Streptococcus pyogenes (stained red), a common group A streptococcal bacterium. PANDAS is hypothesized to be an autoimmune condition in which the body's own antibodies to streptococci attack the basal ganglion cells of the brain, by a concept known as molecular mimicry.
|Classification and external resources|
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) describes 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. 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.
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. There is supportive evidence for the link between streptococcus infection and onset in some cases of OCD and tics, but proof of causality has remained elusive. The PANDAS hypothesis is controversial; whether it is a distinct entity differing from other cases of Tourette syndrome (TS)/OCD is debated.
PANDAS has not been validated as a disease entity; it is not listed as a diagnosis by the International Statistical Classification of Diseases and Related Health Problems (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM). Pediatric acute-onset neuropsychiatric syndrome (PANS) is a 2012 proposal describing another subset of acute-onset OCD cases including "not only disorders potentially associated with a preceding infection, but also acute-onset neuropsychiatric disorders without an apparent environmental precipitant or immune dysfunction".
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. 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.
To establish that a disorder is an autoimmune disorder, Witebsky criteria require
- that there be a self-reactive antibody,
- that a particular target for the antibody is identified (autoantigen)
- that the disorder can be caused in animals and
- that transferring antibodies from one animal to another triggers the disorder (passive transfer).
In addition, to show that a microorganism causes the disorder, the Koch postulates would require one show that the organism is present in all cases of the disorder, that the organism can be extracted from those with the disorder and be cultured, that transferring the organism into healthy subjects causes the disorder, and the organism can be reisolated from the infected party. 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 organisms may cause the symptoms, and the symptoms may be a rare reaction to a common pathogen.
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. 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 hypothesized that PANDAS and Tourette's may be associated; this idea is controversial and a focus for current research.
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. Researchers are pursuing the hypothesis that the mechanism is similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions.
The molecular mimicry hypothesis is a proposed mechanism for PANDAS: 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". 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. 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. Studies neither disprove nor support this hypothesis: the strongest supportive evidence comes from a controlled study of 144 children (Mell et al, 2005), but prospective longitudinal studies have not produced conclusive results.
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". 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. 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).
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 community physicians without conclusive evidence.
Treatment for children suspected of PANDAS is generally the same as the standard treatments for TS and OCD. These include cognitive behavioral therapy and medications to treat OCD such as selective serotonin reuptake inhibitors (SSRIs); and "conventional therapy for tics".
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. 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"; 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".
Evidence is insufficient to determine if tonsillectomy is effective.
Prophylactic antibiotic treatments for tics and OCD are experimental and controversial; overdiagnosis of PANDAS may have 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, but these results are unreplicated by independent studies as of 2010. 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. 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. 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. 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".
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. 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 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.
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." 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, a failure to apply published [PANDAS] criteria, and a lack of scientific support for proposed therapies". A 2012 paper by Swedo, Leckman and Rose proposed instead a new working proposal called pediatric acute-onset neuropsychiatric syndrome (PANS); it was "favored because 'childhood' would exclude adolescents, while 'pediatric' extends to at least age 18 years (and in some definitions, 21 years)".
Pediatric acute-onset neuropsychiatric syndrome
Given the controversy on the etiology of PANDAS (i.e., whether caused by strep throat) and the apparent ambiguity in the definitions of the clinical presentation leading to different research results, a new definition was proposed that would clarify the presentation of symptoms to ensure that research studies were studying the same group of children. This proposed syndrome is called pediatric acute-onset neuropsychiatric syndrome (PANS). PANS removes the requirement of temporal association with strep throat and adds the "abrupt, dramatic onset of obsessive-compulsive disorder (OCD) or severely restricted food intake" coincident with the presence of two or more neuropsychiatric symptoms, while also removing cases better explained as Tourette syndrome. The new proposed criteria come from a decade of comparative studies on the PANDAS hypothesis and argue that the severity, abruptness and dramatic onset of symptoms differentiate the children from traditional childhood OCD.
According to Swedo, Leckman and Rose (2012, Pediatrics & Therapeutics), the pediatric acute-onset neuropsychiatric syndrome proposal is a "working criteria" to assist scientists and clinicians to compare similar children across studies. The criteria will "undergo modifications and refinement as additional clinical and research experience is accrued". The proposed criteria claim that children can be distinguished from traditional childhood-onset OCD by the severity, abruptness and dramatic onset of symptoms. According to Swedo, Leckman and Rose (2012), children and adolescents hypothesized to have PANS would be identified by the following three criteria:
- Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake
- Concurrent presence of additional neuropsychiatric symptoms, with similarly severe and acute onset, from at least two of the following seven categories
- Emotional lability and/or depression
- Irritability, aggression and/or severely oppositional behaviors
- Behavioral (developmental) regression
- Deterioration in school performance
- Sensory or motor abnormalities
- Somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency
- Symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham's chorea, systemic lupus erythematosus, Tourette disorder or others.
There are other conditions that may have similar presentation; diagnostic workup of individuals suspected of PANS should exclude Sydenham's chorea, lupus erythematosus, acute disseminated encephalomyelitis, and Tourette syndrome. Evidence of acute rheumatic fever would exclude a PANS classification. Depending on neuropsychiatric symptoms, diagnostic tests may include magnetic resonance imaging (MRI), lumbar puncture, and electroencephalography (EEG).
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PANDAS is not yet a validated nosological construct.
- Murphy TK, Kurlan R, Leckman J (August 2010). "The immunobiology of Tourette's disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward". J Child Adolesc Psychopharmacol 20 (4): 317–31. doi:10.1089/cap.2010.0043. PMID 20807070.
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Despite continued research in the field, the relationship between GAS and specific neuropsychiatric disorders (PANDAS) remains elusive.
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