PANDAS and PITAND: Reality or New Panacea – Elena Koles, MD

     In our medical practice, before applying any new testing modality or treatment, we use common sense and do not “buy” new ideas before studying their basis and logic. When something new comes onto the health ‘market’, either a medication or technique, it should be analyzed and evaluated. If you use this approach, the number of drug interactions and side effects can be minimized for most patients.

 

      At present, new ideas for the cause of the present autism epidemic have been developed.   

 

     Since  Leeuwenhoeck's development of the microscope and the Koch-Pasteur germ theory, people have looked for internal unseen agents that spread through the human population and cause disease.  Today  scientists know much more about the complexity of microbial symbiosis with humans and the antibody response known as the "humoral" arm of the immune system. But  many physicians are still looking for primitive explanations for all health problems as an “internal enemy” with most illnesses, ranging from stomach pain to cancer, atherosclerosis and even schizophrenia. This simple idea can be easily understood by the general population and provides an easy treatment solution – antibiotic therapy.

  In 1998, a new illness called PITAND (Pediatric Infection-triggered Autoimmune Neuropsychiatric Disorders) was suggested for neurological and behavioral disorders that have no clear explanation of their etiology and pathogenesis.  Many parents have been told that the autism seen in their child might be a manifestation of so called PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci). These parents are told that antibiotics are appropriate and should be used as a long term treatment.  

   Both PANDAS and PITAND are very rare conditions and have specific clinical and diagnostic criteria. associated with them. In late 1990s, PANDAS was diagnosed in children with obsessive compulsive disorder (OCD) and tics.

Children with PANDAS are clinically identified by dramatic, "overnight" onset of symptoms, including motor, facial or vocal  tics, obsessions and/or compulsions,  although this has not been consistent in all studies. Sudden onset should raise suspicion, but note that testing titers can help confirm  the diagnosis if the titers are high for 2 tests taken 4 to 8 weeks apart. 

PANDAS diagnostic criteria

(1) Current or past presence of symptoms (DSM IV) of Obsessive Compulsive Disorder, Tic Disorder (including Tourette's), Autism or Autistic Spectrum Disorder, and Anorexia Nervosa.

(2) Symptom onset between 18 months of age and puberty.

(3) Episodic course of symptom severity characterized by the abrupt onset of symptoms and/or frequent, dramatic symptom exacerbation.

(4) Symptom exacerbation associated with beta-hemolytic streptococcal infection.

(5) Presence of abnormal neuropsychiatric examination, including motor hyperactivity, adventitious movements, tics

(6) Measurable clinical improvement following "steroid burst".

Disqualifying factors (absolute): Presence of symptoms before 1 year of age.

Disqualifying factors (relative): Confirmed diagnosis of Autism and/or Autistic Spectrum Disorder in sibling(s).

PITAND diagnostic criteria

(1) At some time in his or her life, the patient must have met diagnostic criteria (DSM IV) for one of the following neuropsychiatric disorders: Obsessive Compulsive Disorder, Tic Disorder (including Tourette's), Autism, (or Autistic Spectrum Disorder).

(2) Pediatric onset: symptoms of the disorder first become evident between 18 months of age and the beginning of puberty.

(3) The onset of clinically significant symptoms must be sudden (with or without a sub clinical prodrome), and/or there must be a pattern of sudden, recurrent, clinically significant symptom exacerbation and remissions ("wax and waning pattern"). Onset of a specific episode typically can be assigned to a particular day or week, at which time symptoms seem to "explode" in severity, and they are frequently associated with an infectious episode.

(4) There must be evidence of an antecedent or concomitant infection. Such evidence might include a positive throat culture, positive streptococcal serologic findings (anti-streptolysin O or anti-streptococcal DNAse B), or a history of illness (pharyngitis, sinusitis, infection with Epstein-Barr virus, influenza, recurrent otitis media), and possibly recent exposure to childhood vaccination.

(5) Presence of auto antibodies (anticardiolipin, antineuronal, antibody/antigen complexes, etc.)

(6) During the exacerbation, the majority of patients will have an abnormal neuropsychiatric examination, frequently with hyperactivity and adventitious movements ("choreiform" movements).

(7) Measurable clinical improvement following "Steroid Burst".

   

       Many children have OCD and/or tics, and almost all school aged children get strep. throat at some point in their lives. In fact, the average grade-school student will have 2-3 strep. throat infections each year. PANDAS is to be considered when there is a very close relationship between the abrupt onset or worsening or OCD and/or tics, and a preceding strep. infection. If strep is found in conjunction with 2-3 episodes of OCD/tics, then it may be that the child has PANDAS.

   The clinical value of PANDAS rests on the promise of effective antibiotic treatment, and here the results of controlled trials have been, at best, inconclusive. Penicillin prophylaxis did not prevent exacerbations of tics and OCD, but it did not prevent streptococcal pharyngitis either (1).

   For now, the most compelling case for the value of antibiotic treatment comes from an uncontrolled study of 12 children who met PANDAS criteria and improved with antibiotics (2), and the testimonials of clinicians and investigators who have seen tics and OCD symptoms disappear in individual children treated with antibiotics. But clinical observations of this sort, convincing as they might appear, mislead at least as often as they point to useful information. Clinicians who have given antibiotics to children who meet PANDAS criteria have not been uniformly impressed (3).  No wonder, because, please note, PANDAS is considered to be an autoimmune disorder, not an infection. 

The PANDAS theory is only a hypothesis, and a highly controversial one, that has yet to be proven. It has engendered the use of controversial, dangerous and unproven treatment methodologies for children with tics and OCD (obsessive compulsive disorder), such as intravenous immunoglobulin (IVIG), plasma exchange, and the use of prophylactic antibiotics for the prevention of streptococcal infections. The Advisory Boards of the Tourette Syndrome Association do not currently recommend these procedures, and the NIH has also issued a warning about the use of these unproven methodologies.  The recent study does not support the hypothesis that PANDAS and Tourette syndrome are secondary to antineuronal antibodies (4) 

The controversial and still highly contentious concepts of PANDAS and PITAND  were introduced by A. J. Allen and S. Swedo  in the late 1990s. Swedo suggested that these children represent a unique subgroup defined by: (1) OCD and/or a tic disorder; (2) onset between age 2 and the beginning of puberty; (3) episodic course characterized by abrupt onset of symptoms or dramatic symptom exacerbations; (4) temporal association with infection; and (5) neurologic abnormalities (adventitious movements) during symptom exacerbations. They postulated that in susceptible children, an autoimmune response targeted to neurons is triggered.

Certain cases of anorexia nervosa, psychotic symptoms following some viral disease and a few cases of Autistic Spectrum Disorders have all been linked to an infectious agent, and their pathophysiology appears compatible with PANDAS and PITAND syndromes.

   The test used for PANDAS  confirmation is an elevated anti-streptococcal antibody titer (ASO or AntiDNAse-B). But this just means the child has had a strep. infection sometime within the past few months, and his body created antibodies to fight the strep. bacteria. Some children create lots of antibodies and have very high titers (up to 2,000), while others have more modest elevations. The height of the titer elevation doesn’t matter. Further, elevated titers are not a bad thing. They are measuring a normal, healthy response – the production of antibodies to fight off an infection. The antibodies stay in the body for some time after the infection is gone, but the amount of time that the antibodies persist varies greatly between different individuals. Some children have "positive" antibody titers for many months after a single infection. 

  Since each lab measures titers in different ways, it is important to know the range used by the laboratory where the test was done – just ask where they draw the line between negative or positive titers. The lab at NIH considers strep. titers between 0-400 to be normal. Other labs set the upper limit at 150 or 200.
It is important to note that some grade-school aged children have chronically "elevated" titers. These may actually be in the normal range for that child, as there is a lot of individual variability in titer values. Because of this variability, doctors will often draw a titer when the child is sick, or shortly thereafter, and then draw another titer several weeks later to see if the titer is "rising" – if so, this is strong evidence that the illness was due to strep.   

Please note, that other symptoms experienced by children with PANDAS should be considered only in conjunction  with their OCD and/or tics:

1. ADHD symptoms (hyperactivity, attention deficit, fidgety)
2. Separation anxiety (child is "clingy" and has difficulty separating from his/her caregivers)
3. Mood changes (irritability, sadness, emotional lability)
4. Sleep disturbance
5. Night- time bed wetting and/or day- time urinary frequency
6. Fine/gross motor changes (e.g. changes in handwriting)
7. Joint pains

   If diagnosis is confirmed then a battery of appropriate treatments should be applied. Some of them are not efficient.

   Thus, the NIH does not recommend preventive tonsillectomies for children with PANDAS, as there is no evidence that they are helpful.

  The fact that the "steroid burst" tend to control some symptoms of  PANDAS brings it into consideration as a possible treatment for PANDAS. Since short-term steroid treatment only controls the symptoms temporarily and its prolonged use may have rather serious side effects, corticosteroids have not been and should not be used in PANDAS. 

Antidepressants - SSRIs ( Lexapro, Prozac, Luvox, Paxil, Zoloft, etc.) have been frequently prescribed to children with PANDAS syndrome. Few parents understand that these medications are not recommended by manufacturer for children and particularly with PANDAS and are considered "off label" use. In addition, very serious side effects have recently prompted FDA to require so-called "black box" warning to be displayed on the packaging of these drugs. Considering that benefits of SSRIs have not been proven in patients with PANDAS, and that these medications can have serious side effects, their frequent and prolonged use in PANDAS should be seriously questioned. 

   Plasma exchange and IVIG have both been shown to be effective for the treatment of severe strep. triggered OCD and tics, and there were some benefits with these interventions. However, there were a number of side-effects associated with these treatments, including nausea, vomiting, headaches and dizziness. In addition, there is a risk of infection with any invasive procedures such as these. Thus, these treatments should be reserved for severely ill patients, and administered by a qualified team of health care professionals.

Antibiotics have been the mainstay of PANDAS and PITAND treatment. Unfortunately, patients with pronounced behavioral symptoms (severe separation anxiety, i.e.) are less likely to be relieved of all  of their symptoms following the use of antibiotics.

  Penicillin and other antibiotics kill streptococcus and other types of bacteria. The antibiotics may treat the sore throat or pharyngitis caused by the Strep by getting rid of the bacteria. However, in PANDAS,   antibodies produced by the body in response to the infection are the cause of the problem, not the bacteria themselves. Therefore one could not expect antibiotics such as penicillin to treat the symptoms of PANDAS and PITAND. At this time, there is not enough evidence to recommend the long-term use of antibiotics (5) Until their  usefulness is determined, antibiotics should NOT be used as long-term treatment for OCD and tics. It is even more questionable for Autism.

It is well known that even short-term usage of antibiotics can trigger many severe health problems including allergy, asthma, eczema, diabetes, etc. In our practice, we have one boy who developed autism after aggressive antibiotic treatment of his earache considered by his paediatrician as an infection.

Concerns have been raised that PANDAS may be overdiagnosed, as nearly a third of patients diagnosed with PANDAS by community physicians did not meet the criteria when examined by specialists, suggesting that a diagnosis of  PANDAS is sometimes conferred by community physicians without scientific evidence (6).

 

The result of an initial study with 37 children found no effect of antibiotic treatment on infection rate, obsessive-compulsive symptoms or  tic symptom severity (7) The methods in the latter study have been criticized (8).

 

  Again, real PANDAS is very rare.  In one pediatric practice, among 4000 children with streptococcal infection seen over a 3-year period, only 12 (0.3%) had PANDAS (9).

 

How can it be that most autistic children (1 in 150 American children) get this rare entity and are recommended long-term antibiotic treatment for Strep without ever having had an infection in their lives?

 

 From our point of view, the infectious agent may be a trigger for Autism in susceptible individuals. This agent (mycoplasma, mycobacteria tuberculosis, borrelia, etc) should be carefully identified, and only then should the appropriate treatment for it be applied. All children should be tested for parasitic infestation, including exotic protozoa and fungi. The treatment should be highly individualized and carried out with care.

 

REFERENCES:

  1-Garvey MA, Perlmutter SJ, Allen AJ, et al. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry. 1999;45:1564-1571.

2-Murphy ML, Pichichero ME. Prospective identification and treatment of children with PANDAS. Arch Pediatr Adolesc Med. 2002;156:356-361

3- W.A. Brown, MD, PANDAS: Nonexistent or Simply Rare?  

4-Singer HS et al, Neurology, 2005 Dec 13;65(11):1701-7.) 

5-http://intramural.nimh.nih.gov/pdn/web.htm.

6- Moyer, Pa. PANDAS May Be Overdiagnosed, Contributing to Overuse of Antibiotics. Medscape Medical News, AACAP 53rd Annual meeting: Abstract C21. Oct, 2006.)

7- Garvey M, et al, A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry 1999, 45 (12): 1564-71).

8-  Gilbert D, Gerber M (2005). "Regarding "antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders"". Biol Psychiatry 58 (11): 916).

9- Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and IVIG for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354:1153-1158).