The Pediatric Infectious Disease Journal Publish Ahead of Print

DOI: 10.1097/INF.0000000000002295

A Pediatric Infectious Disease Perspective on Pediatric Autoimmune Neuropsychiatric

Disorder Associated with Streptococcal Infection and Pediatric Acute-Onset

Neuropsychiatric Syndrome
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Ellen R. Wald, MD

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 600

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Highland Avenue, Box 4108, Madison, Wisconsin 53792 U.S.A., Phone: 608-263-8558, Fax:

608-265-3397, Email: erwald@wisc.edu

No reprints requested.

Key Words: PANDAS, PANS, Group A streptococcus

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Source of Funding and Conflict of Interest Statement: N/A

Presented in part at the Pediatric Academic Societies’ meeting, May 7, 2018, Toronto, Canada.

“Are the Goal Posts Moving? Current Controversies in the Diagnosis and Management of

Streptococcal Pharyngitis and Its Sequelae.”

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Abbreviated Title/Running Head: A Pediatric ID Perspective: PANDAS and PANS

Acknowledgements
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The author acknowledges the helpful review of the manuscript by Dr. Dominic Co, Dr. Jennifer

Kwon and Dr. Maria Stanley.

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 Pediatric Autoimmune Neuropsychiatric Symptoms Associated with Streptococcal

Infection (PANDAS) as a clinical entity was advanced by investigators at the National Institute

of Mental Health with 5 elements constituting diagnostic criteria: (1) presence of obsessive

compulsive disorder (OCD) and/or tic disorder; (2) pre-pubertal onset of symptoms; (3) episodic

course characterized by acute, severe onset and dramatic symptom exacerbations; (4) temporal

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relationship between group A beta-hemolytic streptococcal (GAS) infections and symptom onset

and exacerbations; and (5) association with neurologic abnormalities (e.g., choreiform

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movements, motor hyperactivity, tics).1 In the original description of 50 patients with PANDAS

approximately 40% of all presentations and exacerbations were able to be related to preceding or

concurrent GAS infections and each patient had at least one episode in which the relationship to

GAS was established.1 PANS is a diagnostic entity advanced more than a decade later to
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broaden the scope of these disorders and allow for other instigator events besides GAS. The

criteria for PANS include abrupt, dramatic overnight onset of OCD or severely restricted food

intake; concurrent abrupt onset of additional severe neuropsychiatric symptoms from at least 2 of

the following 7 categories: (1) anxiety; (2) emotional lability and/or depression; (3) irritability,
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aggression, and/or severe oppositional behaviors; (4) developmental regression; (5) deterioration

in school performance; (6) sensory or motor abnormalities, including heightened sensitivity to

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sensory stimuli, hallucinations, dysgraphia, complex motor, and/or vocal tics; (7) somatic signs

and symptoms, including sleep disturbances, enuresis or urinary frequency and the requirement
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that symptoms are not better explained by a known neurologic or medical disorder.2

In 2013, a PANS Consensus Conference was convened at Stanford University, and

several consensus statements have been published in recent years.3-6 The existence of PANDAS

has been controversial from the time of its first publication.7 For those of us familiar with the

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 sequelae of streptococcal disease and the concerns of community physicians faced with the care

of children with these neuropsychiatric symptoms, the controversy has proven to be a disservice

to both pediatricians and families. It has fostered a dismissive attitude toward important clinical

observations. These controversies relate primarily to two issues:

1. Skepticism regarding the role of GAS as both the initial instigator of

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neuropsychiatric symptoms or the cause of exacerbations.

2. Variable results regarding the presence of different antineuronal antibodies in the

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sera of children diagnosed to have PANDAS.

Sydenham’s chorea

Before critiquing the current literature on PANDAS and PANS, it is essential to learn

lessons from the study of Sydenham’s chorea, which at this time is a bona fide and inarguable
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example of a pediatric autoimmune neuropsychiatric syndrome that is related to streptococcal

infection. It is the careful study and observation of children with Sydenham’s chorea that first

provided the stimulus for Dr. Susan Swedo to begin to think about the possibility of PANDAS.8,9

Critics of PANDAS7 mention that the concept of PANDAS was derived from observations that
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“some” individuals with Sydenham’s chorea have associated psychiatric symptoms. However,

the “some” is actually 70% and in patients with recurrent chorea as a manifestation of acute
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rheumatic fever, the “some” becomes 100%.10,11

There are other characteristics about chorea that make it a unique manifestation of acute
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rheumatic fever. Most important is the long latency period between the incident acute

pharyngitis and the onset of acute rheumatic fever – usually one to 3 months, but sometimes as

long as 9 months. Accompanying this observation is the acknowledgement that given the

possibility of this long latent period, the throat culture is likely to be negative and acute phase

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 reactants (ESR, CRP and WBC) as well as antistreptococcal antibody titers are unlikely to be

elevated.

Lessons from acute rheumatic fever

Other lessons from acute rheumatic fever must be taken into account. First, many

pharyngeal infections caused by GAS that precede the development of acute rheumatic fever are

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either subclinical or so mild that they do not result in medical attention.12,13 Secondly, not all

GAS cause acute rheumatic fever. In fact, only 16 of more than 240 emm types cause acute

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rheumatic fever and approximately 14 emm types are capable of causing acute

glomerulonephritis (another example of a non-suppurative complication of infection with

GAS).14,15 Although the likelihood of developing acute rheumatic fever after infection with a

rheumatogenic GAS that has not been treated ranges from 3-6%, the likelihood of acute
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rheumatic fever after infection with a non-rheumatogenic GAS, or acute glomerulonephritis after

an infection with a non-nephritogenic GAS, is zero.14 Investigators have pondered the low rate

of development of acute rheumatic fever after infection with rheumatogenic GAS.16 They have

recognized that there is definitely a genetic susceptibility that influences the likelihood of
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developing acute rheumatic fever, so that while infection with a rheumatogenic strain of GAS is

“necessary” to cause acute rheumatic fever, it is not sufficient. These same features may be true
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for those GAS that cause PANDAS, i.e., not all GAS may cause PANDAS, those that do may

require a genetic susceptibility, and many infections may not result in the development of this
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non-suppurative complication. The latency period between the incident streptococcal infection

and the onset of PANDAS is also unknown.

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 Streptococcal serology

Regarding antistreptococcal serology, new data available from Hysmith and co-workers,

raise concerns regarding future interpretation of serology in any post-streptococcal entity.17

These investigators reaffirmed the well-described observation that 65% of streptococcal

acquisitions in children occur without symptoms and that the antibody response to a variety of

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antigens is quite variable. Although every instance of a new infection was accompanied by an

antibody response to at least one antigen (average 3.5 antigens), the response to antistreptolysin

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O (ASO) and anti-DNAase B occurred only in 67% of cases and the assays to demonstrate the

remaining antibody responses are not generally commercially available. Furthermore, ASO and

anti-DNAase B titers were shown to be elevated in some children who were carriers, almost

certainly reflecting the acute infection that preceded carriage. Accordingly, the interpretation of
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serologic findings is by no means straightforward.

The controversy: the role of GAS

Hopefully this discussion sheds light on a major concern, expressed repeatedly by critics

of PANDAS in a variety of previous publications,18-20 regarding the entity of PANDAS, that is,
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the “strength of the GAS association with the onset and recurrence of tics, obsessive compulsive

disorder (OCD) or both.”

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Epidemiologic issues

The main approach taken by Gilbert et al in their most recent challenge to the existence
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of PANDAS and its association with GAS is to discuss several epidemiologic studies that have

been reported regarding both PANDAS and PANS.7 They cite two prospective studies, 814

children (4 to 11 years of age) in one21 and 693 children (3 to 12 years) in the other,22 both of

which failed to confirm an association between a preceding streptococcal infection and

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 PANDAS diagnosis. Given the previous discussion regarding rheumatogenic GAS and the

necessary genetic predisposition – this is not a compelling observation. Furthermore, all of the

children in both studies received treatment for their streptococcal infections. One can speculate,

with a great degree of assurance, that there may not have been any cases of acute rheumatic fever

or acute glomerulonephritis observed in either of these two cohorts. Clearly, that would not

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invalidate the existence of these entities nor their association with GAS.

Next, they reviewed two prospective, longitudinal studies that used intensive clinical

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monitoring of cohorts of children known to have PANDAS (31 and 40 patients, respectively)

compared to a control group of children with OCD or Tourette’s syndrome without a PANDAS

history.23,24 They hypothesized that children meeting the criteria for PANDAS would have more

clinical exacerbations temporally linked to bona fide GAS infection than controls. One study
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demonstrated a higher rate24 of exacerbations while the other did not.25 Many exacerbations

were not associated with GAS, an observation made by Swedo in her original papers. Once

again, a failure to link exacerbations of PANDAS to new infections with GAS does not

invalidate the PANDAS concept.

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The controversy: autoimmunity

The second component of the critique focuses on the strength of evidence that PANDAS
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is an autoimmune process. It has been proposed that the pathophysiologic basis for PANDAS is

a form of molecular mimicry in which antibodies produced against streptococcal proteins are
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also targeted to proteins in the basal ganglia. Gilbert outlines the requirements for confirmation

of pathogenicity and focuses on the inconsistent demonstration of antineuronal serum antibodies

in a variety of reported studies and the failure to be able to consistently demonstrate changes in

the levels of antineuronal antibodies as patients improve and worsen. This concern should be

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 mitigated, in least in part, by a study demonstrating that a substantial component of the failure to

demonstrate consistent results were that “control” sera used in a variety of studies demonstrated

significant differences themselves, thereby accounting for the secondary internal

inconsistencies.25 Although this study is cited by the authors, these results were not highlighted.

Animal models may provide additional information to support or refute the diagnostic

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entity of PANDAS. There are strong data in which animals hyperimmunized with GAS

demonstrate behavior consistent with PANDAS.26 When the serum is transferred to naïve

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rodents, similar behavioral and motor problems are observed, strengthening these

observations.27,28 However, Gilbert minimizes the importance of these results by noting that

human sera from patients with PANDAS did not induce behavioral changes in the rodent

model.29 Nonetheless, a study published in 2018 provides evidence that human sera from well-
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characterized patients with PANDAS binds to cholinergic interneurons in the striatum of study

mice.30 Furthermore, convalescent sera from patients after treatment with IVIG were no longer

capable of binding.

Diagnostic evaluation and treatment recommendations

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Gilbert et al7 strongly emphasize that it is essential that the treating physician be

cognizant of the lack of evidence supporting treatment recommendations when considering

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whether or not to follow the PANS Research Consortium’s recommendation, especially

regarding immunomodulation in severe cases. This admonition could be equally well applied to
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the management of almost all autoimmune encephalidities for which “…there is no general

consensus in the literature regarding the best regimen or duration of treatment.”20 Furthermore,

while the guidelines are clearly not evidence-based, as there are few, if any, stringently

performed randomized controlled trials, the clinician must still care for these patients until such

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 time that high quality evidence is available. Many thoughtful and experienced clinicians from

multiple academic medical centers participated in these guidelines.3-6 While these factors do not

ensure that the guidelines are the best they could be, adopting a less critical attitude may help

achieve a more constructive and collaborative consensus in the future.

Foundational questions and recommendations

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1. When is it appropriate to look for the presence of GAS?

When a previously healthy pre-pubertal child presents with the very sudden and severe onset

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of OCD, food aversion, separation anxiety, urinary frequency or incontinence (almost certainly

accompanied by anxiety), a careful history and physical exam, as well as a mental health

evaluation should be performed. In addition, a diagnostic test (culture, rapid antigen detection or

nucleic acid amplification test31) to determine the presence of GAS is appropriate. The
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experience reported by Murphy and Pichichero32 is compelling in this regard. Albeit that this is

a single study in a single community, it demonstrates a very strong association between onset

and treatment of infection with GAS and the occurrence and suppression of symptoms.

Although the Committee on Infectious Diseases of the American Academy of Pediatrics does not
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recommend the performance of a microbiologic test in the absence of symptoms of pharyngitis in

patients suspected to have PANDAS,15 their view is inconsistent with the approach
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recommended for other non-suppurative complications caused by GAS. In general, a

microbiologic test to assess for the presence of GAS is recommended, even in the absence of
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symptoms or signs of pharyngitis, given the high frequency of acute infection with GAS which is

subclinical in patients suspected to have acute rheumatic fever or acute post-streptococcal

glomerulonephritis.17 Penicillin V or amoxicillin are appropriate narrow spectrum drugs which

will effectively eliminate GAS and prevent acquisition of GAS if used prophylactically.

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 What other work-up is appropriate in the child who presents with suspected PANDAS?

Routine evaluation with complete blood count, ESR, CRP and comprehensive metabolic

panel is probably excessive for most children presenting with mild to moderate OCD. Rather,

first line therapy for children who present with the acute onset of psychiatric symptoms should

include those treatments shown to be effective in high quality, randomized controlled trials –

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cognitive behavioral therapy.33

Evaluation of children whose symptoms cannot be related to GAS and especially those who

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do not respond to usual therapy for the acute onset of psychiatric symptoms, should include

imaging of the central nervous system and evaluation of cerebrospinal fluid as well as a

comprehensive evaluation as suggested in the guideline.6 If evidence of inflammation is present,

the use of anti-inflammatory agents should be considered most optimally in the context of
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prospective studies so that there is systematic collection of data before and after treatments.

There is a desperate need for carefully controlled studies to inform our treatment of children with

PANDAS and PANS. A multidisciplinary approach is recommended and endorsed.7

In closing, it is important to appreciate the long-held skepticism that delayed the acceptance
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of acute rheumatic fever as a sequelae of infection with GAS. It took more than 100 years. It

was not until 1984 that evidence of streptococcal infection was made a necessary correlate within
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the Jones Criteria for the diagnosis of acute rheumatic fever to be considered.34,35 PANDAS and

PANS are real entities. Their prevalence is unknown and continued study is essential. However,
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their existence needs to be acknowledged as we work collectively to improve the healthcare of

children presenting with neuropsychiatric symptoms.

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