Authors: Tourette Association of America PANDAS/ PANS Workgroup
Background:
In recent years, there has been much attention—both in the medical literature and in the mainstream media—to the hypothesis that some tic and neuropsychiatric disorders may be triggered by an underlying autoimmune or autoinflammatory response, collectively referred to either as PANDAS (“Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections”) or PANS (“Pediatric Acute-Onset Neuropsychiatric Syndrome”). While these proposed conditions are of scientific interest, they have generated significant confusion amongst medical providers, families, and patients alike, as the diagnostic criteria have evolved over time, and are often conflated or misapplied. Here, we briefly summarize the current research landscape on PANS/PANDAS and Tourette Syndrome (TS).
Tourette Syndrome (TS; also known as Tourette’s Disorder) is defined by the presence of multiple motor and one or more vocal tics that have persisted, though not necessarily concurrently, for more than a year with onset in individuals less than 18 years of age. The diagnosis is made on clinical grounds based on the description and appearance of tics. TS is highly co-occurring with a number of other neuropsychiatric conditions, including Obsessive Compulsive Disorder (OCD), Attention Deficit Hyperactivity Disorder (ADHD), Anxiety Disorders, Mood Disorders, Impulse Control Disorders, and Learning Disorders. While the precise pathophysiology of TS remains incompletely understood, there is a growing body of evidence to suggest that it arises from complex interactions among multiple genes and environmental factors.
PANDAS currently has five distinct diagnostic criteria, including abrupt, “overnight” onset or exacerbation of OCD or dramatic, disabling tics; a relapsing-remitting, episodic symptom course; young age at onset (average of 6–7 years); presence of neurologic abnormalities, such as physical hyperactivity or unusual, jerky movements (i.e., choreiform movements) that are not in the child’s control; and temporal association between symptom onset and Group A Streptococcus (GAS) infection (as documented through throat or nasal cultures).1 Elevated anti-streptococcal antibody and anti-DNase B titers are not a formal part of the diagnostic criteria for PANDAS, and are not sufficient grounds for making a diagnosis or initiating antibiotic treatment.
Since PANDAS can present with tics, it can be challenging—if not impossible—to differentiate PANDAS from a primary tic disorder, such as Tourette Syndrome or Persistent Motor/ Vocal Tic Disorder. Indeed, despite over two decades of research in this area, support for the concept of PANDAS as a cause of tics remains mixed. It is well established that tics can increase in number, frequency, and intensity in the face of various emotional and physical stressors, including infections, but previous studies examining the association between GAS and tic/ OCD exacerbations yielded mixed results. Fortunately, the recently published EMTICS (European Multicenter Tics in Children Studies) study—a longitudinal, observational study conducted at sixteen European centers—overcame the limitations of its predecessors as the largest, prospective cohort assessment of genetic and environmental risk factors for tics to-date. Significantly, this study concluded that there was no indication for a role of new GAS exposures in relation to exacerbations of tic disorders and that any perceived temporal associations were most likely due to chance.2
PANS is defined by the dramatic onset of OCD or severely restricted food intake in the concurrent presence of at least two other acute-onset, severe neuropsychiatric symptoms (anxiety; emotional lability or depression; irritability, aggression and/or severe oppositional behaviors; behavioral/ developmental regression; sudden deterioration in school performance; motor or sensory abnormalities; somatic signs and symptoms, such as sleep disturbances, enuresis, or urinary frequency) in an individual of any age.3 Tics are not part of the core definition of PANS. Tics can be considered to be “motor abnormalities,” but patients presenting with tics alone without OCD, including those with acute-onset of severe tics, can be reassured that they do not have PANS.
It has been suggested that PANS and/or PANDAS are on a continuum with Autoimmune Encephalitis (AE), but how—or whether—the two conditions are related remains a subject of debate. At this point, the diagnostic criteria for PANDAS and AE are distinct, with the diagnosis of possible AE requiring subacute onset of symptoms (working memory deficits, altered mental status, or psychiatric symptoms) and at least one of the following: new focal central nervous system symptoms, new-onset seizures, cerebral spinal fluid pleocytosis, MRI features suggestive of encephalitis, or identification of a known pathologic autoantibody (e.g., anti-NMDA receptor antibodies).4
Conclusion:
Until further scientific evidence becomes available, it is our position that the vast majority of children who present with tics have primary tic disorders that are not caused by immunologic factors. At this time, there is not definitive evidence that Strep (or the immune response to Strep) causes tics, but there is also not definitive evidence that Strep (or the immune response to Strep) cannot cause tics; thus, more evidence is needed before a definitive answer can be reached regarding the relationship between tics and streptococcal infections. Caution is thus advised with regard to clinical or other decision making based on the current level of available evidence.
In short, Tourette Syndrome is a validated diagnosis, in contrast to PANDAS and PANS, which are working hypotheses. The Tourette Association of America will continue to monitor research that is being done in TS as it relates to immunologic triggers. We understand that this is important to the community and will keep the community abreast of new developments in this area.
Given the current mixed research– what clinical action should be taken?
Based on the current evidence, throat cultures should be considered in the setting of complaints of fever, sore throat, malaise, or symptoms of general illness and may be considered in the setting of acute-onset or abrupt exacerbations of tics, particularly when accompanied by abrupt exacerbations of OCD symptoms or neurological abnormalities; however, the results should be interpreted with caution in the absence of constitutional symptoms of infection. Treatment with antibiotics should not be initiated without clinical evidence of infection and a positive throat culture. Experimental treatments based on the autoimmune theory, such as plasma exchange, immunoglobulin therapy, or prophylactic antibiotic treatment, should not be undertaken outside of formal clinical trials.
References:
- Swedo SE, Leondar HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998;155:264-71.
- European Multicenter Tics in Children Studies. courdis.europa.edu. Updated November 26, 2018. Accessed on January 20, 2020. 3.
- Swedo SE, Leckman JF, Rose NR. From Reaearch Subgroup to Clinical Syndrome: Modifying the PANDAS Criteria to Describe PANS (Pedaitric Acute-onset Neuropsychiatric Syndrome). Pediatr Therapeut 21012;2:doi:10.4172/2161-0665.1000113.
- Graus F, Titulaer MJ, Balu R, Benseler S, View CG et al. A Clinical Approach to the Diagnosis of Autoimmune Encephalitis. Lancet Neurology 2016 Apr;15(4):391-404.
