Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a controversial hypothetical diagnosis for a subset of children with rapid onset of obsessive–compulsive disorder (OCD) or tic disorders coming immediately after a Streptococcus infection. Symptoms are proposed to be caused by group A streptococcal (GAS), and more specifically, group A beta-hemolytic streptococcal (GABHS) infections. OCD and tic disorders are hypothesized to arise in a subset of children as a result of a post-streptococcal autoimmune process. The proposed link between infection and these disorders is that an autoimmune reaction to infection produces antibodies that interfere with basal ganglia function, causing symptom exacerbations, and this autoimmune response results in a broad range of neuropsychiatric symptoms.
The PANDAS hypothesis, first described in 1998, was based on observations in clinical case studies by Susan Swedo et al. at the US National Institute of Mental Health and in subsequent clinical trials where children appeared to have dramatic and sudden OCD exacerbations and tic disorders following infections. Whether PANDAS was a distinct entity differing from other cases of tic disorders or OCD is debated. As the PANDAS hypothesis was unconfirmed and unsupported by data, a new definition was proposed by Swedo and colleagues in 2012. In addition to the 2012 broader pediatric acute-onset neuropsychiatric syndrome (PANS), two other categories have been proposed: childhood acute neuropsychiatric symptoms (CANS) and pediatric infection-triggered autoimmune neuropsychiatric disorders (PITAND). The CANS/PANS hypotheses include different possible mechanisms underlying acute-onset neuropsychiatric conditions, but do not exclude GAS infections as a cause in a subset of individuals. PANDAS, PANS and CANS are the focus of clinical and laboratory research but remain unproven.
There is no diagnostic test to accurately confirm PANDAS; the diagnostic criteria are unevenly applied and the conditions may be overdiagnosed. Treatment for children suspected of PANDAS is generally the same as the standard treatments for Tourette syndrome (TS) and OCD. There is insufficient evidence or consensus to support treatment, although experimental treatments are sometimes used, and adverse effects from unproven treatments are expected. The media and the internet have contributed to an ongoing PANDAS controversy, with reports of the difficulties of families who believe their children have PANDAS or PANS. Attempts to influence public policy have been advanced by advocacy networks.
Characteristics The children originally described by Susan Swedo et al. (1998) usually had an abrupt onset of symptoms, including motor or vocal tics, obsessions, or compulsions. In addition to an obsessive–compulsive or tic disorder diagnosis, children may have other symptoms associated with exacerbations such as emotional lability, enuresis, anxiety, and deterioration in handwriting. There may be periods of remission. 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 syndrome (TS or TD, for Tourette's disorder), some researchers hypothesized that PANDAS and TS may be associated; this idea is challenged and a focus for research.
Pediatric acute-onset neuropsychiatric syndrome (PANS) is a hypothesized disorder characterized by the sudden onset of OCD symptoms or eating restrictions, concomitant with acute behavioral deterioration or severe neuropsychiatric symptoms including sleep, emotional and behavioral disturbances, regression in school performance, or motor and sensory issues. PANS eliminated tic disorders as a primary criterion and placed more emphasis on acute-onset OCD, while allowing for causes other than streptococcal infection.
Classification
PANDAS is hypothesized to be an autoimmune disorder that results in a variable combination of tics, obsessions, compulsions, and other symptoms with sudden or abrupt onset that may be severe enough to qualify for diagnoses such as chronic tic disorder, OCD, and TS. As of 2024, the autoimmune hypothesis of PANDAS is controversial and disputed.
PANS, CANS and PITANDs are also hypothesized to be autoimmune disorders.
Cause The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are disputed and unconfirmed. The cause is thought to be akin to that of Sydenham's chorea (SC), which is known to result from childhood group A streptococcal (GAS) infection leading to the autoimmune disorder rheumatic fever of which SC is one manifestation. Like SC, PANDAS is thought to involve autoimmunity to the brain's basal ganglia. Courtesy link to partial pages.
To establish that a disorder is an autoimmune disorder, the 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). Courtesy link to pp. 159–62.
Results of studies investigating an autoimmune cause that meet Witebsky's criteria are inconsistent, controversial, and subject to methodological limitations.
To show that a microorganism causes a disorder, the Koch postulates would require one to 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 that the organism can be re-isolated from the infected party. Giavanonni notes that the Koch postulates are not useful in substantiating PANDAS as a post-infectious disorder 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.
Some studies support acute exacerbations associated with streptococcal infections among clinically defined PANDAS subjects; other studies have found no association between abrupt onset or exacerbation and infection. The PANS hypothesis, then, expands the causes beyond streptococcal infection and postulates that the cause can be genetic, metabolic, or infectious.
Among children with PANS or PANDAS, studies are inconsistent, and the hypothesis that antibodies trigger symptoms is unproven; some studies showed antibodies in children with PANS/PANDAS, but those results were not replicated in other studies. A large multicenter study (EMTICS—European Multicentre Tics in Children Studies) showed no evidence in children with chronic tic disorders of strep infections leading to tic exacerbation, or specific antibodies in children with tics, and a study of the cerebrospinal fluid of adults with TS similarly found no specific antibodies. The antibodies that were found by one group were collectively named the "Cunningham Panel"; subsequent independent testing showed this panel of antibodies did not distinguish between children with and without PANS, and its reliability is unproven. A consensus statement from the British Paediatric Neurology Association (BPNA), states that a "causal infection (rather than coincidental infection) or an inflammatory or autoimmune pathogenesis" has not been confirmed, and that "no consistent biomarkers have been identified that accurately diagnose PANDAS or are reliably associated with brain inflammation".
Mechanism The mechanism is hypothesized to be 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 develop Sydenham's. 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 brain region that may be affected in PANDAS is the basal ganglia, which are believed to be responsible for movement and behavior. It is thought that, similar to Sydenham's, the antibodies cross-react with neuronal brain tissue in the basal ganglia to cause the tics and OCD that characterize PANDAS.
It is unclear if the group of patients diagnosed with PANDAS developed tics and OCD through a different mechanism than seen in other people diagnosed with Tourette Syndrome. Studies are inconsistent: 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, and other studies do not support the hypothesis.
Diagnosis Neither PANDAS nor PANS are listed as a diagnosis in the 2013 fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or confirmed as distinct disorders. PANDAS is mentioned in the World Health Organization's ICD-11, effective in 2022, under autoimmune central nervous system disorders, but diagnostic criteria are not defined and no specific code for PANS or PANDAS is given. See summary here. The 2021 European clinical guidelines developed by the European Society for the Study of Tourette syndrome (ESSTS) did not support the additions made to ICD-11.
Swedo et al. in their 1998 paper proposed five diagnostic criteria 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 proposed PANS criteria call for abrupt onset of OCD (severe enough to warrant a DSM diagnosis) or restricted food intake, along with severe and acute neuropsychiatric symptoms from at least two of the following: anxiety, emotional lability or depression, irritability or oppositional behaviors, developmental regression, academic deterioration, sensory or motor difficulties, or sleep or urinary disturbances. The symptoms should not be better explained by another disorder, such as Syndenham's chorea or Tourette syndrome. The authors stated that all other causes must be excluded (diagnosis of exclusion) for PANS to be considered.
There is no diagnostic test to accurately confirm PANDAS. The diagnostic criteria of all the proposed conditions (PANDAS, PITANDs, CANS and PANS) are based on symptoms and presentation, rather than on signs of autoimmunity. A commercial test known as the Autoimmune Brain Panel (also known as the Cunningham Panel)—intended to diagnose PANDAS and PANS based on assays of antibodies—did not distinguish between children with and without PANS when independently tested.