Oral Health Group
Feature

PANDAS: A Story of Molecular Mimicry


November 22, 2016
by Anne Bosy, M.Sc, M.Ed, RRDH

Background
PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections. This is a condition that affects a small group of children resulting in a sudden and abrupt onset of Obsessive Compulsive Disorder (OCD) symptoms. In the late 1990’s, investigators at the US National Institutes of Mental Health, during a study of childhood onset of OCD, observed that some of the children had an unusually sudden onset of symptoms that differed from the typical cases where symptoms began gradually. These children presented with obsessive thoughts, compulsive behaviors and motor or vocal tics that appeared overnight and worsened rapidly within a day or two. Neuropsychiatric symptoms included irritability and aggressive behavior, anxiety attacks, extreme mood swings, temper tantrums, baby talk, handwriting changes as well as problems with school subjects such as math and reading. The investigators discovered that in this particular group of children, symptoms appeared after streptococcal infections

Bacteria implicated in this disease are Streptococcus pyogenes (group A beta-hemolytic streptococcal bacteria). We associate these bacteria with a common ailment among both children and adults – a very painful condition called strep throat or acute pharyngitis. Scarlet fever, rheumatic fever, Streptococcal Toxic Shock Syndrome and impetigo are also caused by S. pyogenes. This ancient and clever organism survives through a system called molecular mimicry. It hides from the immune system by putting protein molecules on its cell wall that resemble those found in the brain tissues, heart, joints and skin. These molecules are eventually recognized as foreign and the body produces antibodies. Unfortunately, because of the molecular mimicry, the antibodies not only react with S.pyogenes but also with the human molecules that were mimicked. In the case of PANDAS, it appears that the human molecules that are attacked are tissues in the brain, particularly the basal ganglion. These attacks alter the dopamine transmissions, including the release of excess dopamine leading to neuropsychiatric symptoms of tics and OCD.

One of the problems associated with PANDAS is the diagnosis of this streptococcal infection. PANDAS symptoms may follow an asymptomatic and unnoticed infection, thus the neuropsychiatric symptoms may be the first sign of this hidden infection. A child who has strep throat infection usually exhibits fever with sore throat. The asymptomatic child or carrier of the bacteria does not have symptoms and may not be tested to confirm the presence of S.pyogenes. Children and adolescents suffering from PANDAS rarely present with sore throats and therefore often go unrecognized or are misdiagnosed as having a mental illness and prescribed psychiatric medications as an attempt to manage symptoms. In the case of PANDAS, children may have an improvement but if they get another streptococcal infection, the symptoms become dramatically worse.

Diagnostic Criteria
Five criteria were established by the US National Institute of Mental Health group as guidelines to diagnose PANDAS:

  1. The presence of OCD, tics or Attention Deficit Hyperactivity Disorder (ADHD);
  2. Abrupt onset of symptoms
  3. Association with neurological abnormalities including motor hyperactivity and abnormal movements, anxiety, bedwetting and other regressive behaviours such as temper tantrums, personality changes and deterioration in math skills and handwriting
  4. Onset of symptoms from age three to puberty
  5. Associated with group A beta-hemolytic streptococcal infections. This could be verified through a throat culture or evidence of infections such as scarlet fever or by laboratory test evidence, for example the ASO titer.

It is essential to distinguish PANDAS from Tourette’s syndrome, which is a common tic disorder, and from Sydenham chorea, a movement disorder caused by Strepotococcus and associated with rheumatic fever. To complicate matters further, PANDAS is a subgroup of a disorder called PANS or Pediatric Acute-Onset Neuropsychiatric Syndrome. This is described as a treatable autoimmune condition that could be triggered by infections other than strep including B.burgdorferi (Lyme disease) herpes simplex, the common cold and other viruses.

Tests for PANDAS
Streptococcal antibody titers are used to determine if the child has had a previous strep infection. Two strep tests are commercially available: Antistreposysin O (ASO) titer and the Antistreptoccocal DNAse B (AntiDNAase-B) titer. These tests show if there are molecules in the blood that indicate an infection that the child may have had in the last few months and molecules to fight the strep infection have been created. A throat culture can also be done to check if for the presence of S.pyogenes in the oropharynx. If the throat culture is negative, strep infection in the sinus, anus, vagina or penis, although rare, have been known to trigger PANDAS symptoms. If the culture is positive, antibiotic treatment will eliminate the strep infection and PANDAS symptoms will decrease or be eliminated. A commercial polymerase chain reaction (PCR) based test for the detection of S.pyogenes has been developed and has excellent sensitivity and specificity. This may be the test of choice in the future.

Treatment Options
If the disease is recognized as PANDAS, these patients respond well to antibiotic treatment and improvement is seen within a few days. Beta-lactam antibiotics such as penicillin, amoxicillin, and cephalosporins have been shown effective in the treatment of PANDAS. Other antibiotics that have been used with some success are erythromycin, azithromycin and clindamycin. Some resistance has been identified and if there is no improvement, the antibiotic should be changed.

There is some indication that S.pyogenes can exist in oral biofilm and it has been isolated from tooth surfaces and gutta percha in endodontically treated teeth. In discussions with parents whose children have PANDAS, they have identified a connection to exfoliation of teeth. The child will have an increased intensity of symptoms during exfoliation and eruption. Further, S. pyogenes can persist on surfaces of soft toys, books, cribs and other hard surfaces for an extended period of time. This increases the possibility of exposure and re-infection with these bacteria. Since S.pyogenes is transmissible in the same manner as periodontal pathogens, after an episode, the replacement of toothbrushes by children who suffer from PANDAS would be very beneficial to prevent reinfection.

PANDAS has been misunderstood and confusing to doctors. Controversy about treatment and the skepticism in accepting the condition as an infection contributes to the reluctance to prescribe antibiotics. Since the child’s symptoms return upon re-exposure to S.pyogenes and antibiotics are required on a regular basis is another factor. Doctors prefer to treat symptoms with psychiatric medications like Prozac or Zoloft, drugs used for obsessive-compulsive disorders. Unfortunately despite increased doses of these drugs there is little change in the child’s behavior.

Discussion
Recently, a documentary on PANDAS was aired on the program W5 and featured Dr. Wendy Edwards, a physician in Chatham, Ontario who has been treating PANDAS. Several parents whose children exhibited abnormal behavior and who were subsequently diagnosed and treated for PANDAS discussed their experiences. One of the parents described the behavior of her seven-year old son who had been normal, well adjusted and athletic. When playing hockey one day, he suddenly began hopping like a rabbit. Within a week he developed other compulsive behaviours, including angry outbursts such as smashing his head against tables and walls. She read about PANDAS but found it difficult to find a physician who would test her son for strep. Eventually he was tested and found positive for strep. A dose of antibiotics prescribed for seven days subsided the symptoms almost immediately. Unfortunately, after the antibiotics ran out, the rages and other symptoms returned. Retreatment with antibiotics followed by immune system boosting and dietary changes resulted in elimination of the symptoms and a return to normal.

Since individuals can be non-symptomatic carriers of S.pyogenes, this makes a very difficult scenario if one of the children has PANDAS and the other is a carrier. Both children must be treated if the one with the condition is to improve. Suggestions provided for parents and caregivers are to check throat cultures on family members to make sure that none are strep carriers. In a longitudinal study of 100 school-aged children who were followed for a period four years, fifty-three percent were carriers of S.pyogenes
at some point in the study.

There is an ongoing search for a safe and effective vaccine to prevent S.pyogenes infections. Considering that S.pyogenes has been studied intensely, it is surprising that such a vaccine is still not available. If developed, this vaccine would have a significant and positive impact on the treatment of PANDAS.

Lastly, as a response to a couple of physicians, Oravital Inc. is currently working to develop several antibiotic rinses that may help to control S.pyogenes and decrease the amount of systemic antibiotic intake. Since children respond to different antibiotics, this complicates the formulations. However, there has been some success especially in the treatment of those children who are carriers thus decreasing exposure to S.pyogenes and reducing the number of episodes experienced by the PANDAS child.

References
1. Swedo S.E. et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. The American Journal of Psychiatry 1998: 155(2):264-271.
2. Cox C. et al. Antineuronal antibodies antibodies in a heterogeneous group of youth and young adults with tics and obsessive-compulsive disorder. Journal of Child and Adolescent Psychopharmacology 2015;25(1):76–85. [PubMed: 25658702]
3. Spellerberg B. Brandt C. Laboratory diagnosis of streptococcus pyogenes (Group A streptococci) in Streptococcus pygenes: Basic Biology to Clinical Manifestations. 2016; Eds. Ferretti JJ et al.
4. Orefici G et al. Pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections. Basic Biology to Clinical Manifestations. 2016: Eds. Ferretti JJ et al.
5. Mink J, Kurlan R. Acute postinfectious movement and psychiatric disorders in children and adolescents. Journal of Child Neurology. Feb 2011;26(2):214-217.
6. Takemura N et al. Single species biofilm-forming ability of root canal isolates on gutta-purcha points. European Journal of Oral Sciences. 2004;112(6): 523-529
7. http://www.ctvnews.ca/w5/w5-investigates-possible-links-between-common-infection-and-psychiatric-and-neurological-disorders-in-children-1.2233854
8. https://www.nimh.nih.gov/labs-at-nimh/


About the Author
Anne Bosy, M.Sc, M.Ed, RRDH is the Senior Vice President, Scientific Affairs and a founding partner at Oravital Inc. Her experience in education includes that of professor at George Brown College as well as clinical instructor at the University of Toronto. She is a published researcher and has presented on her work for many international organizations including the American Dental Association, the Yankee Dental Congress, IADR and International Society of Breath Odor Research.