SPECIAL ARTICLE The Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infection (PANDAS) Etiology for Tics and ...
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SPECIAL ARTICLE
The Pediatric Autoimmune Neuropsychiatric Disorders Associated
With Streptococcal Infection (PANDAS) Etiology for Tics and
Obsessive-Compulsive Symptoms: Hypothesis or Entity?
Practical Considerations for the Clinician
Roger Kurlan, MD*, and Edward L. Kaplan, MD‡
ABSTRACT. Clinicians have been faced with much reacting with specific areas of the human brain (eg,
publicity and contradictory scientific evidence regarding the basal ganglia) to produce neuropsychiatric and
a recently described condition termed pediatric autoim- behavioral symptoms. The authors hypothesized
mune neuropsychiatric disorders associated with strep- that this condition might be a forme fruste of the
tococcal infection (PANDAS). It has been proposed that pathogenetic process thought to underlie Syden-
children with PANDAS experience tics, obsessive-com-
pulsive behavior, and perhaps other neuropsychiatric
ham’s chorea and therefore also may be related to
symptoms as an autoimmune response to streptococcal rheumatic fever.2,3 The observation that Sydenham’s
infection. We review current scientific information and chorea includes tics4 and sometimes obsessive-com-
conclude that PANDAS remains a yet-unproven hypoth- pulsive symptoms5 contributed to the proposal that a
esis. Until more definitive scientific proof is forthcom- poststreptococcal autoimmune mechanism(s) might
ing, there seems to be insufficient evidence to support 1) lead to a more diverse neurobehavioral symptom
routine microbiologic or serologic testing for group A spectrum. Subsequently, the clinical spectrum asso-
streptococcus in children who present with neuropsychi- ciated with this constellation of neuropsychiatric
atric symptoms or 2) the clinical use of antibiotic or signs and symptoms (PANDAS) was proposed to
immune-modifying therapies in such patients. The opti- include a number of additional manifestations in-
mum diagnostic and therapeutic approach awaits the re-
sults of additional research studies. Pediatrics 2004;113:883–
cluding attention-deficit/hyperactivity disorder,6
886; tics, obsessive-compulsive symptoms, streptococcal myoclonus,7 dystonia,8 paroxysmal dyskinesias,9
infection, autoimmunity, PANDAS. acute disseminated encephalomyelitis,10 and an-
orexia nervosa.11
This PANDAS hypothesis has stimulated clinical
ABBREVIATIONS. OCD, obsessive-compulsive disorder; PAN- and basic research and has resulted in considerable
DAS, pediatric autoimmune neuropsychiatric disorders associated
with streptococcal infection; GABHS, group A -hemolytic strep- clinical and scientific controversy12–14; the contro-
tococcus; TS, Tourette’s syndrome. versy has influenced clinical care. Because of the
implications for the primary care physician, the neu-
rologist, the psychiatrist, the infectious disease spe-
W
ith a description of 50 patients, Swedo et al1 cialist, the cardiologist (if it is to be considered part of
proposed a hypothesis that childhood ob- the rheumatic fever complex, as is Sydenham’s cho-
sessive-compulsive disorder (OCD) and/or rea), and even the basic scientist, it is appropriate to
tics may arise as a result of a poststreptococcal auto- objectively examine available information regarding
immune process; the authors suggested the acronym the hypothesis and to provide recommendations for
PANDAS (pediatric autoimmune neuropsychiatric a current, optimal clinical approach to patients sus-
disorders associated with streptococcal infections). It pected of having PANDAS.
additionally was suggested that, by a process of mo-
lecular mimicry, somatic epitopes of the group A THE DIAGNOSTIC CRITERIA: IS PANDAS AN
-hemolytic streptococcus (Streptococcus pyogenes) ADEQUATELY DEFINED CLINICAL DIAGNOSIS?
(GABHS) evoke antibodies that are capable of cross-
Five criteria were proposed to define the PANDAS
hypothesis1 (see Table 1).
From the *Cognitive and Behavioral Neurology Unit, Department of Neu-
rology, University of Rochester School of Medicine, Rochester, New York; Criterion 1
and ‡Department of Pediatrics, World Health Organization Collaborating
Center for Reference and Research on Streptococci, University of Minnesota
As mentioned, several authors have suggested that
School of Medicine, Minneapolis, Minnesota. tics and OCD may not be the only clinical features of
Received for publication May 23, 2003; accepted Jul 30, 2003. PANDAS, and thus the true boundaries of the PAN-
Address correspondence to Roger Kurlan, MD, Cognitive and Behavioral DAS clinical spectrum remain to be scientifically val-
Neurology Unit, Department of Neurology, University of Rochester idated or standardized. Even considering only tics
School of Medicine, Rochester, NY 14642-8673. E-mail: roger㛭kurlan@urmc.
rochester.edu
and OCD, the level and characteristics of symptom
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- severity required for diagnosis have not been de-
emy of Pediatrics. fined yet by controlled studies.
PEDIATRICS Vol. 113 No. 4 April 2004 883
Downloaded from pediatrics.aappublications.org by guest on September 27, 2015TABLE 1. National Institute of Mental Health Clinical Diag- Criterion 4
nostic Criteria for PANDAS
Onset or exacerbations of neuropsychiatric symp-
1. Presence of OCD or a tic disorder. toms temporally related to GABHS infection has
2. Onset between 3 years of age and the beginning of puberty. been proposed as the sine qua non of the diagnosis of
3. Abrupt onset of symptoms or a course characterized by
dramatic exacerbations of symptoms. PANDAS. Yet, despite limited studies to establish
4. The onset or the exacerbations of symptoms is temporally this, it has not been documented adequately in pro-
related to infection with GABHS. spective studies and remains 1 of the most contro-
5. Abnormal results of neurologic examination (hyperactivity, versial aspects of the hypothesis. GABHS infections
choreiform movements, and/or tics) during an exacerbation.
are very common, and the prevalence of this organ-
ism in the upper respiratory tract of asymptomatic
school children (“carriers”) often is relatively high.19
Criterion 2 This epidemiologic phenomenon of high prevalence
of GABHS has resulted in a number of other disease
The proposed age at onset, ranging between 3 entities (among the best examples are Henoch-
years and the beginning of puberty, may be too Schönlein purpura and Kawasaki disease), which
arbitrary and may simply be the result of referral also have been proposed to be associated with group
patterns for the 50 initially described patients. For A streptococcal infections. However, when ade-
example, the validity of the proposed age-at-onset quately controlled studies were conducted, strepto-
criterion is raised by the report of a 25-year-old with cocci were eliminated as the causal factor.20 The con-
sudden-onset OCD after pharyngitis.15 Furthermore, fusion about the role of GABHS may be promoted
because the vast majority of typical Tourette’s syn- further because, clinically, it is appreciated that tic
drome (TS) manifestations (ie, tics) begin during the disorders and OCD worsen during times of stress or
prepubertal period (75% having onset before 11 illness of any kind. The worsening of symptoms
years old16), the age-at-onset criterion is not suffi- might be expected with streptococcal upper respira-
ciently specific in distinguishing PANDAS from the tory tract infection and could even occur in the rel-
more established diagnostic criteria for TS.17 Recog- atively large percentage of children who are asymp-
nizing a documented higher likelihood of exposure tomatic streptococcal carriers if simultaneous
of schoolchildren to GABHS, no pathogenetic or im- stressful situations occur (from any other cause).
munologic basis has been confirmed to explain why Additionally, review of published studies indi-
the onset might be expected to include only young cates that the temporal boundaries of a proposed
children. “temporal” relationship with streptococcal infections
have never been established. In Sydenham’s chorea,
Criterion 3 often cited as the model for PANDAS, the choreo-
A unique specificity of a clinical course consisting athetoid movements typically appear 3 to 5 months
of abrupt onset or dramatic exacerbations has not after GABHS infection. Swedo et al1 implied that an
been documented adequately. With careful observa- infection up to 9 months before symptom onset may
tion, tics are either present or not; thus, the onset (or be acceptable for the diagnosis of PANDAS but also
parental awareness) of tic disorders is not gradual. have indicated that the presence of GABHS in the
Often with a sudden recognition of tics by parents, in upper respiratory tract (not differentiating infection
retrospect a prior history of milder tics can be elic- from the carrier state) may not be detectable until
ited, making the precise timing of clinical onset con- weeks after onset or exacerbation. Such a lack of
fusing. Experienced neurologists and psychiatrists precision does not assist in establishing a distinct
are aware that tic disorders and OCD characteristi- syndrome.
cally wax and wane spontaneously, with exacerba- Thus, the absence of regular, continuous, prospec-
tions followed by remissions. The degree of clinical tive throat cultures along with streptococcal anti-
change required for recognizing exacerbations to dis- body determinations has made it impossible to es-
tinguish a “PANDAS-like process” from the typical tablish conclusively a temporal relationship between
course of more established tic and OCDs has not streptococcal infection and onset or exacerbation of
been differentiated or quantitated adequately. For neuropsychiatric symptoms. Sufficiently long, longi-
example, 1 recent study of 80 consecutively exam- tudinal, prospective studies conclusively demon-
ined (unselected) patients in a tic-disorders clinic strating streptococcal infection and correlating this
found that 53% reported sudden, explosive onset or with clinical findings are required.
worsening of their tics.18 These patients were not
considered to have met criteria for a diagnosis of Criterion 5
PANDAS. Preliminary evaluation of our own ongo- The final diagnostic criterion, that there must be
ing, case-control epidemiologic study of PANDAS abnormalities on neurologic examination, presents a
indicated that 36% of the carefully selected control difficult and practical clinical problem. For example,
subjects (who had no recognized link between symp- the 1998 report that “choreiform” movements are
toms and GABHS infection) also reported an abrupt often present in patients in whom a diagnosis of
onset or dramatic exacerbations (R. Kurlan, MD, un- PANDAS is considered indicates that the cohort on
published data, 2003). Thus, clinical course does not which the proposed diagnostic criteria were based
seem particularly useful in distinguishing patients may well have included subjects with mild chorea
suspected of PANDAS from children with more typ- that might also be compatible with more conven-
ical cases of TS or OCD. tional Sydenham’s chorea.1
884 PANDAS: HYPOTHESIS OR ENTITY? PRACTICAL CONSIDERATIONS
Downloaded from pediatrics.aappublications.org by guest on September 27, 2015CLINICAL MANAGEMENT OF PATIENTS HAVING later report suggesting improvement of new-onset or
SOME OR ALL OF THESE NEUROPSYCHIATRIC acute exacerbations of symptoms in such children
MANIFESTATIONS with antibiotics provides inadequate support for
Laboratory Testing such an approach, because treatment was not place-
bo-controlled and was unblinded.26 It is well known
An initial concern of pediatricians and primary
in treatment studies of TS that there is a substantial
care physicians about clinical management of pa-
placebo effect; the natural course of TS and OCD is
tients with this symptom complex is which, if any,
such that exacerbations are followed by remissions.
diagnostic laboratory studies should be done. Given
This latter phenomenon of “reversion to the mean”
the current status of as-yet incompletely defined sup-
implies that virtually any intervention at the time of
port for the existence of a specific entity called PAN-
peak symptoms may seem successful. Only a double-
DAS, the physician may be cautious in deciding
blind, placebo-controlled study can identify a true
whether to obtain throat cultures or determine anti-
therapeutic effect.
streptococcal antibodies in all children presenting
Another reason to feel comfortable with avoiding
with neurobehavioral symptoms such as tics, obses-
antibiotic treatment for these patients is that, to date,
sions, or compulsions. Because of potential difficul-
no cases have been reported to develop any rheu-
ties in interpretation of single tests, even with “pos-
matic carditis as occurs in patients with Sydenham’s
itive” culture results, the high prevalence of so many
chorea. This is a very important point to remember,
GABHS carriers in normal populations potentially
because some have attempted to relate this syn-
confuses the issue.
drome to rheumatic fever. It is recognized that as
Patients with signs and symptoms compatible
many as one third of patients with Sydenham’s cho-
with streptococcal upper respiratory tract infections
rea ultimately will have evidence of rheumatic val-
should be studied for the presence of GABHS just as
vular heart disease.27 This issue requires additional
with any other patient. In the absence of symptoms
investigation, because the lack of heart disease
of streptococcal infection, the relevance of a positive
strongly argues against a relationship between PAN-
culture is difficult to interpret. The many uncertain-
DAS and Sydenham’s chorea or other forms of rheu-
ties encountered in interpreting streptococcal anti-
matic fever.
body titers in otherwise normal children are recog-
nized.21 Therefore, to use streptococcal antibody IS THERE A CASE FOR IMMUNOMODULATORS?
tests or throat cultures in an asymptomatic child
either as a screening test or to confirm a diagnosis of Because the postulated mechanism for a PANDAS
PANDAS is problematic. syndrome implies an immunologic dysfunction,
Two research laboratory tests, measurement of cir- therapeutic trials have attempted to modify the ef-
culating antineuronal antibodies and an assay for the fects of an immune response. A published study
presence of an alleged rheumatic fever-associated T involving 29 patients fulfilling suggested criteria for
lymphocyte alloantigen called D8/17,22 have not PANDAS reported sustained benefits both after
been able to correlate reliably and consistently with plasma exchange and in patients after intravenous
suspected PANDAS cases.14 immunoglobulin.28 However, Singer,29 in an accom-
panying commentary, pointed out numerous meth-
Although radiologically suspected enlargement of
odologic concerns about the trial including highly
caudate nuclei has been described in some suspected
selective recruitment, small sample size, lack of se-
patients, routine magnetic resonance imaging cannot
verity matching within treatment groups, limited
be recommended currently, because the validity has
comparisons with controls, absence of sham aphere-
not been substantiated.23
sis, concomitant use of psychotropic medications,
possible treatment-order effects, and adverse effects
Therapy
that occurred in approximately two thirds of subjects
What treatment should be considered for patients receiving active treatment. A subsequent note of cau-
who present with the manifestations associated with tion was issued in 2000 by the National Institute of
the PANDAS constellation of symptoms? Mental Health recommending that, at this time,
plasma exchange and intravenous immunoglobulin
Neuropsychiatric Drugs be reserved only for subjects participating in ap-
Children with disabling tics or OCD should re- proved research protocols because there are distinct
ceive appropriate treatment for their symptoms, in- risks involved.30 To date, there are no additional
cluding medications (eg, tic suppressants such as published data to encourage use of these immune-
␣-agonists, classical or atypical antipsychotics, or an- modifying techniques.
tiobsessional drugs such as selective serotonin-re-
uptake inhibitors) or nonpharmacologic approaches CONCLUSIONS
(eg, cognitive behavioral therapy for OCD).24 The current state of knowledge dictates that the
concept of a constellation of neuropsychiatric signs
Antibiotics to Prevent Strep Infections and symptoms that are associated with GABHS in-
The only published clinical trial of prophylactic fections (the PANDAS hypothesis) should be consid-
penicillin in children with this syndrome revealed no ered only as a yet-unproved hypothesis. History re-
conclusive evidence that the antibiotic reduced clin- minds us that the same autoimmune hypothesis for
ical exacerbations.25 Admittedly, the duration of that childhood autism, including poststreptococcal ele-
study was too short to allow definite conclusions. A ments,31 has been pursued for decades32 without
SPECIAL ARTICLES 885
Downloaded from pediatrics.aappublications.org by guest on September 27, 2015conclusive proof. The PANDAS hypothesis is the 12. Kurlan R. Tourette’s syndrome and “PANDAS”: will the relation bear
out? Neurology. 1998;50:1530 –1534
focus of clinical and laboratory research. There cur- 13. Kaplan EL. PANDAS? or PAND? Or Both? Or Neither? Assessing a
rently is insufficient evidence to support routine lab- possible temporal or pathogenetic relationship with the group A “strep-
oratory testing or antibiotic/immune-modifying tococcal diseases complex.” Contemp Pediatr. 2000;8:81–96
treatment for suspected cases. Although there is 14. Singer HS, Loiselle C. PANDAS. A commentary. J Psychosom Res. 2002;
great need for a more effective diagnostic and ther- 1:1–9
15. Bodner SM, Morshed SA, Peterson BS. The question of PANDAS in
apeutic approach for these children, the clinician is adults. Biol Psychiatry. 2001;49:807– 810
obliged to await additional data from well-controlled 16. Singer HS, Walkup JT. Tourette syndrome and other tic disorders.
prospective studies to determine whether PANDAS Medicine. 1991;70:15–32
is a documentable entity or will remain an unproven 17. American Psychiatric Association. Diagnostic and Statistical Manual for
Psychiatry. 4th ed, Text Revision. Washington, DC: American Psychiat-
hypothesis. ric Association; 2000
18. Singer HS, Giuliano JD, Zimmerman AM, Walkup JT. Infection: a
ACKNOWLEDGMENTS stimulus for tic disorders. Pediatr Neurol. 2000;22:380 –383
This work was supported by National Institutes of Health 19. Kaplan EL, Top F Jr, Dudding BA, Wannamaker LW. Diagnosis of
research grant NS42240 from the National Institute of Neurolog- streptococcal pharyngitis: differentiation of active infection from the
ical Disorders and Stroke. carrier state in the symptomatic child. J Infect Dis. 1971;123:490 –501
20. Ayoub EM, Hoyer J. Anaphylactoid purpura: streptococcal antibody
titers and  1c-globulin levels. J Pediatr. 1969;75:193
REFERENCES 21. Shet A, Kaplan EL. The clinical use and interpretation of group A
1. Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuro- streptococcal antibody tests: a practical approach for the pediatrician or
psychiatric disorders associated with streptococcal infections: clinical primary care physician. Pediatr Infect Dis J. 2002;21:420 – 426
description of the first 50 cases. Am J Psychiatry. 1998;155:264 –271 22. Zabriskie JB, Lavenchy D, Williams RC, et al. Rheumatic fever-
2. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC. Anti- associated B cell alloantigens as identified by monoclonal antibodies.
bodies reacting with cytoplasm of subthalamic and caudate nuclei Arthritis Rheum. 1985;28:1047–1051
neurons in chorea and acute rheumatic fever. J Exp Med. 1976;144: 23. Giedd JN, Rapoport JL, Garvey MA, Perlmutter S, Swedo SE. MRI
1094 –1110 assessment of children with obsessive-compulsive disorder or tics as-
3. Bronze MS, Dale JB. Epitopes of streptococcal M proteins that evoke sociated with streptococcal infection. Am J Psychiatry. 2000;157:281–283
antibodies that cross-react with human brain. J Immunol. 1993;151: 24. Kurlan R. Gilles de la Tourette’s syndrome. In: Rakel RE, Bope ET, eds.
2820 –2828 Conn’s Current Therapy, 2001. Philadelphia, PA: WB Saunders; 2001:
4. Mercadante MT, Campos MC, Marques-Dias MJ, Miguel EC, Leckman 931–935
J. Vocal tics in Sydenham’s chorea. J Am Acad Child Adolesc Psychiatry. 25. Garvey MA, Perlmutter SJ, Allen AJ, et al. A pilot study of penicillin
1997;36:305–306 prophylaxis for neuropsychiatric exacerbations triggered by streptococ-
5. Swedo SE, Leonard HL, Schapiro MB, et al. Sydenham’s chorea: phys- cal infections. Biol Psychiatry. 1999;45:1564 –1571
ical and psychological symptoms of St Vitus dance. Pediatrics. 1993;91: 26. Murphy ML, Pichichero ME. Prospective identification and treatment of
706 –713 children with pediatric autoimmune neuropsychiatric disorder associ-
6. Swedo SE, Leonard HL, Mittleman BB, et al. Identification of children ated with group A streptococcal infection (PANDAS). Arch Pediatr
with pediatric autoimmune neuropsychiatric disorders associated with Adolesc Med. 2002;156:356 –361
streptococcal infections by a marker associated with rheumatic fever. 27. Nausieda PA, Grossman BJ, Koller WC, et al. Sydenham chorea: an
Am J Psychiatry. 1997;154:110 –112 update. Neurology. 1980;30:331–334
7. DiFazio MP, Morales J, Davis R. Acute myoclonus secondary to group 28. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma ex-
A beta-hemolytic streptococcus infection: a PANDAS variant. J Child change and intravenous immunoglobulins for obsessive-compulsive
Neurol. 1998;13:516 –518 disorder and tic disorders in childhood. Lancet. 1999;354:1153–1158
8. Dale RC, Church AJ, Benton S, et al. Post-streptococcal autoimmune 29. Singer HS. PANDAS and immunomodulatory therapy. Lancet. 1999;354:
dystonia with isolated bilateral striatal necrosis. Dev Med Child Neurol. 1137–1138
2002;44:485– 489 30. Marshall L. Plasma exchange and intravenous immunoglobulin lack
9. Dale RC, Church AJ, Surtees RA, Thompson EJ, Giovannoni G, Neville proven benefit and carry risk for children with PANDAS, Tourette
BG. Post-streptococcal autoimmune neuropsychiatric disease present- syndrome or OCD. NIMH-E-NEWS, July 12, 2000. Available at: www.
ing as paroxysmal dystonic choreoathetosis. Mov Disorder. 2002;17: nimh.nih.gov. Accessed October 1, 2003
817– 820 31. Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani
10. Dale RC, Church AJ, Cardoso F, et al. Poststreptococcal acute dissemi- E. Antibodies to neuron-specific antigens in children with autism: pos-
nated encephalomyelitis with basal ganglia involvement and auto- sible cross-reaction with encephalitogenic proteins from milk. J Neuro-
reactive antibasal ganglia antibodies. Ann Neurol. 2001;50:588 –595 immunol. 2002;129:168 –177
11. Sokol MS. Infection-triggered anorexia nervosa in children: clinical 32. Weizman A, Weizman R, Szekely GA, Wijsenbeek H, Livni E. Abnormal
description of four cases. J Child Adolesc Psychopharmacol. 2000;10: immune response to brain tissue antigen in the syndrome of autism.
133–145 Am J Psychiatry. 1982;139:1462–1465
886 PANDAS: HYPOTHESIS OR ENTITY? PRACTICAL CONSIDERATIONS
Downloaded from pediatrics.aappublications.org by guest on September 27, 2015The Pediatric Autoimmune Neuropsychiatric Disorders Associated With
Streptococcal Infection (PANDAS) Etiology for Tics and Obsessive-Compulsive
Symptoms: Hypothesis or Entity? Practical Considerations for the Clinician
Roger Kurlan and Edward L. Kaplan
Pediatrics 2004;113;883
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on September 27, 2015The Pediatric Autoimmune Neuropsychiatric Disorders Associated With
Streptococcal Infection (PANDAS) Etiology for Tics and Obsessive-Compulsive
Symptoms: Hypothesis or Entity? Practical Considerations for the Clinician
Roger Kurlan and Edward L. Kaplan
Pediatrics 2004;113;883
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/113/4/883.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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