tic disorder
(N=26, 52%); 43 (86%) of the children reported obses-
sive-compulsive symptoms, and 40 (80%) of the chil-
dren were found to have motor tics. Boys outnumbered
girls by a ratio of 2.6:1; below age 8 years, the ratio was
4.7:1. Figure 1 shows this gender distribution plotted
against age at onset.
Symptoms of OCD varied by primary diagnosis (ta-
ble 2). Children with primary OCD reported more
washing and checking behaviors than did children with
a primary diagnosis of tic disorder (washing: χ
df=1, p=0.005; checking: χ
=2.8, df=1, p=0.09).
The severity of the obsessive-compulsive symptoms
was moderate, on average, as were motor and vocal tics
(table 3).
Psychiatric comorbidity (table 4) was common for
the children with PANDAS. ADHD, affective disor-
ders, and anxiety disorders were most prevalent (40%,
42%, and 32%, respectively).
The symptoms of the comorbid diagnoses (particu-
larly ADHD) were also reported to be exacerbated fol-
lowing streptococcal infections, although this was not
assessed systematically. In addition, a number of behav-
ioral symptoms were noted to have had their onset con-
comitant with the onset of the OCD/tics and to have a
relapse-remission pattern similar to that of the tics and
obsessive-compulsive symptoms. These symptoms are
listed in table 5. Most notable among them were emo-
tional lability, separation anxiety, motoric hyperactiv-
ity and “fidgetiness,” age-inappropriate behavior, and
nighttime difficulties, including severe nightmares and
new bedtime fears/rituals (e.g., needing to have a night-
light, sleeping outside the parents’ bedroom). The
symptoms were quite distressing to the children and
were clearly distinguishable from the child’s premorbid
state. These comorbid symptoms always started
abruptly, at the same time as the obsessive-compulsive
symptoms and tics began or worsened, and were also
associated with an increase in antistreptococcal anti-
body titers.
Association With Neurological Abnormalities
As previously described, 40 children (80%) had a tic
disorder. No child had overt chorea, by history or ex-
amination. Formal testing for choreiform movements
TABLE 2. OCD Symptoms of 50 Children With PANDAS
and Primary
OCD or Primary Tic Disorder
Symptom N % N % N %
Contamination 16 67 9 35 25 50
Harm to self 938 2 81122
Harm to others 10 42 7 27 17 34
Violent images 833 4151224
Sexual 938 1 41020
Hoarding 833 4151224
Magical 833 4151224
Somatic 11 46 3 12 14 28
Religious 938 5191428
Other 11 46 10 38 21 42
Washing, cleaning, spitting 15 63 6 23 21 42
Checking 12 50 7 27 19 38
Repeating 145812462652
Counting 4 17 2 8 6 12
Ordering, arranging, table
setting 12 50 8 31 20 40
Hoarding 625 312 918
Superstitious 2 8 1 4 3 6
Involves other persons 7 29 3 12 10 20
Other 17 71 11 42 28 56
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections.
TABLE 3. Severity of Symptoms for Children With PANDAS
Primary Tic Disorder or Primary OCD
Primary Tic
Rating Scale Mean SD Mean SD Mean SD
NIMH Obsessive-
Compulsive Scale 4.0 2.5 8.2 3.1 5.9 3.5
Yale-Brown Obsessive
Compulsive Scale sum
Obsessions 8.5 2.8 12.0 5.3 10.5 4.7
Compulsions 5.6 4.9 11.7 6.0 9.1 6.3
Global Assessment Scale 71.0 13.2 56.6 13.6 64.7 15.1
Shapiro tic severity
Motor tics, historical 11.1 4.7 10.1 5.0 10.8 4.7
Vocal tics, historical 8.7 6.1 8.6 5.6 8.7 5.9
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections.
Am J Psychiatry 155:2, February 1998 267
was performed with 26 of the 50 children. Only one
child had no choreiform movements noted on baseline
examination (although she subsequently demonstrated
these movements). Marked choreiform movements
were observed in 13 children (50%); five (19%) had
moderate choreiform movements, and seven (27%) had
minimal choreiform movements. Of note, and contrary
to expectations that the movements would decrease
with increasing age, a similar number of children above
10 years of age (N=4 of 7, 57%) and under the age of
10 (N=9 of 19, 47%) had marked choreiform move-
ments (p=0.66, Fisher’s exact test). Both the choreiform
movements and the tics waxed and waned in severity
over time, with exacerbations temporally linked to
streptococcal infections in a manner similar to the ob-
sessive-compulsive symptoms.
Association Between Symptom Exacerbations and
Streptococcal Infections
Evidence of a temporal relationship between strepto-
coccal infections and symptom exacerbations was ob-
tained from parent history, by comparison of the child’s
pediatric (medical) records to his or her psychiatric re-
cords, and by prospective study. Symptom onset was
associated with GABHS infection in 21 children (42%),
with GABHS exposure in one child (2%), and with
symptoms of pharyngitis (no throat culture obtained)
in 14 subjects (28%). Each child also had at least one
symptom exacerbation that was preceded (within the
prior 6 weeks) by a documented GABHS infection.
Among the 50 children, there were a total of 144 exac-
erbations in which the relationship to GABHS infection
was known. Thirty-three (23%) of these were not asso-
ciated with any sign of GABHS infection within the pre-
ceding month. However, the majority had at least some
evidence of GABHS triggers: 45 (31%) exacerbations
were associated with a positive throat culture or epi-
sode of scarlet fever (which is distinguished by a macu-
lopapular rash pathognomonic for GABHS), six (4%)
had a history of recent upper respiratory infection
symptoms plus known GABHS exposure (sibling or close
friend), and 60 (42%) had a sore throat or upper respi-
ratory infection symptoms with fever, but no culture or
titers were obtained. The last two categories represent
possible GABHS infections, but it is not possible to
make such a diagnosis in the absence of a positive throat
culture or rising antistreptococcal antibody titers.
The 50 children with PANDAS described in this re-
port share many clinical features in common with other
groups of childhood-onset OCD and tic disorders. The
obsessive-compulsive symptoms and patterns of motor
and vocal tics are similar to those previously described,
as is the frequency of comorbid depression and anxiety
disorders (17–19, 31, 35–37). Boys outnumber girls, as
has been previously reported for both tic disorders and
early-childhood onset OCD. Indeed, the PANDAS pa-
tients appear to be remarkably similar to those with
prepubertal symptom onset who were previously de-
scribed as part of an unselected group of subjects with
childhood-onset OCD (17).
The children with PANDAS had several unique clini-
cal characteristics, as defined by the working diagnos-
tic criteria and confirmed by observed symptom exac-
1. Very-young-age-at-onset PANDAS is defined as a
prepubertal disorder so that it is not surprising that the
children had an early age at onset (6.3 years for tics
and 7.4 years for obsessive-compulsive symptoms).
However, the average age at onset of symptoms for
this group was nearly 3 years younger than that for
previous groups of childhood-onset OCD and tic dis-
orders (17, 37).
2. Symptom exacerbations were sudden and dramatic
and were associated with GABHS infections. Positive
throat culture was the most frequent means of demon-
TABLE 4. Comorbid Diagnoses of 50 Children With PANDAS
Diagnosis N %
ADHD 20 40
Oppositional defiant disorder 20 40
Conduct disorder 2 4
Major depression 18 36
Dysthymia 6 12
Mania 0 0
Separation anxiety 10 20
Avoidant disorder 4 8
Overanxious disorder 14 28
Specific phobia 8 16
Eating disorder 1 2
Enuresis 6 12
Encopresis 5 10
Somatization disorder 0 0
Psychoses 0 0
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections.
TABLE 5. Symptoms Associated With Exacerbations of PANDAS
50 Children
Symptom N %
Emotional lability 33 66
Change in school performance 30 60
Personality change 27 54
Bedtime fears/rituals 25 50
Fidgetiness 25 50
Separation anxiety 23 46
Irritability 20 40
Tactile/sensory defensiveness 20 40
Impulsivity/distractibility 19 38
Deterioration in handwriting 18 36
Oppositional/defiant 16 32
Deterioration in math skills 13 26
Nightmares 9 18
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections.
268 Am J Psychiatry 155:2, February 1998
strating an association. Because of this, and because un-
treated GABHS infections can precipitate rheumatic fe-
ver, it was of concern to note how often sore throats
with fever went uncultured. Because rheumatic fever
continues as a risk of untreated GABHS infection, all
parents should be encouraged to seek medical care
whenever their school-age child has symptoms of
GABHS pharyngitis, such as sore throat with fever,
scarlatiniform rash, or a symptom triad of headache,
stomachache, and fever (even without a sore throat).
Two clinical notes should be made. First, not all
symptom exacerbations were preceded by GABHS in-
fections; viral infections or other illnesses could also
trigger symptom exacerbations. This is in keeping with
the known models of immune responsivity—primary
responses are specific (e.g., directed against a particu-
lar epitope on the GABHS), while secondary responses
are more generalized. Thus, the lack of evidence for a
preceding strep infection in a particular episode does
not preclude the diagnosis of PANDAS. (Note, how-
ever, that the diagnosis cannot be made without estab-
lishing a clear association between GABHS infection
and symptom exacerbation, preferably on at least two
occasions.) Second, positive antistreptococcal titers
obtained at the time of a single symptom exacerbation
are not sufficient to prove that a child has PANDAS.
Because antistreptococcal antibody titers may remain
elevated for several months, longitudinal study is nec-
essary to demonstrate that not only is seropositivity
associated with symptom exacerbations, but also that
seronegativity (or falling titers) is associated with
symptom remission. Longitudinal study of a small
number of children with PANDAS suggests that exac-
erbations are associated with a rapid, dramatic (two-
fold or higher) increase in antistreptococcal titers,
while symptom remission and titer decreases occur
more slowly. Data are currently being collected to fur-
ther define this relationship.
3. Frequent association with motoric hyperactivity,
impulsivity, and distractibility. The symptoms met cri-
teria for ADHD, except that the onset frequently oc-
curred after age 6 years. The children with PANDAS
exhibited a peculiar “squirminess” in which the chil-
dren tried very hard to sit still but constantly wriggled
and fidgeted in their chairs. This was not chorea but
was quite reminiscent of early descriptions of St. Vi-
tus’s dance.
4. Comorbid symptoms (emotional lability, separa-
tion anxiety, age-inappropriate behavior, and night-
time difficulties) were also episodic and temporally re-
lated to GABHS infections. The symptoms were present
so frequently that it is tempting to speculate that they
are also manifestations of the PANDAS phenomenon,
particularly since the rates in this group of children are
so much higher than expected in the community (38,
39). Perhaps the syndrome of PANDAS should be ex-
panded to include primary diagnoses of late-onset
ADHD and separation anxiety disorders, as well as
OCD and tic disorders. It is possible that some or all of
these may be manifestations of the pathophysiology
leading to PANDAS. Further study will permit defini-
tion of the relationship between autoimmunity trig-
gered by GABHS infection and other childhood neuro-
psychiatric disorders.
There are several limitations to this investigation that
are worthy of note. First, many of our patients were
referred through the local Tourette’s Syndrome Asso-
ciation, which may have caused an overrepresentation
of tic disorders among the study group. Epidemiologic
studies and application of the PANDAS diagnostic cri-
teria to unselected clinic populations will help ascertain
whether or not tics are as common as reported here
(80% of subjects). Second, the association of GABHS
infection with symptom exacerbations was assigned
retrospectively for the majority of episodes. Ideally, this
relationship would be established by prospective analy-
sis. For example, we established a 6-week cutoff for
preceding GABHS infections. This may have excluded
the triggering GABHS infection, since data from rheu-
matic fever studies demonstrate that the GABHS infec-
tion can precede symptom onset by several months (22,
23), although the lag between subsequent infections
and symptom exacerbations is much shorter—often
only a few days to a week apart. This temporal change
is consistent with known models of immunity in which
the primary response is slow and the secondary re-
sponse is rapid (40).
The present data cannot be used to answer the ques-
tion of how many children with neuropsychiatric disor-
ders have PANDAS, nor can it inform us about the
natural history of the disorder. What happens to these
children? Do they comprise the one in seven individuals
whose OCD and tic disorders spontaneously remit (41)
because they outgrow their symptoms after they pass
through the age of vulnerability? Or perhaps they are
the unfortunate ones who have chronic, treatment-re-
sistant OCD (42, 43) because repeated GABHS infec-
tions have caused irreversible damage to the basal gan-
glia. Answers to these questions will be obtained only
by careful, systematic evaluation of this and other
groups of patients with PANDAS.
We have previously speculated that obsessive-com-
pulsive symptoms might be etiologically similar to Sy-
denham’s chorea and rheumatic fever (5, 13). On the
basis of what is known about the pathogenesis of rheu-
matic fever and our observations of this cohort of 50
children with PANDAS, we have developed the follow-
ing model of pathogenesis of PANDAS: Pathogen +
Susceptible Host Immune Response Sydenham’s
chorea or PANDAS (neuropsychiatric symptoms).
Application of the model permits the recognition
of PANDAS as a distinct clinical syndrome. It also al-
lows for the characterization of particular strains of
GABHS that are prone to the induction of PANDAS in
the susceptible host; the definition of factors that
confer susceptibility for the development of PANDAS
in an individual; the description of the immune re-
sponse associated with the development of the clinical
symptoms; and the identification of the structures and
functions involved in the expression of the clinical symp-
Am J Psychiatry 155:2, February 1998 269
toms. Each of the delineated points can be the focus of
diagnostic testing and therapeutic intervention. The
susceptible host might be rendered less susceptible by
prevention of GABHS infections (antibiotic prophy-
laxis) or by immunization against GABHS infections.
Infection of the host by pathogenic GABHS might be
prevented by colonization of the host with nonpatho-
genic strains of the bacterium or by targeted anti-
GABHS antimicrobials. The immune response might be
influenced by the administration of adjuvants, cyto-
kines, or immunomodulatory agents. End-organ pa-
thology might be prevented by treatments aimed at re-
moving pathogenic autoantibodies or stimulating the
function of specific neural circuits or structures. Each
of these arenas holds tremendous promise for future
therapeutic interventions.
The possibility that pathogens other than GABHS
can induce neuropsychiatric symptoms is suggested by
the presence of non-GABHS-related exacerbations in
the children with PANDAS, as has been reported for
Sydenham’s chorea (23). It is postulated that GABHS
needs to be the initial autoimmunity-inciting event but
that subsequent symptom exacerbations can be trig-
gered by viruses, other bacteria, or noninfectious im-
munologic responses.
In the model of pathogenesis, host factors are also of
critical importance. Male gender appears to be a risk
factor, as three-quarters of the PANDAS subjects are
male, but the mechanism of this increased vulnerability
is unknown. The age of the host also may determine
susceptibility; it is known that rheumatic fever is quite
rare after puberty. It appears that the developmental
changes of adolescence may decrease the vulnerability
to the cross-reactive autoimmunity. It is also possible
that the postpubertal decrease in incidence (44) is re-
lated to the fact that the rate of GABHS infections falls
dramatically around the age of 12, presumably because
the child has developed antibodies against the con-
served portion of the M-protein (i.e., the child is able to
make antibodies that recognize all strains of GABHS)
(V. Fischetti, personal communication, 1994).
Genetic control of the immune response may contrib-
ute to differential vulnerability to PANDAS. Murine ge-
netic models suggest that the response to infectious
pathogens is strain specific. Different strains have re-
sponses that differ qualitatively and quantitatively and
lead to very different clinical outcomes. For example,
the immune response of BALB/c mice to infection with
M. leprae or S. mansoni is extreme and leads to the
death of the animal, whereas similar inocula in C57/
BL6 mice cause self-limited infections (45, 46).
Familial factors may also play a role in the patho-
genesis of PANDAS. “Rheumatogenic families,” in
which the incidence of rheumatic fever far exceeds that
of the general population, were described first by
Cheadle in 1889 (21). Preliminary studies of the mode
of inheritance of this vulnerability suggest that the trait
is autosomal recessive (47, 48) and that it may be re-
lated to a surface characteristic of peripheral blood
mononuclear cells. Individuals who are susceptible to
rheumatic fever have a high frequency of binding of a
monoclonal antibody designated D8/17 (48). We have
previously reported that patients with PANDAS have
rates of D8/17 positivity similar to those seen in pa-
tients with rheumatic fever (and Sydenham’s chorea, a
rheumatic fever variant), and markedly different from
rates found in healthy control subjects (49). The pres-
ence of a biological marker of susceptibility to rheu-
matic fever and PANDAS provides for the development
of prophylactic strategies aimed at preventing the se-
quelae of GABHS disease in susceptible individuals by
either altering host susceptibility or preventing GABHS
The working diagnostic criteria appear to define a
meaningful subgroup of patients with childhood-onset
OCD and tic disorders; with further study, other neuro-
psychiatric symptoms may also be found to be appro-
priately included in the PANDAS spectrum. The identi-
fication of a subgroup of patients with PANDAS may
be important from several aspects. First, children who
develop OCD, tics, motoric hyperactivity, and other
neuropsychiatric symptoms as sequelae of streptococ-
cal infections (i.e., those with PANDAS) may share a
common pathogenetic process that is distinct from
other (non-PANDAS) cases of such disorders. This ho-
mogeneity may be related to genetic vulnerability or
other definable biological factors. Second, if children
with PANDAS share a common pathogenesis, therapies
can be developed that are directed at correcting the un-
derlying pathological process, rather than at mere
symptom palliation alone. Third, hypothesis-driven re-
search directed at defining the susceptible host, the spe-
cific triggers, the host-pathogen interaction, and the
end-organ targeting of the pathogenetic process may
shed light not only on PANDAS, but also on non-PAN-
DAS neuropsychiatric symptoms. Our ongoing work in
the phenomenology and pathogenesis of PANDAS is
designed to address each of these issues.
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Am J Psychiatry 155:2, February 1998 271
... Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a clinical syndrome characterized by the abrupt onset of major personality, movement, and behavioral changes in a patient with a history of streptococcal infection. 1,2 In 1998, Swedo et al. first described PANDAS in a study done on a group of children with b-hemolytic streptococcal infection who developed sudden onset obsessive-compulsive features, tics, and behavioral changes. 2 Recurrent Group A b-hemolytic streptococcal infection, history of rheumatic fever, or any other familial autoimmune disorder in the family might play an important role in determining the rapid onset of neuropsychiatric disturbances. PANDAS are regarded as an autoimmune disease since streptococcal infection exhibits post-infectious autoimmunity by molecular mimicry. ...
... 1,2 In 1998, Swedo et al. first described PANDAS in a study done on a group of children with b-hemolytic streptococcal infection who developed sudden onset obsessive-compulsive features, tics, and behavioral changes. 2 Recurrent Group A b-hemolytic streptococcal infection, history of rheumatic fever, or any other familial autoimmune disorder in the family might play an important role in determining the rapid onset of neuropsychiatric disturbances. PANDAS are regarded as an autoimmune disease since streptococcal infection exhibits post-infectious autoimmunity by molecular mimicry. ...
... A diagnostic criterion has been proposed which includes: (1) the presence of OCD or a tic disorder or both, (2) pediatric onset, (3) episodic course of symptom severity with abrupt onset or dramatic symptom exacerbations, (4) temporal association with Group A b-hemolytic streptococcal infection, and (5) association with neurological abnormalities during symptom exacerbations. 2,7 Children presenting with OCDs should also be tested for a pharyngeal swab and anti-streptococcal antibodies as they are an indicator of exposure to streptococcal infection. 6,8,9 Differential diagnoses to be kept in mind are OCD, Sydenham's chorea, Tourette's syndrome, and autoimmune encephalitis. ...
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a clinical syndrome characterized by the abrupt onset of major personality, movement, and behavioral changes in a patient with a history of streptococcal infection. We aimed to do a bibliometric analysis of the published research on PANDAS. All the published articles available on the PubMed database from the time of inception till August 2022 were included in the study. All the PubMed IDs (PMID) of the articles were entered in Harvard Catalyst, a free online software, for bibliometric analysis, and data were extracted and verified. A total of 289 relevant published articles were identified. The average number of authors per article was 4.89 and the average number of times an article was cited was 11.19 (excluding self-citation). The H-index of the published articles was 31. The Journal of Child and Adolescent Psychopharmacology published the maximum number of articles ( n = 36). The highest number of average citations (39.50 citations/articles) was for the articles published in the American Journal of Psychiatry. The most common type of articles were journal articles ( n = 259) and of which 27 were original research articles. Most of the original research discusses the effectiveness of various interventions (penicillin and other antibiotic prophylaxis, role of immunoglobulin), neuropsychiatric symptoms, and outcomes in the longitudinal course. Though PANDAS is a well-researched entity, more clinical trials, and large-scale studies will help provide better insight on this subject.
... Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a subject that generates significant controversy within the fields of pediatric rheumatology and neurology. In 1998, Swedo et al. published the first description of a cohort of children with PANDAS, defining the disease as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-haemolytic Streptococcus (GAS) infection [1]. The existence of the disease, its pathophysiology, clinical manifestations, and classification criteria are a frequent point of debate, and physicians and academics often have divergent opinions. ...
... According to the first description, the prevalence of the disease appears to be higher in males, with a male to female ratio estimated to be between 2.6 and 4.7 to 1. The mean age of symptom onset for children diagnosed with PANDAS and exhibiting tics is approximately 6.3 years, whereas those presenting with OCD tend to experience symptom onset at around 7.4 years of age [1]. Additionally, more recent research confirmed a male predominance [11]. ...
... Based on these observations, we postulated that children might exhibit only tics or OCD if the "dose" of a presumed etiologic agent was not sufficient to cause frank chorea." [1]. ...
Full-text available
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is one of the most controversial diseases in pediatric rheumatology. Despite its first description being published more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine re-lease in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.
... Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), believed to be a non-suppurative complication of infection with Group A streptococcus (GAS), was first described in 1998 (1). The existence of PANDAS as a clinical entity distinct from Sydenham chorea, childhood onset obsessive-compulsive disorder (OCD) or tic disorder of childhood has been controversial since its initial description (2,3). ...
... Dartmouth UWHC Combined Frontiers in Pediatrics girls. However, the numbers of actual cases are small, and 5 of 6 children with PANDAS were boys, similar to the report by Swedo et al. (1). It is of interest that when Cox et al., were exploring the prevalence of antineuronal antibodies in a large group of children with a history of streptococcal infection and tic and/or OCD they found the highest association with a history of GAS in children with both disorders compared to either tics or OCD alone (27). ...
Full-text available
Objective Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute-Onset Neuropsychiatric syndrome (PANS) are presumed autoimmune complications of infection or other instigating events. To determine the incidence of these disorders, we performed a retrospective review for the years 2017–2019 at three academic medical centers. Methods We identified the population of children receiving well-child care at each institution. Potential cases of PANS and PANDAS were identified by including children age 3–12 years at the time they received one of five new diagnoses: avoidant/restrictive food intake disorder, other specified eating disorder, separation anxiety disorder of childhood, obsessive-compulsive disorder, or other specified disorders involving an immune mechanism, not elsewhere classified. Tic disorders was not used as a diagnostic code to identify cases. Data were abstracted; cases were classified as PANDAS or PANS if standard definitions were met. Results The combined study population consisted of 95,498 individuals. The majority were non-Hispanic Caucasian (85%), 48% were female and the mean age was 7.1 (SD 3.1) years. Of 357 potential cases, there were 13 actual cases [mean age was 6.0 (SD 1.8) years, 46% female and 100% non-Hispanic Caucasian]. The estimated annual incidence of PANDAS/PANS was 1/11,765 for children between 3 and 12 years with some variation between different geographic areas. Conclusion Our results indicate that PANDAS/PANS is a rare disorder with substantial heterogeneity across geography and time. A prospective investigation of the same question is warranted.
... Development of OCD in general is typically described as gradual, with more pronounced episodic and deteriorating courses observed in only about 10% of patients [4]. In even more rare cases of pediatric OCD and tic disorders, onset was reported as very sudden and associated directly with streptococcal infection, as first described in a publication led by investigators at the National Institute of Mental Health [5]. Treatment of the infection in these cases was associated with substantial reduction of primary and associated symptoms, but recurrence of infection was again associated with symptom exacerbation [5]. ...
... In even more rare cases of pediatric OCD and tic disorders, onset was reported as very sudden and associated directly with streptococcal infection, as first described in a publication led by investigators at the National Institute of Mental Health [5]. Treatment of the infection in these cases was associated with substantial reduction of primary and associated symptoms, but recurrence of infection was again associated with symptom exacerbation [5]. Presentation of OCD in these cases, which is much more typical in males than in females and was usually accompanied by concomitant tics, came to be known as PANDAS and has more recently been revised and broadened under the umbrella term PANS [ [6], see Table 1]. ...
Full-text available
Purpose of Review To summarize the current state of the literature on Pediatric Autoimmune Neuropsychiatric Disorders Associated with Strep (PANDAS) and Pediatric Autoimmunie Neuropsychiatric Syndrome (PANS), conditions thought to be related to obsessive-compulsive disorder (OCD). Recent Findings Phenomenology of the PANDAS/PANS subtype of OCD and/or tic-related illness are presented, treatments reviewed, and recommendations made for the management of clinical course including early screening when quintessential signs and symptoms convergent with the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Strep) or PANS (Pediatric Autoimmune Neuropsychiatric Syndrome) presentation are evident. Further, we provide suggestions about how to discuss these syndromes with families in the clinical context to instill hope and optimism for positive outcomes. Summary Efficacy has been established for multiple treatments for pediatric OCD including pharmacotherapies both alone and in combination with cognitive behavioral therapies. Novel approaches are now being investigated to address PANDAS/PANS specifically, but our recommendation is, where feasible, to intervene with the treatments of established efficacy for OCD first, as there is evidence for their efficacy regardless of the etiology of symptom onset. Treatment development efforts and further exploration of OCD’s etiology, biological correlates, and longitudinal course continue.
... Sydenham chorea (SC) is a movement disorder after GAS infection, and the neurologic manifestation results in random, involuntary, and uncoordinated movements [11]. Another GAS neurological disorder is PANDAS, used to describe acute-onset obsessive-compulsive disorders and/or tics along with psychological symptoms in children with prior Streptococcus infection [12]. Although the identification of specific markers to diagnostically distinguish Sydenham chorea and PANDAS is progressing [67,68], both disorders are characterized by autoantibodies targeting the basal ganglia of the brain. ...
Full-text available
Group A streptococcus (GAS) is a global pathogen associated with significant morbidity and mortality for which there is currently no licensed vaccine. Vaccine development has been slow, mostly due to safety concerns regarding streptococcal antigens associated with autoimmunity and related complications. For a GAS vaccine to be safe, it must be ensured that the antigens used in the vaccine do not elicit an antibody response that can cross-react with host tissues. In this study, we evaluated the safety of our GAS vaccine candidate called VaxiStrep in New Zealand White rabbits. VaxiStrep is a recombinant fusion protein comprised of streptococcal pyrogenic exotoxin A (SpeA) and exotoxin B (SpeB), also known as erythrogenic toxins, adsorbed to an aluminum adjuvant. The vaccine elicited a robust immune response against the two toxins in the rabbits without any adverse events or toxicity. No signs of autoimmune pathology were detected in the rabbits’ brains, hearts, and kidneys via immunohistochemistry, and serum antibodies did not cross-react with cardiac or neuronal tissue proteins associated with rheumatic heart disease or Sydenham chorea (SC). This study further confirms that VaxiStrep does not elicit autoantibodies and is safe to be tested in a first-in-human trial.
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The International PANS Registry (IPR) is the first centralized, epidemiologic database of children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and PANS-like features and their siblings. PANS is a relatively new umbrella syndrome that lacks diagnostic biomarkers and is characterized by a set of working criteria. The failure to find a diagnostic biomarker is likely due to underpowered studies and inherent biological heterogeneity within PANS. Until the IPR was established, a critical barrier to large-scale longitudinal studies had been the absence of a large-scale epidemiologic study and a centralized database of children with PANS and PANS-like features. The IPR was created to serve as a translational health tool to accelerate research on the broad spectrum of complex pediatric neuroimmune conditions with the long-term goal of enabling a paradigm shift in this field from symptom-based evaluation and treatment towards biology-based diagnoses, treatments, screening, and surveillance. To date, the IPR has registered 1,666 families (3,247 children) and is the largest database in the world that gathers in-depth information on children with PANS and PANS-like features and their siblings. Enrollment in the IPR is open and ongoing; longitudinal follow up is planned. Participating families enroll their children with PANS and PANS-like features and their healthy siblings in the IPR via an online survey platform. The selection criteria for IPR enrollment are intentionally less restrictive than the current working criteria for PANS to generate a large recruitment pool and enable study of the broad spectrum of PANS-like conditions. The IPR is designed to enable ancillary study recruitment based on detailed selection criteria and to grow and expand in scope in the future. The IPR team is committed to data sharing and invites collaborators who will leverage existing data from the IPR database and extend knowledge in an area beyond the original scope of the IPR.
Background: The pediatric autoimmune neurologic disorders associated with streptococcal infections (PANDAS) comprise a group of patients who, after infection with group A β-hemolytic streptococci (GAS), exhibit a spectrum of neuropsychiatric symptoms that include obsessive thoughts, compulsive behaviors, tics, hyperactivity, inattention, and mild choreiform movements. More recently, a group of patients with a symptom complex similar to PANDAS without evidence of streptococcal etiology was given the acronym pediatric acute-onset neuropsychiatric syndrome (PANS). Despite more than several decades of study and increasing numbers of patients being identified with PANDAS and PANS, there are ongoing controversies, which range from disagreements about specific pathogenetic mechanisms to whether these entities actually exist. Objective: The purpose of this report was to examine the current body of evidence that deals with the relationship(s) of immunologic host responses to infection and putative immunologic mechanisms involved in the pathogenesis of these disorders, to evaluate the effectiveness of anti-inflammatory and immunomodulatory therapies with intravenous immunoglobulin (IVIG), and to consider the extent to which allergist/immunologists might be involved in their management. Methods: An extensive literature review was conducted in medical literature data bases by applying terms such as PANDAS, PAN, autoimmune encephalitis, neuroinflammation, and autoimmune obsessive-compulsive disorders. Results: PANDAS and its later iterative form, PANS, continue to challenge clinicians, patients, and their families. Although the precise reason why these disorders develop remains unknown, both are considered to have an autoimmune basis related to the production of antibodies directed at antigens of the putative causative infectious disease agents that are cross-reactive with antigenic epitopes on selected brain nuclei, which lead to the neuroinflammatory sequelae responsible for the neuropsychiatric symptoms of these conditions, a phenomenon referred to as molecular mimicry. Conclusion: The PANDAS/PANS disorders are a continuing burden for growing numbers of patients, health-care providers, and the global health-care systems, and are a particular challenge for the allergist/immunologist who is increasingly being called upon for their management. Because of the importance of immunologic factors in the pathogenesis and treatment of these conditions with anti-inflammatory and immune-modulating treatments, the allergist/immunologist is well poised to offer consultative care.
Background: Flares of autoimmune conditions can happen after coronavirus disease 2019 (COVID-19) infection and after COVID-19 vaccines. Patients and clinicians confront difficult decisions about vaccine safety when considering efforts to balance the risks of disease exacerbation after vaccines versus the protection that vaccines offer to potential serious life-threatening complications of COVID-19 infection. Objective: To examine symptom flares after COVID-19 infection and vaccines in the case of a form of autoimmune encephalitis that primarily affects children and young adults (pediatric acute-onset neuropsychiatric syndrome [PANS] / pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections [PANDAS]). Method: A cross-sectional study that used a survey distributed through PANS/PANDAS groups, organizations, and clinics. Results: Surveys were completed by 496 parents and/or caregivers of children with PANS/PANDAS. Among the children reported to have had a COVID-19 infection (n = 178), 43% reported severe flares of PANS/PANDAS symptoms, 23% reported mild flares, and 30% reported no symptom flares. Among those who had received COVID-19 vaccines (n = 181), 65% observed no changes in PANS/PANDAS symptoms after the vaccine, 19% reported mild flares, and 15% reported severe flares. Paired sample t-tests showed that, after COVID-19 infections, children with PANS/PANDAS were significantly more likely to experience a severe symptom flare than a mild flare or no change in symptoms. In contrast, after receiving COVID-19 vaccines, children were significantly more likely to experience no change in PANS/PANDAS symptoms than to endure a mild or severe symptom flare. In addition, children who recovered from PANS/PANDAS were significantly more likely to have no symptom change versus children who were managing the condition, both after COVID-19 infection (92% versus 25%) and vaccine receipt (100% versus 66%). Conclusion: These results support COVID-19 vaccination for most individuals with PANS/PANDAS given that the frequencies of symptom flares and setbacks after COVID-19 infection were significantly higher than after the COVID-19 vaccine. Nonetheless, further studies are needed to fully assess the risk-benefit balance and to provide a more individualized approach to disease prevention in people with immune vulnerabilities.
There have been many attempts to find predictors of the therapeutic response to the clomipramine treatment of obsessive-compulsive disorder. The majority of studies have failed to identify such predictors. Possible reasons for this failure include the small sample size of most studies, samples homogeneous with respect to the study factors of interest, and the use of statistical procedures that are insensitive to individual differences or that inadequately control for confounding. We have reanalyzed data from Ciba-Geigy's large, multicenter clinical trial of clomipramine for obsessive-compulsive disorder, using stratification and regression techniques to identify multiple prognostic factors and control for confounders. We assessed the relationship between therapeutic response and baseline measures such as severity of symptoms, type of symptoms (obsessions, compulsions, depression), length of illness, age of onset, and other demographic factors (age, race, and sex). We found age of onset to be a strong predictor of response to clomipramine: people who develop obsessive-compulsive disorder later in life have a better chance of responding than do those who become ill earlier, independent of length of illness. We also found that baseline depression is associated with response, but the association appears to be nonlinear.
† The Global Assessment Scale (GAS) is a rating scale for evaluating the overall functioning of a subject during a specified time period on a continuum from psychological or psychiatric sickness to health.In five studies encompassing the range of populations to which measures of overall severity of illness are likely to be applied, the GAS was found to have good reliability. GAS ratings were found to have greater sensitivity to change over time than did other ratings of overall severity or specific symptom dimensions. Former inpatients in the community with a GAS rating below 40 had a higher probability of readmission to the hospital than did patients with higher GAS scores.The relative simplicity, reliability, and validity of the GAS suggests that it would be useful in a wide variety of clinical and research settings.
• The prevalence of obsessive-compulsive disorder was measured in five US communities among more than 18500 persons in residential settings as part of the National Institute of Mental Health (Bethesda, Md)—sponsored Epidemiologic Catchment Area program. Lifetime prevalence rates ranged from 1.9% to 3.3% across the five Epidemiologic Catchment Area sites for obsessive-compulsive disorder diagnosed without DSM-III exclusions and 1.2% to 2.4% with such exclusions. These rates are about 25 to 60 times greater than had been estimated on the basis of previous studies of clinical populations.
46% of sera from 30 children with rheumatic chorea showed IgG antibody reacting with neuronal cytoplasm of human caudate and subthalamic nuclei. The antibody was also detected in 14% of 50 children with active rheumatic carditis. 55 normal control sera, as well as 148 sera from a broad variety of other disease states showed a low prevalence (1.8-4.0%) of positive reactions. In rheumatic chorea the presence of anti-neuronal antibody appeared to correlate with severity and duration of clinical attacks. Antibody reacting with neuronal cytoplasm was completely removed by absorption with Group A streptococcal membranes or with isolated human neurons from caudate nucleus. Partial absorption of antibody was also recorded using Group A cell wall preparations but not with Group A carbohydrate. No absorption of positive reactions was seen with streptococcal Group D membranes or cell walls. In rheumatic chorea, anti-neuronal antibody appeared to represent cross-reaction with antigens shared by Group A streptococcal membranes.
Dans le domaine de l'epidemiologie, il est difficile d'identifier les causes des maladies mentales infantiles. Les etudes se basent generalement sur la categorisation du DSM III (3eme edition du Manuel Statistique et Diagnostique des troubles mentaux). L'article donne un apercu de cinq etudes recentes sur les facteurs de risques en psychopathologie de l'enfance
• 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.
• The development design and reliability of the Yale-Brown Obsessive Compulsive Scale have been described elsewhere. We focused on the validity of the Yale-Brown Scale and its sensitivity to change. Convergent and discriminant validity were examined in baseline ratings from three cohorts of patients with obsessive-compulsive disorder (N = 81). The total Yale-Brown Scale score was significantly correlated with two of three independent measures of obsessive-compulsive disorder and weakly correlated with measures of depression and of anxiety in patients with obsessive-compulsive disorder with minimal secondary depressive symptoms. Results from a previously reported placebo-controlled trial of fluvoxamine in 42 patients with obsessive-compulsive disorder showed that the Yale-Brown Scale was sensitive to drug-induced changes and that reductions in Yale-Brown Scale scores specifically reflected improvement in obsessive-compulsive disorder symptoms. Together, these studies indicate that the 10-item Yale-Brown Scale is a reliable and valid instrument for assessing obsessive-compulsive disorder symptom severity and that it is suitable as an outcome measure in drug trials of obsessive-compulsive disorder.