PANDAS

Streptococcus pyogenes (stained red), a common group A streptococcal pathogen.

PANDAS is an abbreviation for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. This diagnosis is used to describe a set of children who have a rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorders such as Tourette syndrome (TS), following group A beta-hemolytic streptococcal (GABHS) infections such as "strep throat" and scarlet fever.^[1] The proposed link between infection and these disorders is an autoimmune reaction, where antibodies produced by the infection interfere with neuronal cells.^[2]

This diagnosis is controversial and its usefulness is disputed by some scientists who think this sub-set of patients do not differ significantly from the remainder of the patient population, and that infections do not increase the risk of OCD or tics.^[3] Consequently, the PANDAS model is a complex and rapidly-moving area of medical research, with a 2009 review stating that the link between streptococcal infections and tic disorders has remained unclear, despite a great deal of work in the area.^[4] PANDAS is currently not listed as a diagnosis by the International Statistical Classification of Diseases and Related Health Problems (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM).

Classification

A possible relationship between PANDAS and other early-onset conditions.^[5] Other sources note periods of remission^[6] and extend PANDAS to other diagnoses such as ADHD.^[7]

PANDAS is hypothesized to be caused by an autoimmune disorder that results in a variable combination of tics, obsessions, compulsions, and other symptoms that may be severe enough to qualify for diagnoses such as chronic tic disorder, OCD, and Tourette's. The cause is thought to be akin to that of Sydenham's chorea, which is known to result from childhood Group A streptococcal (GAS) infection leading to the autoimmune disorder acute rheumatic fever of which Sydenham's is one manifestation. Like Sydenham's, PANDAS is thought to involve autoimmunity to the brain's basal ganglia. Unlike Sydenham's, PANDAS is not associated with other manifestations of acute rheumatic fever, such as inflammation of the heart.^[7]

PANDAS has not been validated as a disease classification, for several reasons. Its proposed age of onset and clinical features reflect a particular group of patients chosen for research studies, with no systematic studies of the possible relationship of GAS to other neurologic symptoms. There is controversy over whether its symptom of choreiform movements is distinct from the similar movements of Sydenham's. It is not known whether the pattern of abrupt onset is specific to PANDAS. Finally, there is controversy over whether there is a temporal relationship between GAS infections and PANDAS symptoms.^[7]

Identification

According to the National Institute of Mental Health (NIMH), children with PANDAS are clinically identified by five criteria. They are:

"Presence of obsessive–compulsive disorder and/or a tic disorder
Pediatric onset of symptoms (age 3 years to puberty)
Episodic course of symptom severity
Association with group A Beta-hemolytic streptococcal infection (a positive throat culture for Strep or history of Scarlet Fever)

Association with neurological abnormalities (motoric hyperactivity, or adventitious movements, such as choreiform movements)."^[1]

The children usually have dramatic, "overnight" onset of symptoms, including motor or vocal tics, obsessions, and/or compulsions.^[1] Some studies have shown no acute exacerbations associated with streptococcal infections among clinically defined PANDAS subjects^[8][9] whilst others have shown a profound one.^[10][11]

In addition to an OCD or tic disorder diagnosis, children may have other symptoms associated with exacerbations such as emotional lability, enuresis, anxiety, and deterioration in handwriting.^[11] 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's syndrome, some researchers hypothesize that PANDAS and Tourette's may be associated; this idea is controversial and a focus for current research.^[3][12]

Concerns have been raised that PANDAS may be overdiagnosed, as nearly one-third of patients diagnosed with PANDAS by community physicians did not meet the criteria when examined by specialists, suggesting that the PANDAS diagnosis is conferred by community physicians without conclusive evidence.^[13]

Proposed mechanism

At present, whether the group of patients diagnosed with PANDAS have developed tics and OCD through a different mechanism (pathophysiology) than seen in other people diagnosed with Tourette syndrome is unclear.^[8][14] However, researchers at the NIMH are pursuing a hypothesis that the mechanism is similar to that of rheumatic fever, an autoimmune disorder triggered by streptococcal infections, where antibodies attack the brain and cause neuropsychiatric conditions.^[1]

In a typical bacterial infection, the body produces antibodies against the invading bacteria, and the antibodies help eliminate the bacteria from the body. However in rheumatic fever, the antibodies mistakenly recognize and "attack" the heart valves, joints, and/or certain parts of the brain.^[15] This phenomenon is called "molecular mimicry", which means 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 get heart disease (especially mitral valve regurgitation), arthritis, and/or abnormal movements known as Sydenham's chorea or "St. Vitus' Dance".^[16] In PANDAS, it is believed that tics and OCD are produced in a similar manner. One part of the brain that may be affected in PANDAS is the basal ganglia, which is believed to be responsible for movement and behavior. It is thought that similar to Sydenham's chorea, the antibodies cross-react with neuronal brain tissue in the basal ganglia to cause the tics and OCD that characterize PANDAS.^[1][12][14] However, current data neither disprove nor support this hypothesis, indeed one recent study found no association between treated streptococcal infections and the risk of PANDAS symptoms.^[17]

Experimental treatments

A single study of PANDAS patients showed efficacy of immunomodulatory therapy to symptoms.^[12] According to the NIMH and the Advisory Board of the Tourette Syndrome Association, experimental treatments based on the autoimmune theory such as intravenous immunoglobulin (IVIG) or plasma exchange should be "reserved for severely ill patients" and should not be undertaken outside of formal clinical trials.^[1][18]

The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are controversial.^{[8][19][20][21][22]} Prophylactic antibiotic treatments for tics and OCD are experimental.^[4] An initial study with 37 children found no effect of prophylactic antibiotic treatment on either infection rate or obsessive-compulsive or tic symptom severity,^[23] a second study on 23 children later suggested that antibiotics were beneficial.^[24] However, the methods in both studies have been criticized.^[25]

See also

• Neurobiological brain disorder

References

1. ^ ^{a b c d e f} NIH. PANDAS. Retrieved 7 September 2009.
2. ^ Kirvan CA, Swedo SE, Kurahara D, Cunningham MW (2006). "Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea". Autoimmunity 39 (1): 21–9. doi:10.1080/08916930500484757. PMID 16455579. 
3. ^ ^{a b} Singer HS, Williams PN (2006). "Autoimmunity and pediatric movement disorders". Adv Neurol 99: 166–78. PMID 16536363. 
4. ^ ^{a b} Shulman ST (February 2009). "Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update". Curr. Opin. Pediatr. 21 (1): 127–30. doi:10.1097/MOP.0b013e32831db2c4. PMID 19242249. "Despite continued research in the field, the relationship between GAS and specific neuropsychiatric disorders (PANDAS) remains elusive." 
5. ^ Leckman JF, Bloch MH, King RA (2009). "Symptom dimensions and subtypes of obsessive–compulsive disorder: a developmental perspective" (PDF). Dialogues Clin Neurosci 11 (1): 21–33. PMID 19432385. http://www.dialogues-cns.org/brochures/40/pdf/40.pdf. 
6. ^ Lombroso PJ, Scahill L (2008). "Tourette syndrome and obsessive–compulsive disorder". Brain Dev 30 (4): 231–7. doi:10.1016/j.braindev.2007.09.001. PMC 2291145. PMID 17937978. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2291145. 
7. ^ ^{a b c} Pichichero ME (2009). "The PANDAS syndrome". Adv Exp Med Biol (Springer) 634: 205–16. ISBN 9780387798370. PMID 19280860. http://books.google.com/?id=CxfTmEAqdAoC&lpg=PR2&pg=PA205#v=onepage&q=pichichero. 
8. ^ ^{a b c} Luo F, Leckman J, Katsovich L, et al (2004). "Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections". Pediatrics 113 (6): e578–85. doi:10.1542/peds.113.6.e578. PMID 15173540. http://pediatrics.aappublications.org/cgi/content/full/113/6/e578. 
9. ^ Singer HS, Hong JJ, Yoon DY, Williams PN. Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls. Neurology. 2005 Dec 13;65(11):1701–7. PMID 16207842
   * Loiselle CR, Wendlandt JT, Rohde CA, et al. Antistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome. Pediatr Neurol. 2003 Feb;28(2):119-25. PMID 12699862
   * Loiselle CR, Lee O, Moran TH, Singer HS. Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes. Mov Disord. 2004 Apr;19(4):390-6. PMID 15077236
10. ^ Murphy TK, Sajid M, Soto O, et al. (2004). "Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics". Biol Psychiatry 55 (1): 61–8. doi:10.1016/S0006-3223(03)00704-2. PMID 14706426. 
11. ^ ^{a b} Moretti G, Pasquini M, Mandarelli G, Tarsitani L, Biondi M (2008). "What every psychiatrist should know about PANDAS: a review". Clin Pract Epidemol Ment Health 4 (1): 13. doi:10.1186/1745-0179-4-13. PMC 2413218. PMID 18495013. http://cpementalhealth.com/content/4/1/13. 
12. ^ ^{a b c} Singer HS (March 2005). "Tourette's syndrome: from behaviour to biology". Lancet Neurol. 4 (3): 149–59. doi:10.1016/S1474-4422(05)01012-4. PMID 15721825. 
13. ^ Moyer, Paula. PANDAS May Be Overdiagnosed, Contributing to Overuse of Antibiotics. Medscape Medical News, from AACAP 53rd Annual Meeting: Abstract C21. Presented 26 October 2006. Retrieved 13 March 2007.
14. ^ ^{a b} Swedo S (2002). "Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)" (PDF). Mol Psychiatry. 7 Suppl 2 (s2): S24–5. doi:10.1038/sj.mp.4001170. PMID 12142939. http://www.nature.com/mp/journal/v7/n2s/pdf/4001170a.pdf. 
15. ^ Rullan E, Sigal L (2001). "Rheumatic fever". Curr Rheumatol Rep 3 (5): 445–52. doi:10.1007/s11926-996-0016-4. PMID 11564377. 
16. ^ Bonthius D, Karacay B (2003). "Sydenham's chorea: not gone and not forgotten". Semin Pediatr Neurol 10 (1): 11–9. doi:10.1016/S1071-9091(02)00004-9. PMID 12785743. 
17. ^ Perrin E, Murphy M, Casey J, et al (2004). "Does group A beta-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children?". Arch Pediatr Adolesc Med 158 (9): 848–56. doi:10.1001/archpedi.158.9.848. PMID 15351749. http://archpedi.ama-assn.org/cgi/content/full/158/9/848. 
18. ^ Scahill L, Erenberg G, Berlin CM, et al. (April 2006). "Contemporary assessment and pharmacotherapy of Tourette syndrome". NeuroRx 3 (2): 192–206. doi:10.1016/j.nurx.2006.01.009. PMID 16554257. http://download.journals.elsevierhealth.com/pdfs/journals/1545-5343/PIIS1545534306000289.pdf. 
19. ^ Singer HS, Loiselle C (July 2003). "PANDAS: a commentary". J Psychosom Res. 55 (1): 31–9. doi:10.1016/S0022-3999(02)00582-2. PMID 12842229. 
20. ^ Kurlan R, Kaplan EL (Apr 2004). "The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive–compulsive symptoms: hypothesis or entity? Practical considerations for the clinician" (PDF). Pediatrics 113 (4): 883–86. doi:10.1542/peds.113.4.883. PMID 15060240. http://pediatrics.aappublications.org/cgi/reprint/113/4/883.pdf. 
21. ^ Dale RC. Post-streptococcal autoimmune disorders of the central nervous system. Dev Med Child Neurol. 2005 Nov;47(11):785-91. Review. PMID 16225745
22. ^ Johns Hopkins Medicine. A Strep - Tourette Connection? Brain Waves Fall 2004 Volume 16, Number 4. Retrieved 25 November 2006
23. ^ Garvey M, Perlmutter S, Allen A, et a; (1999). "A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections". Biol Psychiatry 45 (12): 1564–71. doi:10.1016/S0006-3223(99)00020-7. PMID 10376116. 
24. ^ Snider L, Lougee L, Slattery M, Grant P, Swedo S (2005). "Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders". Biol Psychiatry 57 (7): 788–92. doi:10.1016/j.biopsych.2004.12.035. PMID 15820236. 
25. ^ Gilbert D, Gerber M (2005). "Regarding "antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders"". Biol Psychiatry 58 (11): 916. doi:10.1016/j.biopsych.2005.08.004. PMID 16242119. 

External links

• National Institute of Mental Health, PANDAS Information
• PANDAS Foundation website