Issue: October 2012
Perspective from Stanford T. Shulman, MD
October 01, 2012
13 min read

PANDAS to CANS: Evolution of a controversial disorder

Little consensus exists on role of group A streptococcal infection in autoimmune/neurological phenomenon.

Issue: October 2012
Perspective from Stanford T. Shulman, MD
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Infectious disease specialists, neurologists and everyday pediatricians have long speculated on the etiology of an acute-onset obsessive-compulsive disorder that affects some children. The disorder is marked by a broad range of presentations and symptoms and, consequently, has confounded the clinical community for decades.

In recent years, several steps have been made to resolve disagreement surrounding this affliction. In July 2010, the National Institute of Mental Health (NIMH) Pediatric and Developmental Neuroscience Branch convened a group of researchers, clinicians and public health advocates to address incidence of acute-onset obsessive-compulsive disorder, regardless of potential cause. Additionally, experts from a variety of fields — from ID to neurology — have conducted their own research, using basic science and drawing from multiple patient populations.

The good news is that these efforts have not been in vain. More is known about this disorder than ever before. The bad news is that the clinical and research communities have not yet come to a consensus on etiology or definition.

Infectious Diseases in Children spoke to a number of clinicians and researchers about the topic, including Susan E. Swedo, MD, chief of the pediatrics and developmental neuroscience branch at NIMH, and Harvey Singer, MD, professor in the departments of neurology and pediatrics at The Johns Hopkins Hospital Children’s Center. Although Swedo and Singer are key players in the effort to shed light on this disorder, they have differing opinions on some aspects of it. However, they do share areas of agreement.

Nancy H. O’Hara, MD, MPH, FAAP, of the Center for Integrative Health, said a standardized set of questions should be developed to identify patients with this neuropsychiatric condition.

Source: Friedman P

“An independent review board has yet to take a critical look at all of the relevant data,” Swedo said. “Until that happens, it will be difficult to put this controversy to rest.”

Singer put the issue in more clinical terms. “We have to make sure that all of the hypotheses that have been presented can stand up to critique,” he said.

Some of the other clinicians interviewed by Infectious Diseases in Children commented on the complexities surrounding the diagnosis of these children, why some of the treatment strategies may be harmful, and how research needs to progress. First, however, it is necessary to review some landmark research that is relevant to the present state of the discussion, and to outline exactly how the name of this disorder has evolved.

Definition of terms

The term PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) was coined in 1998 by Swedo and colleagues in a paper published in the American Journal of Psychiatry. However, the NIMH investigators recognized that streptococcal infections were not the inciting factor, having first reported on cases seemingly triggered by influenza or varicella infections, as well as by strep. Because an etiologic model was available for post-streptococcal autoimmune disorders (ie, Sydenham’s chorea and other manifestations of acute rheumatic fever), the NIMH group chose to focus on PANDAS, rather than the larger group of patients labeled as PITANDS (pediatric infection-triggered autoimmune neuropsychiatric disorders).

Throughout the 2000s, attempts were made to firmly attach group A streptococcal (GAS) to the symptoms, but the data have been inconclusive, according to some researchers. This, in part, prompted the 2010 NIMH group meeting.

Harvey Singer

Harvey Singer

The result of this meeting was that Swedo and Singer published separate papers, both of which introduced broader terms for the disorder: PANS (pediatric acute-onset neuropsychiatric syndrome) from Swedo’s group and CANS (childhood acute neuropsychiatric symptoms) from Singer’s group.

“Despite continued debates about the role of group A streptococcal infections in the etiopathogenesis of PANDAS . . . . experts on both sides of the controversy agree that a subgroup of children with obsessive-compulsive disorder (OCD) have an unusually abrupt onset of symptoms, accompanied by a variety of comparably severe and acute neuropsychiatric symptoms,” Swedo and colleagues wrote. “The acuity of symptom onset is the hallmark feature of their clinical presentation and the basis for the name proposed for an expanded clinical entity,” which they called PANS.

The workshop participants proposed three diagnostic criteria for PANS:

  • Abrupt, dramatic onset of OCD (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:
    1. Anxiety (including separation anxiety);
    2. Emotional lability and/or depression;
    3. Irritability, aggression and/or severely oppositional behaviors;
    4. Behavioral (developmental) regression;
    5. Deterioration in school performance;
    6. Sensory or motor abnormalities;
    7. 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’s disorder or others.

Singer and colleagues noted that the differential diagnosis of this condition may involve infectious, post-infectious, drug-induced, autoimmune, metabolic, traumatic, psychogenic, and other factors, but not yet a scientific association with streptococcus.

“On the basis of inconclusive and conflicting scientific support for this diagnosis [PANDAS], a broader concept of CANS is proposed,” they wrote. “Although inclusion in CANS requires only the acute dramatic onset of symptoms, we mandate a comprehensive history and examination, consideration of a differential diagnosis, an active search for a specific etiology through appropriate laboratory testing, and treatment with the most appropriate therapy.”

Noel R. Rose, MD, of the Center for Autoimmune Disease Research at the Johns Hopkins School of Medicine, may be able to offer the most unique perspective on the debate. “I don’t actually work in the PANDAS or PANS field,” he said. “I was brought in as a neutral mediator by Drs. Singer and Swedo.”

Rose said the group did not aim to rule anything out, but to “try to establish the clinical criteria to do a sound epidemiologic or etiologic study. Hopefully, this paper by Dr. Swedo is a step along the way of getting a handle on what this neurological disease actually is.”

The streptococcal debate

By his own admission, Edward L. Kaplan, MD, professor of pediatrics in the department of pediatrics at the University of Minnesota Medical School, has been dealing with streptococcal infections “since a little after Columbus came to America.”

“Streptococcal infection is an occupational disease of schoolchildren,” he said. “Some published studies suggest that bona fide strep occurs at least three times before children are 13 years old. No matter whether we are talking about ingrown toenails or lumps on the ear, a significant proportion of children who have had whatever it is are going to demonstrate evidence of GAS infection.”

Kaplan paraphrased Infectious Diseases in Children Editorial Board member Stanford T. Shulman, MD, chief of the division of infectious diseases at Ann & Robert H. Lurie Children’s Hospital of Chicago, who quipped that a lot of people who fall out of apple trees have had streptococcal infections, but that does not mean that strep infections cause you to fall out of apple trees.

Kaplan cited data indicating that streptococci would be found in the throat culture of 5% to 20% of schoolchildren in a temperate climate during the fall, winter and early spring months. He added that not all children with streptococcal bacteria develop an infection, that many, perhaps half, are simply carriers.

“In recent studies, we have shown that you can have high titers of strep antibodies but not be infected,” he said. “Children can get antibody titers from having been infected with strep and maintain them at certain levels for months, sometimes up to a year, without any evidence of strep being recoverable by culture whatsoever. You can imagine with that kind of background, there is an opportunity for confusion.”

Kaplan said that all of this information must be considered when approaching the unique set of neuro-psych symptoms that has been described. He does not doubt that these children develop symptoms overnight, and that many of them are either carriers of streptococcus or have experienced streptococcal infection at some time in their lives.

“There have been some very nice case reports and several studies conducted, but I don’t think the existing data are evident to document a causative relationship,” he said. “This is another source of controversy.”

Nancy H. O’Hara, MD, MPH, FAAP, of the Center for Integrative Health, noted another layer of complication to the discussion. “Symptoms may lag behind the infection by 6 months or more,” she said.

Kaplan and Singer both acknowledge the possibility that streptococcus may play a role in the development of the disease. “They may be linked,” Kaplan said. “But I would like to see carefully constructed research with objective assessment to prove it.”

Singer echoed this opinion and said that research into the proposed mechanism of infection might clear up the issue. The mechanism is that the antibodies the body develops to fight streptococcal infection interfere with the neurological system. This, in turn, induces the tics or other OCD behaviors. But this, too, has raised debate.

In keeping with the theme of continually attempting to shed light on this disorder, Swedo highlighted research conducted by Cunningham and colleagues in which male Lewis rats were exposed to GAS antigen. She and colleagues aimed “to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of [Sydenham’s chorea] and other streptococcal-related neuropsychiatric disorders.”

Noel Rose

Noel Rose

They observed that these rats exhibited motor symptoms and compulsive behavior. They found that the symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine. They added, “Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of [Sydenham’s chorea] and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulindependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from [Sydenham’s chorea] and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in [Sydenham’s chorea] and other streptococcal-related neuropsychiatric disorders.”

Another model of antistreptococcal antibody induced behavior was shown in mice by Hornig and colleagues who passively administered antistreptococcal antibody that resulted in behavior changes in the mice.

Swedo commented on these results. “We believe that these animal models have demonstrated the mechanisms of this disease,” she said.

Antibody response

Madeleine W. Cunningham, PhD, George Lynn Cross Research Professor at the University of Oklahoma Health Sciences Center, along with Kirvan and colleagues, studied associations between anti-neuronal antibody responses and behavioral and movement disorders PANDAS and Sydenham’s chorea.

“In our study, antibodies in [PANDAS and Sydenham’s chorea] reacted with the neuronal cell surface and caudate–putamen and induced neuronal cell signaling through calcium-calmodulin dependent protein (CaM) kinase II activity in human neuronal cells,” they wrote. “Depletion of serum IgG abrogated CaM kinase II cell signaling and reactivity of [cerebrospinal fluid] was blocked by streptococcal antigen N-acetyl-beta-D-glucosamine (GlcNAc). Results suggest that antibodies from an infection may signal neuronal cells in some behavioral and movement disorders.”

Conversely, Martino and colleagues measured anti-basal ganglia antibodies in 15 children with a diagnosis of PANDAS and compared them with those in 15 controls.

“ELISA optical density values did not differ between PANDAS patients and controls across all preparations,” they wrote. “[This suggests] a lack of major antibody changes in this disorder.”

While results from Swedo and colleagues may signal a new direction for research and evaluation, clinicians are still forced to deal with children who present with symptoms that are rarely consistent and not easily categorized.

Heterogeneity of symptoms

“A year ago, we realized that there may be two or more groups of patients,” Cunningham said. “For example, those PANDAS cases that have the small piano playing choreiform movement are probably different immunologically from the ones that do not. The patients that Dr. Singer studies are probably different from the original group of 50 studied by Dr. Swedo. Thus, heterogeneity of the group is among the biggest factors in the confusion surrounding this disease.”

In a presentation at the 2012 Pediatric Academic Societies’ annual meeting, Swedo discussed the similarity of PANDAS or PANS to more established syndromes such as Tourette’s or Sydenham’s chorea.

“These children do not present with garden variety OCD or tic disorders,” she said. “In these children, everything is coming on simultaneously. Severe OCD, separation anxiety, personality change, movement disorders or sensory abnormalities, and daytime urinary frequency. All of the symptoms start all at once and seemingly out of the blue. Children are being possessed overnight.”

Moreover, the course of the disease features relapsing and remitting symptoms. “There are triggers,” Swedo said. “The first onset is strep triggered, but subsequent exacerbations can be triggered by other immunological challenges, including a wide variety of infections and psychosocial stressors.”

The on-again, off-again nature of the symptoms contributes to the heterogeneity and the subsequent difficulties in pinning down a diagnosis in any individual patient. “One group of PANDAS patients may have more OCD behaviors,” Cunningham said.

Adding to the confusion is that some of the symptoms may present not only as Sydenham’s chorea, but also as Tourette’s.

“Sydenham’s chorea is very overt, very clear,” Cunningham said. “In PANDAS, tics can be confused with Tourette’s. What is interesting is that Tourette’s has been loosely connected to strep, but this relationship also has not been studied thoroughly.”

Even as questions regarding the diagnosis remain open, clinicians are forced to decide on an etiology and begin treating the disorder, which presents another set of complications.

Complexities of treatments

A small body of research and clinical experience have suggested that plasma exchange and intravenous immunoglobulin (IVIG) may be beneficial, but Kaplan and Singer expressed reservations with these approaches. “Many courses of IVIG have been administered to these children, but we can’t know if it is helping until we know exactly what this disease is,” Kaplan said.

“Plasmapheresis is a dramatic treatment that is potentially harmful,” Singer added, also noting that such therapies should be discontinued until more definitive information on the disorder is available.

Kaplan commented on the treatment of streptococcal infection as a possible therapy for the neurological disorder. “We know that to treat strep, you have to treat people for 10 days to eradicate the organism from the throat,” he said, noting that this treatment regimen is recommended by the AAP, the IDSA, the American Heart Association and WHO. “There are case reports demonstrating that a patient receives one dose of this or that antibiotic and they get better overnight. It doesn’t make sense to me.”

Singer offered a practical solution. “Until we fully understand this thing, our approach should be to treat symptoms,” he said. “There are medicines that work with tics, so treat that. If they have OCD, there are medicines that treat that. If they have anxiety, we have drugs for that.”

Future research

All agreed that further research is necessary.

“Someone needs to put all of this together,” Singer said. “We need to have broad criteria. If someone comes in with these particular symptoms, they should undergo a complete evaluation. Every detail of the results should all be quantified and tabulated and followed, and we should develop a registry to aid in future research.”

O’Hara suggested a personal approach for clinicians to follow. “We need to develop a standardized group of questions that each family would get asked,” she said. “Part of the questionnaire should pertain to acute onset. Weed out kids who have had this for 2 to 3 years and it recently got worse.”

Kaplan spoke in more general terms. “Good research raises more questions than it answers,” he said. “If we don’t pin this thing down with one or two longitudinal studies, we need to continue studying and be careful about which patients are included.”

Kaplan added that carefully designed prospective trials and intensive serial observations with controls would go a long way in resolving many of the conflicts associated with this set of symptoms.

Swedo commented on behalf of the children and families faced with this disorder. “While we wait for an independent review, I can only hope that additional children won’t suffer,” she said.

Further research may prove that some of these children are experiencing an atypical form of Sydenham’s chorea, or another type of neurologic disease, according to Rose.

“It could be a syndrome that follows streptococcal infection,” he said. “But it might not. Strep is very common in children. First, one has to do large scale epidemiology to see if there is a statistical relationship. Then we need a plausible biologic mechanism. The good news is that some progress was made at the NIMH meeting, and we are one step closer to establishing clinical criteria for such a study.” — by Rob Volansky

For more information:

  • Brimberg L. Neuropsychopharmacology. 2012; doi: 10.1038/npp.2012.56.
  • Kirvan CA. Nat Med. 2003; 9: 914-920.
  • Kirvan CA. J Neuroimmunol. 2006;179:173–179.
  • Martino D. Mov Disord. 2005;20:116-117.
  • Singer HS. J Pediatr. 2012;160:725-731. 
  • Swedo SE. Am J Psychiatry. 1998;155:264-271. 
  • Yaddanapudi, K. Mol Psychiatry. 15: 712-726.
  • Madeleine W Cunningham, PhD, can be reached at University of Oklahoma Health Sciences Center, Biomedical Research Center, 975 NE 10th Street, Oklahoma City, OK 73104; email: L. Kaplan, MD, can be reached at the Department of Pediatrics, University of Minnesota Medical School, 420 Delaware St., SE, MMC 296, Minneapolis, MN 55455.
    Nancy H. O’Hara, MD, MPH, FAAP, can be reached at the Center for Integrative Health, 3 Holly Hock Lane, Wilton, CT 06897; email:
    Noel R. Rose, MD, did not provide contact information.
    Harvey Singer, MD, can be reached at Rubenstein Child Health Building, 200 North Wolfe Street, Suite 2141, Baltimore, Maryland 21287; email:
    Susan E. Swedo, MD, can be reached at the following email address:
  • Disclosures: Cunningham receives research support from the National Institute of Mental Health, National Heart Lung and Blood Institute, Oklahoma Center for Advancement of Science and Technology, Harvard University David Judah Fund, Pepsico and Global Giving Fund, and the PANDAS Research Fund. She also receives salary from Moleculera Labs, her company for diagnostic testing of autoantibodies in neuropsychiatric disorders. Kaplan, O’Hara and Rose report no disclosures. Singer receives research grant support from Psyadon (study of ecopipam for tic suppression), the National Institute of Health (study of glutamate modulators for tic suppression and PET imaging studies in Tourette syndrome), and JAEB Center for Health Research (consultant for levodopa pilot study for pediatric eye disease). He is on the Board of the journal The Neurologist. He reports no conflicts of interest. Suk and Swedo reports no relevant financial disclosures.