The recognition of a new disease is a slow process that demands repeated
observations and data analyses. This was true for rheumatic fever (RF), and so
it is for PANDAS, a poststreptococcal disease whose actual existence has been
term PANDAS is an acronym that stands for pediatric autoimmune neuropsychiatric
disease associated with streptococcal infection.
The major clinical manifestations include tics and obsessive-compulsive symptoms.
This type of neuropsychiatric symptoms are also observed in Sydenham's chorea,
sometimes before the onset of uncoordinated and involuntary movements. Since Sydenham's
chorea is a poststreptococcal disease, it has been suggested that this kind of
symptoms could occur in the absence of chorea. Research into this hypothesis has
shown that this might actually happen, leading researchers to propose the existence
of a new entity termed PANDAS. These patients did not present with classic choreiform
movements or other symptoms of RF, but only with tics and/or obsessive-compulsive
idea of a new disease described in the late 20th century was certainly viewed
with suspicion and, despite numerous published and also ongoing studies, there
has been a lot of debate over its real existence. Some pathogenic mechanisms suggested
for RF have been considered for PANDAS, as an attempt to show that they have the
same etiology, but different clinical manifestations.
Review of the scientific literature using MEDLINE database, searched between
1989 and 2006, with the aim of determining the basis for the diagnosis of PANDAS
and also the evidence surrounding its etiopathogenesis, treatment and prophylaxis.
etiology of tics and obsessive-compulsive disorders (OCD) is unknown, although
both might result from genetic and environmental factors.
environmental factors, infection is an etiologic possibility. The oldest correlation
between tics and infection dates back to 1929, being later reiterated in 1957
among patients with sinusitis.
Only in 1989, when the criteria for OCD had been established, Swedo et al. identified
OCD and tics in two thirds of patients with Sydenham's chorea, a disease recognizably
associated with streptococci.
In Brazil, in a study of 30 patients with chorea, OCD and/or tics were observed
in 70% of cases.
Studies comparing children with OCD and/or tics and a healthy control group revealed
that the former were more closely associated with streptococcal infections, suggesting
that the symptoms might result from infectious autoimmune phenomena.
examined two siblings with tics associated with previous streptococcal infection,
one diagnosed with PANDAS and the other with rheumatic chorea. This association
may demonstrate genetic predisposition to movement disorders caused by streptococci
or may act in favor of certain types of strains associated with neuropsychiatric
The selection of 50 patients that helped establish the diagnostic
criteria for PANDAS was based on the past history of oropharyngeal infection,
positive throat swab culture and increase in antistreptococcal antibody levels.
No association between PANDAS and streptococcal infections at other sites, such
as the skin, has been investigated, and no investigation has been made into whether
some subtype of streptococcus could be causing the symptoms. The diagnosis based
on elevated antistreptolysin O (ASO) levels is also inaccurate, since it may occur
after group A, C and G beta-hemolytic streptococcal infection.
Streptococcal infections are common among children,
but neuropsychiatric symptoms are not. This suggests that only some patients are
predisposed to PANDAS after streptococcal infection. A study on the presence of
tics and OCD in 157 first-degree relatives (100 parents and 57 siblings) of 54
children diagnosed with PANDAS showed that the frequency of these symptoms was
much higher than in the healthy population, but similar between those previously
reported for tics and OCD.
decades ago, some studies attempted to encounter some evidence of genetic predisposition
for RF, and found a B-cell marker, later identified by a monoclonal antibody known
as D8/17. The test consists in determining the percentage of B cells positively
stained with the monoclonal antibody, and a positive result is characterized by
the recognition of a certain amount of B cells stained with this antibody (around
12%). The first results showed a 90% positivity among rheumatic patients and only
15% in the healthy population.
Parents and siblings of patients with RF also had a large number of stained cells,
suggesting genetic susceptibility to RF.
These findings obtained with D8/17 in RF were not reproduced in a similar fashion
in all study populations.
upon the similarities between chorea (symptom of RF) and PANDAS, some studies
sought to define whether this marker was also more frequent in patients with tics,
OCD and PANDAS.
The presence of this marker was investigated in 27 boys with PANDAS, nine with
chorea and 24 healthy controls: 85% of PANDAS, 89% of chorea and 17% of controls
These data support the idea that there must a group of susceptible children, in
which D8/17 acts as a marker for the development of PANDAS or RF.
to tics, whether or not they are associated with streptococcal infections, the
presence of D8/17 was also investigated. A group of 31 children with Tourette's
syndrome and OCD without any association with streptococcal infection and a group
of 21 healthy children revealed positivity in all patients with tics and OCD and
in only one patient (5%) in the control group.
with the aim of assessing the importance of D8/17 in identifying genetic susceptibility
to PANDAS, the presence of tics and OCD was investigated in unselected children,
who had been classified as positive and negative for D8/17. Of 2,681 Mexican children
who had been typed, 240 were still being followed up and could be investigated.
Of these, 108 were positive and 132 were negative for D8/17, but no significant
association was observed between positive D8/17 and the presence of tics and OCD.
recent studies have not confirmed the usefulness in determining the presence of
D8/17 in RF or Tourette's syndrome.
In conclusion, the functional importance of this marker remains unknown, the test
is not commercially available and D8/17 positivity is not enough to flag abnormal
immune susceptibility to streptococci. Therefore, D8/17 is not currently regarded
as useful for the diagnosis of PANDAS.
Clinical manifestations of tics and OCD are observed in
both chorea and PANDAS, and both diseases may be associated with other symptoms,
such as attention deficit hyperactivity disorder. This suggests that an autoimmune
process affecting the basal ganglia can be triggered by streptococci in genetically
rheumatic chorea and PANDAS have persisted throughout the last 10 years. In addition
to clinical symptoms, autoimmune disorders were also investigated. The suggested
hypothesis was based on molecular mimicry, in which streptococcal infection in
susceptible individuals evokes antibodies that are capable of cross-reacting with
the cellular components of the basal ganglia.
hypothesis that both PANDAS and rheumatic chorea are autoimmune diseases caused
by streptococci was suggested by the detection of antineuronal antibodies with
the same reactivity in both diseases.
In 1993, Kissiling published a study showing the relationship between the presence
of antineuronal antibodies in patients with tics without chorea, as had been shown
for chorea (44 versus 46%).
has been a paucity of evidence confirming the autoimmune mechanism proposed for
PANDAS. The presence of anti-basal ganglia antibodies was observed in 64% of a
group of 22 patients with PANDAS and in only 9% of 22 patients in the control
group, made up of children with streptococcal infection not associated with neuropsychiatric
symptoms, suggesting that the presence of these antibodies cannot be explained
only by the history of group A beta-hemolytic streptococcal infection.
Another study of 48 patients with PANDAS, 46 with Tourette's syndrome and 43 healthy
patients of similar ages assessed the presence of antineuronal antibodies using
ELISA and Western immunoblotting against a wide variety of epitopes on the nerve
tissue, but it did not reveal any difference between the groups, nor did it show
immunoreaction against supposedly pathological antigens. The repetition of tests
after preabsorption of sera with streptococcal epitopes also did not demonstrate
loss of reactivity, thus not supporting the hypothesis that PANDAS and Tourette's
syndrome are secondary to antibodies.
chorea and PANDAS show abnormal magnetic resonance imaging findings. In a study
of 24 cases of chorea and 48 controls and in another one of 34 cases of PANDAS
and 82 controls, the caudate nucleus, globus pallidus and putamen were
enlarged, which could be compatible with inflammation of the basal ganglia, since
these findings were not observed in the thalamus or total cerebrum or in the thalamus.
The presence of inflammation is consistent with the hypothesis of autoimmune response
Two types of immunomodulatory therapy – plasmapheresis
(PMP) and intravenous immunoglobulin (IVIG) – shortened the course of symptoms
and helped with the recovery of patients with PANDAS, suggesting that an autoimmune
process is implicated in its pathogenesis.
criteria for PANDAS
The diagnostic criteria for PANDAS were established
in 1998, based on the information obtained from the analysis of 50 cases with
144 episodes isolated from symptom exacerbations.
1: age at onset
PANDAS is a pediatric disease that affects both
sexes, but it is predominant among males (2.6:1). Age at onset ranges from 3 years
to the beginning of puberty: tics (6.3 years) and OCD (7.4 years), which corresponds
to nearly 3 years before the mean age for these nonstreptococcal symptoms. Adolescents
and adults are likely to have infection-mediated tics and OCD, but this has not
been investigated yet, and should then not be termed PANDAS.
2: tics and OCD
The diagnosis of tics and OCD is based on the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV) published by the American
of Psychiatry. The same percentage of patients with tics and OCD (48 and 52%,
respectively) was observed among the analyzed patients; however, 80% presented
with both types of symptoms.
The prevalence of PANDAS among children with
tics and OCD is not known, but it has been reported that 11% of a group of patients
with tics showed symptom exacerbation within 6 weeks of an episode of streptococcal
3: onset and course of the disease
The dramatic onset of symptoms
is of major importance. Usually, patients remember how and when the symptoms developed,
and sometimes they even remember the day and time when they appeared. Resolution
is slow and gradual, taking weeks, months, or even longer. Patients have an uneventful
recovery for weeks or months until a new streptococcal infection causes a new
outbreak of tics and OCD, characterizing a clinical course with remissions and
Criterion 4: streptococcal infection
streptococci were suggested as etiologic factor of RF, fierce controversy broke
out over this issue. Likewise, several debates have taken place about the concept
of tics and OCD caused by streptococcal infections. It is recommended to ascertain
whether streptococci are still colonizing the oropharynx or whether antistreptococcal
antibody titers have increased. The antistreptococcal antibodies used include
ASO, whose titer is at its peak 3 to 6 weeks after streptococcal infection, and
anti-DNase after 6 to 8 weeks. The rate of increase is irrelevant, since elevated
titers do not translate into increased severity. However, looking only at the
elevated titers of these antibodies is not sufficient for the diagnosis of infection,
since these titers may remain elevated for months after the infection. Therefore,
initial antibody levels should be measured, and then measured again after some
weeks to check whether antibody titers are rising, which then means recent infection.
should be underscored that if PANDAS is somewhat similar to RF as autoimmune response
to streptococci, not every outbreak of streptococcal infection will be followed
by exacerbation, and exposure will vary from one year to the next. As pharyngitis
and tics are common among children, the best way to confirm whether they share
some association is to follow up children, trying to observe at least two episodes
that include streptococcal infection.
Streptococci are the causative agent
of initial autoimmunity, and subsequent exacerbations may be caused by new streptococcal
infections. Nevertheless, one should not rule out the hypothesis that other stimuli
may cause an outbreak, as occurs in chorea.
Criterion 5: associated
During an outbreak of PANDAS, neuropsychiatric
symptoms other than tics and OCD may appear. The most common symptoms include
learning difficulty, attention deficit hyperactivity disorder, depression, anxiety,
mood swings (irritability, sadness, emotional lability), sleep disorders, and
fine or gross motor impairment (writing).
PANDAS is an autoimmune disease, immunosuppressive therapy is a reasonable option
to treat persistent symptoms. We, as rheumatologists, think of steroids, immunosuppressive
drugs, PMP, and IVIG when treating autoimmune diseases.
was not the first option to be tested, since a publication in 1993 reported on
the worsening of OCD in a child submitted to treatment with this type of drug.
Nonetheless, there are some reports on the improvement of movements in Tourette's
syndrome and in one case of PANDAS after steroid therapy.
and PMP were initially chosen, as they proved safe and efficacious in some autoimmune
diseases. Patients with PANDAS were randomized into three groups: IVIG (1 g/kg/day/2
days), PMP, and placebo (10 PMP, nine IVIG and 10 placebo). All of them had severe
symptoms at the beginning of the study, according to a symptom scoring system.
After 1 month, the assessment of children with IVIG and with PMP showed improvement
of tics and OCD, of anxiety and of the general function, differently from the
control group, which remained unchanged. After 1 year, 20% of the patients from
the PMP group had recurrent episodes, and half of them required medications in
equal or larger doses, so it is not clear whether immunomodulatory therapy brought
any benefits. Another hypothesis that should be considered is that some children
might have improved spontaneously after 1 year, especially with regard to tics.
study assessed the efficacy of PMP for 2 weeks in five patients with chronic OCD
not associated with streptococci. None of the patients benefited from the therapy,
suggesting that it was not appropriate for OCD of nonstreptococcal etiology.
due to the lack of randomized controlled trials, these treatment modalities are
not recommended, as it is necessary to assess the real value of these expensive
therapies, which are not risk-free and have not yielded reliable results.
the report of a case of two siblings, one with OCD and the other one with tics,
who improved after tonsillectomy,
there was a case in which tonsillectomy preceded OCD symptoms.
that PANDAS is a new disease related to an infection, it has been argued whether
antibiotic therapy should be used. Antibiotics eradicate bacteria, but PANDAS
is not an infectious disease, but rather a postinfectious one, in which an autoimmune
mechanism is implicated.
In the acute phase of RF, we use antibiotics in
case there are still some viable bacteria in the oropharynx that have to be eliminated.
The latency period of rheumatic chorea may be long, lasting some months, and it
is often difficult to confirm the presence of streptococcal infection in a throat
swab culture or serological tests. In PANDAS, the latency period seems to be much
shorter (few days to 1 week) and the oropharynx is likely to be still colonized.
first prospective study showing that PANDAS was associated with streptococcal
infection was published in 2002. Antibiotics were administered to 12 patients
who met the criteria for PANDAS and whose symptoms followed beta-hemolytic streptococcal
infection in the oropharynx after a short latency period, ranging from days to
1 week (sentinel episode). All children recovered quickly (in nearly all of them
the symptoms of tics OCD were eliminated). During the follow-up period, reinfection
and a new episode of PANDAS (no case of PANDAS occurred without infection) occurred
in six patients. Response to antibiotic therapy occurred on average after 14 days
of treatment (being faster with cephalosporin than with penicillin and amoxicillin),
supporting the assumption that these patients were not mere carriers of the disease.
benzathine penicillin is efficacious in the prevention of RF, a study was carried
out to verify whether antibiotics may prevent outbreaks of PANDAS. The first study
on PANDAS was quite small, compared to other studies on the efficacy of RF prevention
using penicillin and that included hundreds of patients during several years.
double-blind, cross-sectional pilot study on the prophylaxis of PANDAS followed
37 children for 8 months, comparing the use of oral penicillin versus placebo.
Patients received either placebo or oral penicillin (Pen-Ve 250 mg x 2) for 4
months. Patients swapped treatments after the fourth month. Throughout the study,
patients were clinically monitored and submitted to monthly throat swab cultures
and to antistreptococcal antibody tests. An identical number of infections was
observed in the active and placebo phases, and symptoms did not worsen. The duration
of the study was too short and the study failed to prove the efficacy of this
type of prophylaxis with oral penicillin. Prophylactic failure does not allow
for favorable conclusions, and further studies with a larger patient population,
longer observation period or use of more efficacious drugs are needed.
study, published in 2005, compared the efficacy of oral penicillin prophylaxis
(250 mg twice a day) with two doses of 250 mg of azithromycin once a week. Both
drugs showed favorable responses to the number of streptococcal infections and
to the number of recurrent neurological symptoms when compared to data from the
previous year, without prophylaxis. However, the study has some shortcomings,
since the data from the previous year were retrospective and history-based, the
patient population was small, and besides, there was no control group.
date, antibiotic prophylaxis, which is efficient against RF, is arguable and is
still being investigated in patients with PANDAS.
A recent Brazilian study
on rheumatic chorea revealed that relapses occurred even among those patients
receiving regular secondary prophylaxis. Out of 85 cases of chorea, Terreri detected
one or more relapses in 25 (29%); of these, 17 were followed for later analysis,
and 14 relapses of chorea occurred, but in 71% of patients there was no failure
in the secondary prophylaxis.
In PANDAS, as also occurred in chorea, patients receiving prophylactic treatment
may have new outbreaks caused by different stimuli from streptococcal infection.
No studies have been carried out showing what the treatment
of PANDAS should be like. Current guidelines underscore the confirmation of streptococcal
infection by means of throat swab culture, and treatment of positive cases with
oral penicillin for 10 days or any other appropriate antibiotic. If the culture
is negative and if OCD symptoms and/or tics appeared less than 4 to 6 weeks ago,
antistreptococcal antibody levels should be measured as an attempt to detect the
recency of streptococcal infection and to perform the longitudinal assessment.
prospective analysis of streptococcal infections by throat swab culture must be
performed in every child with tics or OCD in order to confirm the actual association
with these symptoms.
The usefulness of antibiotic prophylaxis is still unclear,
but it should be determined by the physician on a case-by-case basis, who should
weigh both risks and benefits.
Immunomodulatory therapy is not risk-free
and is only recommended in study protocols. Based on the available findings, first-line
treatment should consist of the conventional therapy used for tics and OCD: serotonin
reuptake inhibitors (SRI) (response of 50 to 75%) and cognitive behavioral therapy
(67 to 100%).
In the last few years, in addition to tics and OCD, other neuropsychiatric
symptoms, such as anorexia nervosa (AN), attention deficit hyperactivity disorder
(ADHD), acute disseminated encephalomyelitis (ADEM), autism and separation anxiety
disorder, have been suggested as variants of PANDAS, but there is only flimsy
evidence, based mainly on the presence of streptococci, on the increase in antistreptococcal
antibody titers and on D8/17 positivity.
first four patients (11 to 15 years) with probable AN related to PANDAS met at
least four of the five criteria for PANDAS, all of them with positive throat swab
culture or positive serological tests (ASO/anti-DNase) showing previous streptococcal
infection. Two of them had the diagnosis of OCD as comorbidity. All of them were
positive for D8/17 (> 12% of positive B cells). Conventional treatment and
antibiotic therapy resulted in weight gain.
Two years later, the same authors analyzed 16 patients with AN, aged 7 to 21 years,
and termed the disease PANDAS anorexia nervosa, since 81% of 16 patients had >
12% of B lymphocytes positively stained with D8/17, differently from the control
group, without any eating disorder, in which positive results were found in only
12%. In these cases, the diagnosis of previous streptococcal infection was inconsistent
because it was solely based upon serological test results and on the history of
sinusitis. The validity of this study is questionable, since the authors did not
consider the percentage of patients with anorexia nervosa without PANDAS.
deficit hyperactivity disorder
It may be a comorbidity with Tourette's
syndrome and OCD, but recent literature postulates that “pure” ADHD,
without association of tics or OCD, may also belong to the PANDAS spectrum, since
children can have elevated ASO and anti-DNase titers.
This is an immune inflammatory disease
that mainly affects the gray matter. Viruses, bacteria and vaccines have been
implicated as etiologic factors. Recently, 10 cases with dystonic movements and
behavioral disorders associated with group A beta-hemolytic streptococci showed
an increase in anti-basal ganglia antibody titers comparatively to cases not associated
of autism as part of PANDAS remains circumstantial based solely on the presence
of D8/17. The frequency of D8/17 was higher in 18 autistic patients than in the
control group. D8/17-positive children had more repetitive behaviors and higher
compulsion score, suggesting that there may be an autoimmune basis in a subgroup
of patients in autism, even though this is still quite controversial.