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REVIEW ARTICLE
Pediatric Autoimmune
Neuropsychiatric Disorders
Associated with Streptococcal
Infection (PANDAS)
Deborah Levy Miller1, MD
FRCPC and Ronald M Laxer2, MD FRCPC
1Fellow, Division of Pediatric Rheumatology
Children’s Hospital of New York Presbyterian
Columbia University, New York, NY
2Professor of Pediatrics and Medicine
University of Toronto
Vice-President, Clinical and Academic Affairs
Hospital for Sick Children, Toronto
Ontario Canada
Corresponding Author:
Deborah Levy Miller, MD FRCPC
Pediatric Rheumatology
Children’s Hospital of New York Presbyterian
CHN 106
3959 Broadway
New York, NY 10032
Phone: 212-305-2231
Fax: 212-305-4932
Email: deblevymiller@yahoo.com
Abstract
Several
inflammatory disorders have been associated with preceding streptococcal
infections, including acute rheumatic fever (ARF), post- streptococcal reactive
arthritis, erythema nodosum, post-streptococcal glomerulonephritis and
cutaneous polyarteritis. The spectrum of
poststreptococcal disease has expanded with the addition of Pediatric
Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection
(PANDAS). PANDAS are a recently
described subgroup of childhood disorders, and there has been a great deal of
public and physician interest in their pathophysiology, diagnosis and
management. The possibility that
neuropsychiatric disorders such as Tourette’s syndrome and obsessive-compulsive
disorder (OCD) are related to a preceding streptococcal infection is certainly
controversial. The pediatric
rheumatologist may be asked to utilize his or her expertise of childhood
autoimmune diseases to evaluate the use of immunomodulatory therapies in these
children.
Clinical criteria proposed for the diagnosis of PANDAS include: the presence of OCD or a tic disorder;
childhood onset; an abrupt onset of symptoms; exacerbations of symptoms
temporally related to a preceding streptococcal infection; and the association
of neurological abnormalities. This review will discuss PANDAS in more detail, and present the
literature as to the relationship between PANDAS and Sydenham’s chorea. Additionally, the clinical features,
evidence for treatment and prevention of PANDAS will be reviewed.
Introduction
Obsessive-Compulsive
Disorder (OCD), tic disorders, Tourette’s syndrome (TS) and Sydenham’s chorea
(SC) are neurobiologic disorders that are likely due to basal ganglia
abnormalities. Both tics and OCD can
result from damage to the basal ganglia, and obsessive-compulsive symptoms
occur frequently in patients with SC.
Group A beta-hemolytic streptococcus (GABHS), the etiologic agent
responsible for acute rheumatic fever and SC, has recently been proposed to
trigger tic disorders and OCD in genetically predisposed children.
OCD is observed in one to two percent of school-aged children. Obsessions and compulsions may change in both content and severity over time with no clear pattern of progression [1]. The disorder is chronic and disabling, but the course may wax and wane with exacerbations and remissions [2]. Comorbidities are very common, with tic disorders seen in 30% of children, major depression in 26%, attention deficit hyperactivity disorder (ADHD) in 10%, and other developmental disorders in approximately 20% [3]. Treatment of OCD includes behavioral and/or pharmacologic therapy, usually with selective serotonin reuptake inhibitors (SSRIs). Relapses often occur when treatment is discontinued, but fortunately complete remission may occur by late adolescence. Family studies and twin studies fit best with an autosomal dominant inheritance, however, since no gene has yet been identified, it is difficult to separate environmental and genetic factors.
TS has a lifetime prevalence of 1:1000, and is characterized by the
childhood onset of chronic motor and vocal tics [4]. TS has a variable course,
with symptoms often waxing and waning.
Severity varies from a social nuisance to a severely debilitating
condition [5]. Neuroleptics are the
medications of choice for reducing tic severity, although symptoms are rarely
entirely eliminated by therapy. TS is
inherited in an autosomal dominant manner, although a mixed genetic and
environmental model has been proposed.
Monozygotic twin studies have shown that although both twins are generally
affected, the severity of tics is discordant [6].
SC is a variant of acute rheumatic fever (ARF). It occurs in childhood, with a peak age of
onset between four and fourteen years of age.
Pathophysiologically, the manifestations of ARF likely result from
molecular mimicry, the immunologic process whereby antibodies to GABHS
cross-react to self-proteins to induce an inflammatory autoimmune
response. Specifically, antibodies
against GABHS cross react with neuronal cells to produce inflammation in the
CNS (particularly within the basal ganglia), resulting in the movement
disturbances observed in SC [7].
SC follows a streptococcal infection by as much as nine months, but may
occur as early as a few weeks after GABHS infection. Clinical manifestations include motor symptoms, emotional
lability and behavioral changes (Table 1).
Obsessive-compulsive symptoms are observed in greater than 70% of
patients with SC, often preceding the chorea by days to weeks [8].
As similarities between SC and other neuropsychiatric disorders became
more evident both clinically and pathophysiologically, pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infection (PANDAS) was
proposed as a distinct subgroup of childhood OCD and tic disorders.
PANDAS
To make a diagnosis of PANDAS, patients must fulfill proposed criteria
[9] (Table 2) and have a clear association between GABHS infection and symptom
exacerbation must be demonstrated.
Evidence of GABHS infection includes a positive throat culture for
GABHS, or elevated or increasing antibody titers (ASO, anti-DNase B)
demonstrating a recent GABHS infection.
However, not all PANDAS exacerbations follow GABHS infection
exclusively, and non-GABHS related exacerbations have been documented
[10]. Similarly, exacerbations of SC
have been observed following non-GABHS infection [11]. GABHS is thought to be
the initial autoimmune-inducing event, with subsequent exacerbations triggered
by recurrent GABHS, or by other bacterial or viral infections.
PANDAS and SC
have similar clinical features, including emotional lability, attention and
impulsivity difficulties, motor hyperactivity and clumsiness, abnormal
choreiform hand movements, and deterioration in fine motor skills, which are
often observed at the onset of an exacerbation. True chorea must be differentiated from isolated choreiform
movements, and although there is no strict definition, the presence of chorea
excludes the diagnosis of PANDAS.
The
first fifty PANDAS patients were reported in the literature in 1998 by Swedo et
al) [9]. Two hundred and seventy
patients referred to the National Institute of Mental Health (NIMH) were
initially screened, of whom 50 ultimately met PANDAS criteria. The mean age of onset of tics was 6.3 years,
and 7.4 years for OCD, almost 3 years younger than the average age of onset for
childhood OCD and tic disorder. Among
the 50 children, there were 144 separate episodes of symptom exacerbations,
although only one third were associated with documented GABHS infection. A recent study prospectively identified 12
patients fulfilling PANDAS criteria, with onset of symptoms following GABHS
pharyngitis. All children responded to
antibiotic therapy with prompt improvements (in most cases, eradication) of
their tic and OCD behaviors [12]. Since
the writing of this paper, the authors have prospectively identified 13
additional children, observing that patients fall into three categories: sixteen of 25 presented acutely with
explosive onset of symptoms, 4 of 25 presented after weeks of behavior change
with significantly elevated streptococcal serology, and 5 of 25 patients were
diagnosed after several episodes of worsening behaviors following GABHS
[13]. In a recent case-control study,
Cardona [14] studied 150 consecutive children presenting with tics
demonstrating a significantly higher mean antistreptolysin O titers in the
patients compared to controls. They
noted a positive correlation between ASO titer and severity of tic disorder,
but could not confirm that their patients fulfilled criteria for PANDAS as
patients were not assessed longitudinally.
Is this an Immunologic Process?
The biologic
evidence that PANDAS in an autoimmune-mediated process is compelling, but not
conclusive. A potential B cell marker
was identified, magnetic resonance imaging of the brain demonstrates basal
ganglia changes consistent with inflammation, and immunomodulatory therapies
have been studied with benefit in some patients. Antibiotic prophylaxis, although effective in ARF, remains
questionable in PANDAS.
D8/17 Lymphocyte Marker
The B cell marker D8/17 was identified as a predictor of ARF and SC,
diseases recognized to have genetic susceptibility. The cell surface marker was discovered on a subset of HLA-DR
positive B cells in the peripheral circulation, and the alloantigen was
recognized by a monoclonal antibody labelled D8/17[15], a mouse monoclonal IgM
antibody[16]. Testing involves staining
peripheral B cells with the antibody and counting positively stained
cells. A positive result is defined as
greater than 11.8% of B cells stained (one standard deviation above historical
comparison values). The percent of
antigenic expression is inherited, either in an autosomal recessive or
autosomal dominant manner with variable penetrance [15].
The D8/17 marker has high sensitivity for ARF, in that 90 to 100% of
individuals with ARF are positive regardless of the disease activity. In initial studies, the marker’s specificity
was high, as only 5-15% of healthy controls had positive expression. Therefore, it appeared to function as a
trait marker for ARF. Additional
support was provided when patients with poststreptococcal glomerulonephritis
were found to express low numbers of positive cells. Siblings and parents of patients with ARF and SC also demonstrate
higher numbers of positive D8/17 B cells than control subjects [17], which
lends further support to a genetic susceptibility to ARF.
Based on the similarities of SC to other neuropsychiatric disorders, it
was further hypothesized that the D8/17 marker might also be able to identify
patients with OCD and TS. A group of 31
children with TS and/or OCD and 21 healthy controls were studied [18]. All patients positively expressed the D8/17
marker versus only one positive among the control patients. A subsequent study examined 27 children with
PANDAS, 9 children with SC, and 24 healthy controls [19]. Eighty-five percent of the PANDAS children
were positive, 89% in the SC group were positive, and only 17% of controls were
positive (p<0.0001 for both comparisons).
These results support the hypothesis that there may be a group of
children who are susceptible to developing PANDAS instead of SC or other
manifestations after streptococcal infections.
Testing for the presence of the D8/17 marker cannot alone differentiate
children with TS and OCD from those with PANDAS since in the first study 100%
of OCD and TS patients were positive for the marker, regardless of levels of
antistreptococcal antibodies.
Additionally, as this test is not commercially available, it’s utility
in the diagnosis of PANDAS remains unclear.
MRI Studies
Abnormalities in the basal ganglia region are seen on MRI in patients
with SC, predominantly increased volumes of the caudate nucleus, putamen and/or
globus pallidus [20,21]. In a MRI study
of 34 children with PANDAS compared to 82 age and sex-matched controls,
significantly larger basal ganglia volumes were demonstrated in the PANDAS
group[22]. There was no significant
difference in total brain volume, which suggests the specificity of basal
ganglia involvement. The increased
volumes are presumably due to acute inflammation within the basal ganglia.
The clinical application of MRI studies is limited, as the increased
volumes observed on MRI do not correlate with symptom severity in children with
PANDAS. If a control group of children
with OCD or TS not associated with GABHS infections had demonstrated normal
sized basal ganglia, this information would have been clinically more important.
Therapeutic Options
SC is generally a self-limited disorder, with symptoms resolving in
weeks to months. As antibodies are
thought to be instrumental in its pathogenesis, immunosuppressive therapy might
be a reasonable treatment option for patients with persistent symptoms. Corticosteroids have been used, although not
well studied in the treatment of SC exclusive of other signs of ARF such as
carditis. Alternatively,
immunomodulatory treatment with either intravenous immunoglobulin (IVIG) or
plasma exchange may hasten recovery. In
one non-randomized study (published in abstract form) of 9 patients, 5 patients
underwent plasma exchange and improved without recurrences for 10 months, and 4
patients received IVIG, with 3 demonstrating recurrent chorea several weeks
later[23].
Prior to establishing the large cohort of PANDAS patients, case reports
of patients benefiting from immunosuppressive
therapy were published. The
first report of successful treatment of patients with a post infectious
PANDAS-like illness with IVIG, plasma exchange and prednisone studied only four
patients[10]. A larger treatment trial
has recently demonstrated that plasma exchange or IVIG may be effective
therapies for children with severe recalcitrant PANDAS[24]. Thirty children with PANDAS were randomized
to IVIG, plasma exchange, or “placebo” (saline infusion resembling IVIG
infusion); a placebo for plasma exchange was not used. All patients had “severe” symptoms at time
of entry, based on several rating scores.
At one month, the children in both the IVIG and plasma exchange groups
had symptom improvement, but those in the placebo group were unchanged. At one year, 80% of patients who had
received plasma exchange had sustained improvement. However, 50% of children were on the same or higher doses of
their baseline medications, thus it is not entirely clear that immunomodulatory
therapy was beneficial. Additionally,
it is possible that some of these children’s symptoms, especially tics,
spontaneously improved after one year.
IVIG and plasma exchange are invasive and costly therapies. In addition, significant side effects were
observed in 7/10 patients who received plasma exchange, 6/10 patients who
received IVIG, and 2/10 patients who received placebo. These adverse events included nausea,
abdominal pain, headache and fever.
To
identify plasma exchange as a superior treatment would have also required a
control group for the plasma exchange group, although sham plasma exchange was
not an ethically viable option.
Interestingly, the children in the placebo group (IVIG control group)
subsequently received plasma exchange in an open trial, and had only minor
improvements. A larger randomized
controlled trial of immunomodulatory therapy is required before recommending this
treatment, and the NIMH (National Institute of Mental Health) recommends this
therapy only as part of a research protocol.
Prophylaxis – is it useful?
Penicillin
prophylaxis is efficacious for the prevention of recurrent rheumatic
fever. The original trials evaluating
prophylaxis and recurrence of rheumatic fever included more than 400 patients
who were followed over five years[25,26].
A pilot study of prophylaxis for PANDAS examined 37 children over eight
months in a double-blind cross-over study with oral penicillin vs.
placebo[27]. An equal number of
infections were observed in the active and placebo phases, and no significant
changes were observed in OCD or tic severity.
The duration of the study was limited, and since the study failed to
demonstrate effective streptococcal prophylaxis with penicillin, at this time
there is no recommendation for antibiotic prophylaxis for PANDAS.
Widening the PANDAS spectrum
Over the last few years, in addition to OCD and TS, anorexia nervosa,
attention deficit hyperactivity disorder (ADHD), and autism have also been
considered, though not yet accepted, to fit under the PANDAS umbrella.
An infection-triggered, autoimmune subtype of anorexia nervosa (AN) has
been proposed. A recent report
described four children with possible PANDAS AN who were treated with
antibiotics in an open trial[28]. The
patients were followed at a large eating disorders clinic, and also received
conventional therapy including nutrition, behavioral therapy and pharmacologic
treatments. All four children fulfilled
DSM-IV criteria for AN, in addition to at least four of five criteria for
PANDAS. Two of the four patients had a
comorbid diagnosis of OCD, and all four had evidence of a prior GABHS infection
with positive antistreptococcal antibody titers. Sinusitis was documented in relation to AN symptom exacerbations
and treatment with amoxicillin resulted in significant weight gain and
improvement in restricting behaviors in all children. Despite inconsistencies in the evidence of GABHS infection, and
in the antibiotic dosage and duration, this study may provide preliminary
evidence of a subtype of AN that fits into the PANDAS spectrum. A further study examining the D8/17 antigen
expression in 16 PANDAS AN patients demonstrated that 81% of patients had
positive levels, compared to 12% D8/17 positive in a group of comparison
subjects (17 psychiatric patients without eating disorders)[29]. The validity of this study is questioned
because the authors did not examine eating disordered patients without PANDAS
symptoms.
ADHD is a frequent comorbid feature of TS and OCD, but recent
literature postulates ADHD without tics or OCD as part of the PANDAS
spectrum[30]. Peterson suggests that
evidence of recurrent streptococcal infections in a patient with ADHD predicts
increased basal ganglia volumes as seen in patients with SC and
PANDAS[31].
The evidence for autism as part of the PANDAS spectrum remains
circumstantial. A study of 18 children
with autism demonstrated a higher frequency of D8/17 positive B cells than a
control group. The D8/17 positive
children had more severe repetitive behaviors and significantly higher
compulsion scores[32], suggesting that autism may have an autoimmune basis in a
subset of patients, which in itself remains controversial.
Conclusions
Certainly many controversies arise when a new diagnostic construct is proposed. The prevalence of acute or recent streptococcal infection in school-aged children is high, and tics, TS and OCD are prevalent in this age group. OCD and tic disorders typically wax and wane, and may be exacerbated by stress, anxiety, fatigue and illness (such as streptococcal infection).
Many questions remain. PANDAS (like SC) are purported to be post-streptococcal disorders, yet exacerbations often present long after the acute symptoms of infection, when antibody titers may have already normalized and throat cultures are negative. Immunomodulatory therapies such as IVIG and plasma exchange have significant risks, and cannot be universally prescribed before larger randomized controlled trials are conducted. Although only small studies have been completed, prophylaxis remains ineffective in preventing exacerbations, and the utility of treating positive surveillance cultures (as has been done in prophylaxis studies) needs to be objectively evaluated. Most importantly, the recent prospective study by Murphy[12] lends credence to the PANDAS entity, demonstrating that an antecedent GABHS infection is specifically associated with the onset and exacerbation of tic disorders or OCD. Additionally, in this cohort of patients OCD and tic symptoms were relieved in all children with antibiotic therapy of the acute streptococcal infection, with none requiring “immunomodulatory” therapy.
PANDAS are a group of disorders recently recognized as a clinical
entity. Recent GABHS infection should
be considered in a child who presents with a sudden explosive onset of tics or
OCD symptoms. However, in considering
the prevalence of childhood onset TS and OCD, the diagnosis of PANDAS is
rare. This spectrum of disorders may
broaden to include anorexia nervosa, ADHD, and autism in the future as more
conclusive research emerges. For now,
the diagnosis of PANDAS must be made by strict criteria, and although the D8/17
marker may be useful in identifying patients at risk, until it is a universally
accepted, replicable and commercially available test, its utility remains
limited. At present, there is no
clearly effective immunomodulatory treatment, nor has prophylaxis been
effective in the prevention for PANDAS, and large, well-designed randomized
controlled trials examining these problems are eagerly awaited. Ongoing NIMH studies accepting new patients
are detailed on the PANDAS website[33] and interested patients and families
should be referred for further information.
TABLES
|
Table
I: Motor Manifestations of Sydenham’s
Chorea |
|
Ballismus |
|
Facial grimacing |
|
Tongue fasciculations |
|
Loss of fine motor control |
|
Hypotonia |
|
Motor impersistence (“milkmaid’s
grip”) |
|
Gait Disturbance |
|
Speech Abnormalities (dysarthria,
explosive speech) |
|
Table
2: Criteria for PANDAS diagnosis |
|
1. Presence of OCD and/or tic disorder (by
DSM-IV criteria) |
|
2. Onset in childhood, between 3 years and
onset of puberty |
|
3. Abrupt onset of symptoms, or course
characterized by dramatic exacerbations |
|
4. Onset of
exacerbations of symptoms temporally related to GABHS infection (preferably on two or more occasions) |
|
5. Abnormal neurologic examination (hyperactivity, choreiform movements,
tics) during an exacerbation |
|
|
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