Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcus (PANDAS)
The potential link between common childhood infections and lifelong neuropsychiatric disorders is among the most tantalizing and clinically relevant concepts in modern neuroscience. This link may be most relevant in the group of disorders collectively described as "PANDAS" (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus") and actively studied as a clinical entity by investigators at the National Institute of Mental Health (NIMH) and elsewhere. However, public awareness of this potential link has outpaced our scientific knowledge base, with magazines, newspaper articles and Internet chat rooms carrying this issue into the public's attention. Compared to about 15 case reports or series listed on Medline - many involving a single patient, others reporting the same patients in different papers - there are over 200 sites on the internet where the putative streptococcus/obsessive-compulsive disorder (OCD)/Tourette Syndrome (TS) relationship is discussed. There is a particular shortage of studies of basic cellular and immune mechanisms underlying PANDAS.
This meeting was organized based on discussions between the Tourette Syndrome Association (TSA), the NIMH and the National Institute of Neurological Disorders and Stroke (NINDS) as a forum to discuss research relevant to PANDAS. The TSA initiated these discussions to address the several ways in which it has been impacted by the gap in our basic understanding of PANDAS and by the growing public awareness of a potential infectious link to the pathogenesis of TS. The TSA has been funding an increasing amount of research on immune- and PANDAS-related hypotheses for the pathogenesis of TS. Last year, almost 50% of the TSA investigator grant budget was applied towards studies of streptococcal and immune mechanisms contributing to TS and OCD. Both NIMH and NINDS have supported research on TS, OCD and PANDAS. Findings by Dr. Susan Swedo at the NIMH suggest that immunomodulatory therapies may hold promise for the treatment of PANDAS, and there has been a sense that these findings may have even greater impact if they are replicated and extended outside of the NIH.
The agenda of this meeting focused on two general sets of issues: (A) basic biological mechanisms underlying the potential relationship between streptococcal infections and the symptoms of TS and OCD, and (B) clinical issues related to the development and application of optimal therapies for PANDAS-related conditions.
- What is the relationship between Group A streptococcal infections in children and the onset of symptoms of TS and/or OCD?
- What epidemiological studies are needed to establish or refute a causal relationship between streptococcal infections and symptoms of TS and/or OCD?
- How do we study the potential causal relationship between a waxing and waning clinical syndrome (TS/OCD) and an infection that is nearly ubiquitous, serologically complex and often asymptomatic in carrier states?
- What standards (e.g., temporal relationships, assays, designs, etc.) should be adopted for epidemiologic or population studies aimed at understanding this relationship?
- What neuroimmunological / neuropathological studies are needed to understand the mechanism whereby streptococcal infections might impact the brain to trigger symptoms of TS and/or OCD?
- How can we identify the mechanisms by which antibodies are proposed to gain access to brain tissue to trigger the injury responsible for symptoms of PANDAS?
- Are there resources that exist now (e.g., brain bank tissue), or that should be established, to store tissue, sera or other material that will be useful for basic neuropathological / neuroimmune studies of the possible streptococcus/OCD/TS relationship?
- What other neuropsychiatric conditions are now considered "PANDAS" candidates (e.g., attention deficit hyperactivity disorder, autism, and separation anxiety)? Based on clinical or population features, do any of these conditions offer advantages as targets of epidemiological and/or mechanistic studies?
- What other infectious pathogens, besides streptococcus, can be considered as possible precipitants of neuropsychiatric sequelae such as TS and/or OCD (e.g., mycoplasma pneumoniae), and how does this alter our perception of the specific relationship between streptococcal infections and the "PANDAS" complex? Are there some pathogens that stand out as high-yield targets based on epidemiological differences from group A beta hemolytic streptococcus (GABHS)?
- How can we clarify the relationship between PANDAS and SC? How can we best understand the relationship between D8/17, Sydenham's Chorea (SC), PANDAS and OCD/TS?
- Assuming that the PANDAS subgroup is a viable entity:
- What are the unique clinical characteristics of the PANDAS subgroup? Is it possible to make subgroup assignment through retrospective history? If so, does long-term prognosis vary for PANDAS vs. other forms of OCD/tic disorders?
- How can we identify susceptible patients before symptom onset? What is the potential value of at-risk siblings studies, epidemiologic investigations, and genetics studies (D8/17 variant?)
- Is antibiotic prophylaxis warranted for subjects with PANDAS?
- How can acute, severe exacerbations be prevented and treated in a non-invasive way? Intravenous immunoglobulin and plasmapheresis have been shown to be effective in a placebo-controlled trial, but there is a need for replication of these findings.
- Why do the neuropsychiatric sequelae occur? There is a need for studying both host pathophysiologic characteristics and streptococcus factors.
Minutes of the Roundtable discussions, contained below, have been compiled and reviewed by the discussants.
Diagnostic Criteria: There is a need to clarify certain aspects of the clinical distinction among PANDAS, Sydenham's Chorea (SC) and TS. Two specific aspects of the clinical features of PANDAS were discussed:
- Chorea vs. choreiform movements: One distinction between PANDAS and SC relates to the presence of choreiform movements (in PANDAS) vs. the chorea (in SC). However, discussants commented on the vagueness of this distinction, citing that even the most experienced movement disorder specialists cannot agree on the distinction between these conditions on a case-by-case basis.
- The "abruptness" of the onset of symptoms: One distinction between PANDAS and TS relates to the fact that symptom onset is more abrupt in PANDAS, compared to TS. However, because a tic is a unitary event, it either happens or it doesn't; thus, by definition, the first tic of TS has an abrupt onset. Dr. Swedo commented that one experienced TS clinician's (Dr. Harvey Singer) review of charts supported this distinction between PANDAS and TS. Nonetheless, this criterion will need a more crisp operational definition to be of use in segregating these diagnoses for any research endeavor. The inter-rater reliability and test/re-test stability of the diagnosis of PANDAS need to be established across research and clinical settings.
- The possible association of PANDAS with major criteria of acute rheumatic fever (carditis, polyarthritis, erythema marginatum, subcutaneous nodules) needs to be investigated.
Neuroimmunology: There are large gaps in our knowledge base in a variety of areas related to possible neuroimmune processes underlying the central nervous system (CNS) impact of streptococcal infections, such as:
- The potential role of abnormalities of the blood/brain barrier;
- The CNS involvement of cytokines in post-streptococcal sequelae;
- Are there antibodies to the central nervous system in PANDAS, and, if so, what are these antibodies targeted at, how do they get there, or are they already there? The functional characteristics of these antibodies were felt to be important; specifically, what do they do? Do the antibodies produce the CNS pathology, or are they formed in response to pathology produced by a different process? Similar questions were raised regarding cytokines and T-cells. The specificity of "antineuronal antibodies" was discussed: neurons tend to be particularly "sticky" and thus antibody binding may be non-specific. The importance of cerebrospinal fluid (CSF) studies, particularly those that might identify the presence of oligoclonal bands, were discussed.
More generally, because of the effectiveness of antibiotic therapy in treating streptococcal infections, many basic facts regarding the systemic and CNS immune responses to streptococcus remain unknown and unstudied. Because these basic immune mechanisms may play a central role in PANDAS or related syndromes, and may ultimately be the likely targets for rational PANDAS therapies, it is critical that basic immune studies of streptococcus be undertaken. For example, it was noted that the cellular immune response to streptococcal infections in SC patients vs. controls might be very informative, but even the most basic in vivo studies in controls have not been fully pursued. If differences between SC and controls are identified, comparisons of PANDAS cellular immune response might be informative regarding the basic immunologic relationship between SC and PANDAS.
Surrogate markers: Because of the variability in clinical presentations, and some ambiguity in the diagnostic boundaries of SC, PANDAS, TS and OCD, it was felt that surrogate markers would be particularly valuable additions to the research process. Because of diagnostic heterogeneity, these markers would be closer to the biology of the CNS impact of streptococcus, than would the diagnoses themselves. The idea would be to establish the marker pattern for SC as a disorder that is presumably most homogeneous and most clearly neuroimmune and streptococcal in origin and to compare this marker profile to that of PANDAS, TS and OCD. This would allow us to both identify an experimental measure of CNS streptococcal impact, and to assess whether PANDAS, TS and/or OCD exhibited such evidence of CNS-streptococcus injury. Specific types of surrogate markers for the CNS effects of streptococcal infections were discussed:
- Neuroimaging markers, including positron emission tomography (PET), magnetic resonance spectroscopy (MRS), and functional magnetic resonance imaging (fMRI);
- Animal models of post-streptococcal CNS pathology;
- Mathematical models of the temporal patterns of symptoms in SC, PANDAS, OCD, and TS.
Neuroimaging markers were discussed briefly. Of note, there are no published neuroimaging studies of SC. Such information could serve as a "marker phenotype" to compare the pattern of this presumably most homogeneous neuroimmune disorder to the neuroimaging profiles of PANDAS, TS and OCD. There are significant impediments to the use of radio-isotopes in pediatric PET studies. Importantly, measures of brain metabolic activity identify essentially opposite patterns of abnormality in TS and OCD, so it is clear that no single "marker phenotype" will span all of these four disorders. Investigators are attempting to develop useful activation tasks for fMRI studies in OCD and TS; presumably, such tasks could be applied to an SC population to establish a profile of the "most homogeneous" condition.
However, because these four conditions exhibit substantial overlap in symptomatology, it would be very likely that they would share some degree of overlap in neural circuit pathology as detected by neuroimaging. Thus, it would be important to determine which neuroimaging features of SC are the closest "signature" of the streptococcus-induced injury, rather than the symptoms (e.g., stereotyped movements, tics, obsessions, etc.). How one could accomplish this is unclear.
Regarding animal models, there are presently no accepted animal models for SC, PANDAS, or TS. Such models would obviously assist us in developing and testing hypotheses at mechanistic and intervention levels, that cannot be practically approached in humans. The TSA is supporting some pilot work in this area in rodents and infrahuman primates, but more generally, this is an undertaking requiring a basic investment beyond the scope of the TSA's abilities.
Temporal patterns of tic behaviors are being studied and may provide useful surrogate markers reflecting fundamental time constants of underlying neural circuit interactions. These patterns might be useful ways of identifying similarities and/or differences in the basic symptom properties of SC, PANDAS and TS.
Alternative Hypotheses and Models: The consensus of the discussants was that despite the fact that the PANDAS hypothesis was exciting and of tremendous potential importance, it would be important to not too quickly rule out other alternative hypotheses, that might bring the observations surrounding the streptococcus/TS/OCD relationship into a context that may be more generally relatable to neuropsychiatric manifestations of immune insults. Specifically, it will be important to develop "null" and "2nd level" hypotheses. These hypotheses might address issues such as:
- If symptoms are being generated by something other than infections, what might this "other" event be?
- If the symptoms are due to an infectious agent other than streptococcus, what agents might be suspicious?
- If it is streptococcus, what strains of streptococcus are involved?
- If the symptoms are being generated by streptococcus, is this streptococcus trigger necessary only on the initial episode, with subsequent episodes being triggered by other pathogens or non-specific events such as stress? There is some suggestion that this might occur in SC.
- If there is a streptococcus-etiology for PANDAS/TS/OCD, what proportion of PANDAS/TS/OCD arises via this mechanism? Is streptococcal infection the major pathway to these disorders, or a minor one?
The potential role of viruses in the activation of secondary exacerbations was discussed. A substantial amount of time was spent discussing the potential importance of more complex models related to the possible synergism between streptococcus and a second condition (susceptible host). In one model, streptococcus might activate some cascade that leads to symptoms, and at a later time some other precipitant might trigger that cascade in the absence of streptococcus.
Using SC as a model disorder for PANDAS, TS, OCD, etc.: SC has been grossly understudied as a relatively "simple" and homogeneous comparison for understanding more complex conditions such as PANDAS, TS and OCD. For example, discussion addressed the importance of pursuing mechanistic studies in SC populations. There may be as many as 200 new SC patients per year in the United States, and systematic studies of SC would require networks of collaborating investigators to contribute to recruitment and ascertainment. It was agreed that organizing such a collaborative network would be an extremely valuable undertaking. Another suggestion was to determine whether there were commonalities and/or differences between PANDAS and other autoimmune disorders, such as might be found in B-cell activation markers.
Needs and priorities for PANDAS research:
- The diagnostic criteria for PANDAS, and particularly for the distinction between PANDAS and SC, are critically important; studies should use comparable diagnostic criteria, and it was generally agreed that the NIH diagnostic instrument/interview should be viewed as the working model of a "gold standard" at this time, particularly for treatment intervention studies. Nonetheless, the specific criteria should be viewed as an evolving research tool.
- There is a critical need for epidemiological and mechanistic studies to establish the "gold standards" for streptococcal markers, including quantitative markers and markers to differentiate active versus carrier states.
- A critical step in all of this work is to establish criteria for demonstrating that PANDAS/Sydenham's Chorea is immunopathologically mediated. It was felt that such criteria could be constructed with relatively little disagreement, and that determining that PANDAS/SC meet these criteria would be a major impetus to future studies.
- It will be important to develop the null hypotheses, and the complex hypotheses of synergism, priming, and non-streptococcal insults or pathogens that might result in PANDAS (described above).
- Determine the immune/neuroimmune mechanisms responsible for PANDAS, focusing on the blood/brain barrier and CNS antibodies. Discussion ensued regarding the importance of identifying the cellular immune response to streptococcal infection. This process could be studied in vitro, and this cellular immune response to streptococcus could then be compared between patients with SC vs. controls, and if differences are identified, then PANDAS patients could be added to this comparison.
- It will be important to understand which developmental features contribute to the susceptibility of the juvenile immune and/or neurological systems to the PANDAS pathology.
- Substantial gains should be made in the development of surrogate markers in neuroimaging, temporal measures (which might include non-linear dynamic models), and animal models. These tools could be particularly useful for efforts to investigate pathophysiological mechanisms related to PANDAS.
- The need to collect data on first episode or "antibiotic-free" episodes was discussed, as a means to clarify a number of critical issues, including questions related to PANDAS epidemiology, etiologic hypotheses, the distinction between "causes" and "triggers," etc. It was determined that designs for identifying pre-antibiotic first episodes of PANDAS would be extremely difficult for many reasons, including the fact that the latent period between GABHS infection and the onset of PANDAS might be many months (as it is for SC). Nonetheless, two strategies were discussed for accomplishing the important task of determining the potential association between streptococcal infections and PANDAS. First, longitudinal studies could be done in subjects using exacerbations rather than first episodes in within- and between-subjects designs. Some experts shared their impression that the high prevalence of apparent infectious "triggers" for TS or OCD exacerbations makes this type of study feasible, and with appropriate statistical modeling, such work could be highly informative. However, there are considerable difficulties in such studies that relate to the unknown interval between trigger events and exacerbations, high background rates of streptococcal infection and/or colonization in the community, uncertainty of interpretation of antibody responses, and other potential confounds.
Second, high-risk populations could be studied for their first episode. Two sets of high risk populations were discussed: (1) isolated populations with high incidence of acute rheumatic fever (e.g., Salt Lake City, Maori of NZ, aborigines), and (2) siblings of PANDAS patients.
A cooperative study was described that might involve the assistance of the TSA, the Obsessive Compulsive Foundation (OCF), and NIH. This study would pursue the second, "high risk" strategy. In one example of an experimental design, such a study might follow prospectively the younger siblings of patients with PANDAS, TS, or OCD with serial serology, blood spots, clinical assessments, and throat swabs. Blood spots would be frozen for later studies of antibodies and cytokines. There would be some standardized algorithm for treatment (with a recommendation to not treat unless there are symptoms consistent with a GABHS pharyngitis), and some standardized immune markers and cytokine measures from the blood. Buccal swabs would also be obtained once. Sera could be frozen and examined for other pathogens at a later time, in individuals who eventually exhibited PANDAS.
- Neuropathological studies with existing TS brain tissue might be done to examine inflammatory changes using elution and IGg immunoglobulin measures. Tissue could also be examined to determine whether it was cross reactive to sera from patients with TS, OCD, or PANDAS. Other potentially valuable tissue resources may exist in a Sydenham's Brain Bank in Iowa.
- Studies could be done using CSF from PANDAS patients. In one example, it might be possible to isolate CSF antibodies, which could then be used as probes for antigens to understand the cellular immune response in PANDAS. This work might be undertaken using existing samples or protocols, as a cooperative study between existing groups at the NIH.
- Lastly, studies were discussed that might attempt to replicate the reported findings of a therapeutic benefit of intravenous immunoglobulin administration (IVIG) in PANDAS. Specifically, it was discussed that a set protocol should be established based on existing studies at NIH and a contract might be sought to replicate these precise methodologies, (including Dr. Swedo's PANDAS diagnostic instrument), at extramural sites. Sample sizes would be adequate to provide power to test the hypothesis of clinical effectiveness of this intervention.
Linda Brady, Ph.D.
Chief, Molecular & Cellular Neuroscience Research Branch
Division of Neuroscience and Basic Behavioral Science
NIMH, MSC 9641
Bethesda, MD 20892-9641
Xavier Castellanos, M.D.
Child Psychiatry Branch
NIH Bldg. 10/6N240
10 Center Drive
Bethesda, MD 20982
Michael Gerber, M.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive
Bethesda, MD 20892
Wayne Goodman, M.D.
Chairman, Dept. of Psychiatry
University of Florida Brain Institute, Suite L4-100
P.O. Box 100256 Gainesville, Fl 32610-0256
Peter Hollenbeck, Ph.D.
Dept of Biological Sciences
2237 Lilly Hall
West Lafayette, IN 47907
Steve Jacobson, M.D.
NINDS, Bldg. 10, Room 5N214
Bethesda, MD 20892
Director, Medical and Scientific Programs
Tourette Syndrome Association, Inc.
42-40 Bell Boulevard
Bayside, NY 11361-2820
Robert Lisak, M.D.
Dept. of Neurology
Wayne State University School of Medicine
University Health Center, 8D
4201 St. Antoine
Detroit, MI 48201
Barbara B. Mittleman, M.D.
Director, Office of Scientific Interchange
BLDG 10 Rm 9ET
Bethesda MD 20892-1820
Tanya Murphy, M.D.
Division of Child and Adolescent Psychiatry
P O Box 100256
Gainesville, FL 32610-0256
Karin Nelson, M.D.
NINDS, Federal Bldg., Room 714A
Bethesda, MD 20892
Stanford T. Shulman, M.D.
Professor of Pediatrics
Northwestern University Medical School
Chief, Division of Infectious Diseases
Children's Memorial Hospital
Giovanna Spinella, M.D.
Program Director, NINDS
Neurogenetics and Development
Neuroscience Center, Rm. 2132
6001 Executive Blvd.
Rockville, MD 20892-9527
David M. Stoff, Ph.D.
HIV/AIDS and Mentally Ill and Developmental Disorders Programs
Division of Mental Disorders, Behavioral Research and AIDS
Office on AIDS Research
National Institute of Mental Health
6001 Executive Blvd, Room 6210, MSC 9619
Bethesda, MD 20892-9619
Susan Swedo, M.D.
Chief, Pediatric & Development
NIH Bldg. 10/6N208
10 Center Drive
Bethesda, MD 20982
Neal Swerdlow, M.D., Ph.D.
Professor, Dept. of Psychiatry
University of California, San Diego
School of Medicine
9500 Gilman Dr.
La Jolla, CA 92093-0804
Benedetto Vitiello, M.D.
Chief, Child & Adolescent Treatment &
Preventive Interventions Research Branch
NIMH, Room 7147
6001 Executive Blvd., MSC 9633
Bethesda, MD 20892-9633
Lois Winsky, Ph.D.
Chief, Neuroimmunology and Neuroendocrinology Research Program
Division of Neuroscience and Basic Behavioral Science
NIMH, MSC 9641
Bethesda, MD 20892-9641
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