PANDAS

Pediatric autoimmune neuropsychiatric disorders associated with

PANDAS
streptococcal infections (PANDAS) is a hypothesis that there exists a
subset of children with rapid onset of obsessive-compulsive disorder
(OCD) or tic disorders and these symptoms are caused by group A
beta-hemolytic streptococcal (GABHS) infections.[1] The proposed
link between infection and these disorders is that an initial
autoimmune reaction to a GABHS infection produces antibodies that
interfere with basal ganglia function, causing symptom exacerbations.
It has been proposed that this autoimmune response can result in a
broad range of neuropsychiatric symptoms.[2][3]

The PANDAS hypothesis was based on observations in clinical case

studies at the US National Institutes of Health and in subsequent
clinical trials where children appeared to have dramatic and sudden
OCD exacerbations and tic disorders following infections.[4] There is
supportive evidence for the link between streptococcus infection and
onset in some cases of OCD and tics, but proof of causality has
Streptococcus pyogenes (stained red), a
remained elusive.[5][6][7] The PANDAS hypothesis is controversial;
common group A streptococcal bacterium.
whether it is a distinct entity differing from other cases of Tourette
PANDAS is hypothesized to be an autoimmune
syndrome (TS)/OCD is debated.[3][8][9][10][11]
condition in which the body's own antibodies to
PANDAS has not been validated as a disease entity;[4] it is not listed as
streptococci attack the basal ganglion cells of
a diagnosis by the International Statistical Classification of Diseases
the brain, by a concept known as molecular
and Related Health Problems (ICD) or the Diagnostic and Statistical
mimicry.
Manual of Mental Disorders (DSM).[12] Specialty Neurology

Contents
Characteristics
Mechanism
Diagnosis
Classification
Treatment
Experimental treatments
Society and culture
History
Research directions
See also
References
External links

Characteristics
In addition to an OCD or tic disorder diagnosis, children may have other symptoms associated with exacerbations such as emotional
lability, enuresis, anxiety, and deterioration in handwriting.[1] In the PANDAS model, this abrupt onset is thought to be preceded by a
strep throat infection. As the clinical spectrum of PANDAS appears to resemble that of Tourette's syndrome, some researchers
[3][8][9][10][11]
hypothesized that PANDAS and Tourette's may be associated; this idea is controversial and a focus for current research.

Mechanism
The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are
controversial.[1][3][9][13][14][15]

Whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism
(pathophysiology) than seen in other people diagnosed with Tourette syndrome is unclear.[10][11][13][16] Researchers are pursuing the
hypothesis that the mechanism is similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections,
[1]
where antibodies attack the brain and cause neuropsychiatric conditions.

The molecular mimicry hypothesis is a proposed mechanism for PANDAS:[17] this hypothesis is that antigens on the cell wall of the
streptococcal bacteria are similar in some way to the proteins of the heart valve, joints, or brain. Because the antibodies set off an
immune reaction which damages those tissues, the child with rheumatic fever can get heart disease (especially mitral valve
regurgitation), arthritis, and/or abnormal movements known as Sydenham's chorea or "St. Vitus' Dance".[18] In a typical bacterial
infection, the body produces antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. In
some rheumatic fever patients, autoantibodies may attack heart tissue, leading to carditis, or cross-react with joints, leading to
arthritis.[17] In PANDAS, it is believed that tics and OCD are produced in a similar manner. One part of the brain that may be
affected in PANDAS is the basal ganglia, which is believed to be responsible for movement and behavior. It is thought that similar to
Sydenham's chorea, the antibodies cross-react with neuronal brain tissue in the basal ganglia to cause the tics and OCD that
characterize PANDAS.[1][19] Studies neither disprove nor support this hypothesis: the strongest supportive evidence comes from a
[13]
controlled study of 144 children (Mellet al, 2005), but prospective longitudinal studies have not produced conclusive results.

Diagnosis
According to Lombroso and Scahill, 2008, "(f)ive diagnostic criteria were proposed for PANDAS: (1) the presence of a tic disorder
and/or OCD consistent with DSM-IV; (2) prepubertal onset of neuropsychiatric symptoms; (3) a history of a sudden onset of
symptoms and/or an episodic course with abrupt symptom exacerbation interspersed with periods of partial or complete remission;
(4) evidence of a temporal association between onset or exacerbation of symptoms and a prior streptococcal infection; and (5)
adventitious movements (e.g., motoric hyperactivity and choreiform movements) during symptom exacerbation".[17] The children,
originally described by Swedo et al in 1998, usually have dramatic, "overnight" onset of symptoms, including motor or vocal tics,
obsessions, and/or compulsions.[20] Some studies have supported acute exacerbations associated with streptococcal infections among
clinically defined PANDAS subjects (Murphy and Pichichero, 2002; Giulino et al, 2002); others have not (Luo et al, 2004; Perrin et
al, 2004).[1]

Concerns have been raised that PANDAS may be overdiagnosed, as a significant number of patients diagnosed with PANDAS by
community physicians did not meet the criteria when examined by specialists, suggesting the PANDAS diagnosis is conferred by
[13][21]
community physicians without conclusive evidence.

Classification
PANDAS is hypothesized to be an autoimmune disorder that results in a variable combination of tics, obsessions, compulsions, and
other symptoms that may be severe enough to qualify for diagnoses such as chronic tic disorder, OCD, and Tourette syndrome (TS or
TD). The cause is thought to be akin to that of Sydenham's chorea, which is known to result from childhood Group A streptococcal
(GAS) infection leading to the autoimmune disorder acute rheumatic fever of which Sydenham's is one manifestation. Like
Sydenham's, PANDAS is thought to involve autoimmunity to the brain's basal ganglia. Unlike Sydenham's, PANDAS is not
associated with other manifestations of acute rheumatic fever, such as inflammation of the heart.[4] Pichechero notes that PANDAS
has not been validated as a disease classification, for several reasons. Its proposed age of onset
and clinical features reflect a particular group of patients chosen for research studies, with no
systematic studies of the possible relationship of GAS to other neurologic symptoms. There is
controversy over whether its symptom of choreiform movements is distinct from the similar
movements of Sydenham's. It is not known whether the pattern of abrupt onset is specific to
PANDAS. Finally, there is controversy over whether there is a temporal relationship between
GAS infections and PANDAS symptoms.[4]

To establish that a disorder is an autoimmune disorder

, Witebsky criteria require

1. that there be a self-reactive antibody,

2. that a particular target for the antibody is identified (autoantigen)
3. that the disorder can be caused in animals and A possible relationship
4. that transferring antibodies from one animal to another triggers the disorder between PANDAS and other
(passive transfer).[22] early-onset conditions.[19]
In addition, to show that a microorganism causes the disorder, the Koch postulates would Other sources note periods
require one show that the organism is present in all cases of the disorder, that the organism can of remission[17] and extend
PANDAS to other diagnoses
be extracted from those with the disorder and be cultured, that transferring the organism into
such as ADHD.[4]
healthy subjects causes the disorder, and the organism can be reisolated from the infected
party.[22] Giovanonni notes that the Koch postulates cannot be used in the case of
postinfection disorders (such as PANDAS and SC) because the organism may no longer be present when symptoms emerge, multiple
[22]
organisms may cause the symptoms, and the symptoms may be a rare reaction to a common pathogen.

Treatment
Treatment for children suspected of PANDAS is generally the same as the standard treatments for TS and OCD.[2][5][16] These
include cognitive behavioral therapyand medications to treat OCD such as selective serotonin reuptake inhibitors (SSRIs);[5][16] and
"conventional therapy for tics".[2]

A controlled study (Garvey, Perlmutter, et al, 1999) of prophylactic antibiotic treatment of 37 children found that penicillin V did not
prevent GABHS infections or exacerbation of other symptoms; however, compliance was an issue in this study. A later study (Snider,
Lougee, et al, 2005) found that penicillin and azithromycin decreased infections and symptom exacerbation. The sample size,
controls, and methodology of that study were criticized.[1] Murphy, Kurlan and Leckman (2010) say, "The use of prophylactic
antibiotics to treat PANDAS has become widespread in the community, although the evidence supporting their use is equivocal. The
safety and efficacy of antibiotic therapy for patients meeting the PANDAS criteria needs to be determined in carefully designed
trials";[5] de Oliveira and Pelajo (2009) say that because most studies to date have "methodologic issues, including small sample size,
retrospective reports of the baseline year, and lack of an adequate placebo arm ... it is recommended to treat these patients only with
conventional therapy".[2]

Evidence is insufficient to determine if tonsillectomy is effective.[2]

Experimental treatments
Prophylactic antibiotic treatments for tics and OCD are experimental[6] and controversial;[13] overdiagnosis of PANDAS may have
[13]
led to overuse of antibiotics to treat tics or OCD in the absence of active infection.

A single study of PANDAS patients showed efficacy of immunomodulatory therapy (intravenous immunoglobulin(IVIG) or plasma
exchange) to symptoms,[1] but these results are unreplicated by independent studies as of 2010.[17][13] Kalra and Swedo wrote in
2009, "Because IVIG and plasma exchange both carry a substantial risk of adverse effects, use of these modalities should be reserved
for children with particularly severe symptoms and a clear-cut PANDAS presentation.[16] The US National Institutes of Health and
American Academy of Neurology 2011 guidelines say there is "inadequate data to determine the efficacy of plasmapheresis in the
treatment of acute OCD and tic symptoms in the setting of PANDAS" and "insufficient evidence to support or refute the use of
plasmapheresis in the treatment of acute OCD and tic symptoms in the setting of PANDAS", adding that the investigators in the only
study of plasmapherisis were not blind to the results.[8] The Medical Advisory Board of the Tourette Syndrome Association said in
2006 that experimental treatments based on the autoimmune theory such as IVIG or plasma exchange should not be undertaken
outside of formal clinical trials.[23] The American Heart Association's 2009 guidelines state that, as PANDAS is an unproven
hypothesis and well-controlled studies are not yet available, they do "not recommend routine laboratory testing for GAS to diagnose,
long-term antistreptococcal prophylaxis to prevent, or immunoregulatory therapy (e.g., intravenous immunoglobulin, plasma
exchange) to treat exacerbations of this disorder".[24]

Society and culture

The debate surrounding the PANDAS hypothesis has societal implications; the media and the Internet have played a role in the
PANDAS controversy.[5][25] Swerdlow (2005) summarized the societal implications of the hypothesis, and the role of the Internet in
the controversy surrounding the PANDAS hypothesis:

... perhaps the most controversial putative TS trigger is exposure to streptococcal infections. The ubiquity of strep
throats, the tremendous societal implications of over-treatment (e.g., antibiotic resistance or immunosuppressant side
effects) versus medical implications of under-treatment (e.g., potentially irreversible autoimmune neurologic injury)
are serious matters. With the level of desperation among Internet-armed parents, this controversy has sparked
.[25]
contentious disagreements, too often lacking both objectivity and civility

Murphy, Kurlan and Leckman (2010) also discussed the influence of the media and the Internet in a paper that proposed a "way
forward":

The potential link between common childhood infections and lifelong neuropsychiatric disorders is among the most
tantalizing and clinically relevant concepts in modern neuroscience ... The link may be most relevant in this group of
disorders collectively described as PANDAS. Of concern, public awareness has outpaced our scientific knowledge
base, with multiple magazine and newspaper articles and Internet chat rooms calling this issue to the public's
attention. Compared with ~ 200 reports listed on Medline—many involving a single patient, and others reporting the
same patients in different papers, with most of these reporting on subjects who do not meet the current PANDAS
criteria—there are over 100,000 sites on the Internet where the possible Streptococcus–OCD–TD relationship is
discussed. This gap between public interest in PANDAS and conclusive evidence supporting this link calls for
increased scientific attention to the relationship between GAS and OCD/tics, particularly examining basic underlying
cellular and immune mechanisms.[5]

History
Susan Swedo first described the entity in 1998.[20] In 2008 Lombroso and Scahill described five diagnostic criteria for PANDAS.[17]
[26][27]
Revised criteria and guidelines for PANDAS was established by the NIMH in 2012 and updated in 2017.

Research directions
In a 2010 paper calling for "a way forward", Murphy, Kurlan and Leckman said: "It is time for the National Institutes of Health, in
combination with advocacy and professional organizations, to convene a panel of experts not to debate the current data, but to chart a
way forward. For now we have only to offer our standard therapies in treating OCD and tics, but one day we may have evidence that
also allows us to add antibiotics or other immune-specific treatments to our armamentarium."[5] A 2011 paper by Singer proposed a
new, "broader concept of childhood acute neuropsychiatric symptoms (CANS)", removing some of the PANDAS criteria in favor or
requiring only acute-onset. Singer said there were "numerous causes for CANS", which was proposed because of the "inconclusive
and conflicting scientific support" for PANDAS, including "strong evidence suggesting the absence of an important role for GABHS,
[28]
a failure to apply published [PANDAS] criteria, and a lack of scientific support for proposed therapies".
See also
Neurobiological brain disorder

References
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External links
Classification ICD-9-CM: V · T · D
279.49 · MeSH:
PANDAS - Questions and Answers, NationalInstitute of Mental Health
From Paresis to PANDAS, Former NIMH Director Thomas Insel, MD
C537163
External Patient UK:
resources PANDAS ·
Orphanet: 66624

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