Pediatric Autoimmune Neuropsychiatric Disorders 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) prepubertal onset of symptoms; (3) episodic course characterized by acute, severe onset and dramatic symptom exacerbations; (4) temporal relationship between group A beta-hemolytic streptococcal (GAS) infections and symptom onset and exacerbations and (5) association with neurologic abnormalities (eg, choreiform 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 1 episode in which the relationship to GAS was established.1 Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a diagnostic entity advanced more than a decade later to 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, aggression and/or severe oppositional behaviors; (4) developmental regression; (5) deterioration in school performance; (6) sensory or motor abnormalities, including heightened sensitivity to sensory stimuli, hallucinations, dysgraphia, complex motor and/or vocal tics and (7) somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency and the requirement 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 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 2 issues:
- Skepticism regarding the role of GAS as both the initial instigator of neuropsychiatric symptoms or the cause of exacerbations.
- Variable results regarding the presence of different antineuronal antibodies in the sera of children diagnosed to have PANDAS.
Before critiquing the current literature on PANDAS and PANS, it is essential to learn lessons from the study of Sydenham chorea, which at this time is a bona fide and inarguable example of a pediatric autoimmune neuropsychiatric syndrome that is related to streptococcal infection. It is the careful study and observation of children with Sydenham chorea that first provided the stimulus for Swedo8,9 to begin to think about the possibility of PANDAS. Critics of PANDAS7 mention that the concept of PANDAS was derived from observations that “some” individuals with Sydenham chorea have associated psychiatric symptoms. However, the “some” is actually 70%, and in patients with recurrent chorea as a manifestation of acute rheumatic fever, the “some” becomes 100%.10,11
There are other characteristics about chorea that make it a unique manifestation of acute rheumatic fever. Most important is the long latency period between the incident acute pharyngitis and the onset of acute rheumatic fever—usually 1–3 months, but sometimes as long as 9 months. Accompanying this observation is the acknowledgment that given the possibility of this long latent period, the throat culture is likely to be negative and acute phase reactants (erythrocyte sedimentation rate, C-reactive protein and white blood cells) 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 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 rheumatic fever, and approximately 14 emm types are capable of causing acute glomerulonephritis (another example of a nonsuppurative 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% to 6%, the likelihood of acute rheumatic fever after infection with a nonrheumatogenic GAS, or acute glomerulonephritis after an infection with a nonnephritogenic 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 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 for those GAS that cause PANDAS, that is, 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 nonsuppurative complication. The latency period between the incident streptococcal infection and the onset of PANDAS is also unknown.
Regarding antistreptococcal serology, new data available from Hysmith et al17, raise concerns regarding future interpretation of serology in any poststreptococcal entity. 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 antigens is quite variable. Although every instance of a new infection was accompanied by an antibody response to at least 1 antigen (average 3.5 antigens), the response to antistreptolysin O 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, antistreptolysin O 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 serologic findings is by no means straightforward.
THE CONTROVERSY: THE ROLE OF GAS
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, the “strength of the GAS association with the onset and recurrence of tics, obsessive compulsive disorder (OCD) or both.”
The main approach taken by Gilbert et al7 in their most recent challenge to the existence of PANDAS and its association with GAS is to discuss several epidemiologic studies that have been reported regarding both PANDAS and PANS. They cite 2 prospective studies, 814 children (4–11 years of age) in one21 and 693 children (3–12 years of age) in the other,22 both of which failed to confirm an association between a preceding streptococcal infection and 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 2 cohorts. Clearly, that would not invalidate the existence of these entities nor their association with GAS.
Next, they reviewed 2 prospective, longitudinal studies that used intensive clinical monitoring of cohorts of children known to have PANDAS (31 and 40 patients, respectively) compared with a control group of children with OCD or Tourette 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 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.
THE CONTROVERSY: AUTOIMMUNITY
The second component of the critique focuses on the strength of evidence that PANDAS 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 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 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 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 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-characterized patients with PANDAS bind to cholinergic interneurons in the striatum of study mice.30 Furthermore, convalescent sera from patients after treatment with intravenous immunoglobulin were no longer capable of binding.
DIAGNOSTIC EVALUATION AND TREATMENT RECOMMENDATIONS
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 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 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 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
When Is It Appropriate to Look for the Presence of GAS?
When a previously healthy prepubertal child presents with the very sudden and severe onset of OCD, food aversion, separation anxiety, urinary frequency or incontinence (almost certainly accompanied by anxiety), a careful history and physical examination, 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 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 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 recommended for other nonsuppurative complications caused by GAS. In general, a microbiologic test to assess for the presence of GAS is recommended, even in the absence of 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 poststreptococcal glomerulonephritis.17 Penicillin V or amoxicillin are appropriate narrow-spectrum drugs which will effectively eliminate GAS and prevent acquisition of GAS if used prophylactically.
What Other Work-up Is Appropriate in the Child Who Presents With Suspected PANDAS?
Routine evaluation with complete blood count, erythrocyte sedimentation rate, C-reactive protein 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—cognitive behavioral therapy.33
Evaluation of children whose symptoms cannot be related to GAS and especially those who 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 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 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 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, their existence needs to be acknowledged as we work collectively to improve the healthcare of children presenting with neuropsychiatric symptoms.
The author acknowledges the helpful review of the article by Dr. Dominic Co, Dr. Jennifer Kwon and Dr. Maria Stanley.
1. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998;155:264–271.
2. Susan SE, Leckman JF, Rose NR. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome
). Pediatr Therapeut. 2012;2:113.
3. Thienemann M, Murphy T, Leckman J, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome
: part I-psychiatric and behavioral interventions. J Child Adolesc Psychopharmacol. 2017;27:566–573.
4. Frankovich J, Swedo S, Murphy T, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome
: part II-use of immunomodulatory therapies. J Child Adol Psychop. 2017;27:574–593.
5. Cooperstock MS, Swedo SE, Pasternack MS, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome
: part III-treatment and prevention of infections. J Child Adol Psychop. 2017;27:594–606.
6. Chang K, Frankovich J, Cooperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome
(PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25:3–13.
7. Gilbert DL, Mink JW, Singer HS. A pediatric neurology perspective on pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection and pediatric acute-onset neuropsychiatric syndrome
. J Pediatr. 2018;199:243–251.
8. Swedo SE, Rapoport JL, Cheslow DL, et al. High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry. 1989;146:246–249.
9. Swedo SE, Leonard HL, Schapiro MB, et al. Sydenham’s chorea: physical and psychological symptoms of St Vitus dance. Pediatrics. 1993;91:706–713.
10. Swedo SE. Sydenham’s chorea. A model for childhood autoimmune neuropsychiatric disorders. JAMA. 1994;272:1788–1791.
11. Asbahr FR, Ramos RT, Negrão AB, et al. Case series: increased vulnerability to obsessive-compulsive symptoms with repeated episodes of Sydenham chorea. J Am Acad Child Adolesc Psychiatry. 1999;38:1522–1525.
12. Wald ER, Dashefsky B, Feidt C, et al. Acute rheumatic fever in western Pennsylvania and the tristate area. Pediatrics. 1987;80:371–374.
13. Veasy LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr. 1994;124:9–16.
14. Carapetis JR, Currie BJ, Mathews JD. Cumulative incidence of rheumatic fever in an endemic region: a guide to the susceptibility of the population? Epidemiol Infect. 2000;124:239–244.
15. American Academy of Pediatrics Redbook. Group A Streptococcal Infections. 2018 Report of the Committee on Infectious Diseases. 2018.31st ed. Itasca, IL: American Academy of Pediatrics.
16. Bryant PA, Smyth GK, Gooding T, et al. Susceptibility to acute rheumatic fever based on differential expression of genes involved in cytotoxicity, chemotaxis, and apoptosis. Infect Immun. 2014;82:753–761.
17. Hysmith ND, Kaplan EL, Cleary PP, et al. Prospective longitudinal analysis of immune responses in pediatric subjects after pharyngeal acquisition of group A Streptococci. J Pediatric Infect Dis Soc. 2017;6:187–196.
18. Singer HS, Gilbert DL, Wolf DS, et al. Moving from PANDAS to CANS. J Pediatr. 2012;160:725–731.
19. Singer HS. PANDAS: the need to use definitive diagnostic criteria. Tremor Other Hyperkinet Mov (N Y). 2015;5:327.
20. Singer HS. Autoantibody-associated movement disorders in children: proven and proposed. Semin Pediatr Neurol. 2017;24:168–179.
21. Perrin EM, Murphy ML, Casey JR, et al. Does group A beta-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? Arch Pediatr Adolesc Med. 2004;158:848–856.
22. Murphy TK, Snider LA, Mutch PJ, et al. Relationship of movements and behaviors to Group A Streptococcus
infections in elementary school children. Biol Psychiatry. 2007;61:279–284.
23. Kurlan R, Johnson D, Kaplan EL; Tourette Syndrome Study Group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics. 2008;121:1188–1197.
24. Leckman JF, King RA, Gilbert DL, et al. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011;50:108–118.e3.
25. Singer HS, Mascaro-Blanco A, Alvarez K, et al. Neuronal antibody biomarkers for Sydenham’s chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PLoS One. 2015;10:e0120499.
26. Brimberg L, Benhar I, Mascaro-Blanco A, et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012;37:2076–2087.
27. Lotan D, Benhar I, Alvarez K, et al. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav Immun. 2014;38:249–262.
28. Yaddanapudi K, Hornig M, Serge R, et al. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection
. Mol Psychiatry. 2010;15:712–726.
29. Loiselle CR, Lee O, Moran TH, et al. Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes. Mov Disord. 2004;19:390–396.
30. Frick LR, Rapanelli M, Jindachomthong K, et al. Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum. Brain Behav Immun. 2018;69:304–311.
31. Tanz RR, Zheng XT, Carter DM, et al. Caution needed: molecular diagnosis of pediatric Group A Streptococcal Pharyngitis. J Pediatric Infect Dis Soc. 2018;7:e145–e147.
32. Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002;156:356–361.
33. Franklin ME, Sapyta J, Freeman JB, et al. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive-compulsive disorder: the Pediatric OCD Treatment Study II (POTS II) randomized controlled trial. JAMA. 2011;306:1224–1232.
34. Garvey MA, Giedd J, Swedo SE. PANDAS: the search for environmental triggers of pediatric neuropsychiatric disorders. Lessons from rheumatic fever. J Child Neurol. 1998;13:413–423.
35. Shulman ST, Kaplan EL, Bisno AL, et al. Jones criteria (revised) for guidance in the diagnosis of rheumatic fever. Circulation. 1984;69:203A–208A.