PANDAS

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

PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. This term describes a hypothesis that a set of children develop rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorders 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 to the infection interfere with neuronal cells.[2]

PANDAS has been discussed and debated for over a decade.[3] The PANDAS hypothesis is based on observations in clinical case studies at the National Institute of Health and in subsequent clincial trials where children matching a particular profile appeared to have OCD exacerbations and tic disorders following infections.[4] A ten-fold increase in tic disorders during an outbreak of strep throat in Rhode Island prompted the researchers to focus on Group A Beta-hemolytic streptococcal infections (strep throat).[4] The attractiveness of the hypothesis is that if true, new avenues of treatment and prevention might be available;[4] however, although there is evidence linking infection and onset in some OCD/tic cases, proving a true causal relationship has remained elusive and controversial.[3][5] 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.[6] Consequently, the PANDAS model is a complex and rapidly-moving area of medical research. PANDAS is 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).

Pediatric acute-onset neuropsychiatric syndrome (PANS) is a newer hypothesis used to describe a subset of acute-onset OCD cases;[1] the newer hypothesis includes "all cases of abrupt onset OCD, not just those associated with streptococcal infections".[1]

Contents

[edit] Classification

OCD and chronic tic disorders intersect but neither is a subset of the other. Tic-related OCD is their intersection. PANDAS is a small subset of the union of OCD and tic disorders, and is in all three subregions of their union.
A possible relationship between PANDAS and other early-onset conditions.[7] Other sources note periods of remission[8] and extend PANDAS to other diagnoses such as ADHD.[4]

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.[4]

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.[4]

[edit] Identification

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

  1. Existence of obsessive-compulsive disorder or a tic disorder.[1][4]
  2. Abrupt symptom onset[1] with an episodic (relapsing/remitting) course of symptom severity.[4]
  3. Onset before puberty.[1][4]
  4. May include other neuropsychiatric symptoms (with similarly abrupt onset).[1][4]
  5. Associated with Group A Beta Hemolytic Stretococcal infection.[1][4]

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[9][10][11] whilst others have shown a profound one.[12][13]

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.[13] 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 hypothesized that PANDAS and Tourette's may be associated; this idea is controversial and a focus for current research.[6][14]

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.[unreliable medical source?][15]

[edit] Proposed mechanism

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.[9][16] 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.[17] 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".[18] 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][14][16] 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.[19]

[edit] Experimental treatments

The PANDAS diagnosis and the hypothesis that symptoms in this subgroup of patients are caused by infection are controversial.[9][20][21][22][23] Prophylactic antibiotic treatments for tics and OCD are experimental.[3] An initial study with 37 children found no effect of prophylactic antibiotic treatment on either infection rate or obsessive-compulsive or tic symptom severity,[24] a second study on 23 children later suggested that antibiotics were beneficial.[25] However, the methods in both studies have been criticized.[26] A single study of PANDAS patients showed efficacy of immunomodulatory therapy to symptoms.[14] 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][27]

[edit] Pediatric acute-onset neuropsychiatric syndrome

Given the controversy on the etiology of PANDAS (i.e., whether caused by strep throat) and apparent ambiguity in the definitions of the clinical presentation, an alternate research criteria for working purposes was defined. The new proposal, PANS, attempts to define for study a subset of children; it removes the requirement of temporal association with strep throat and adds the "abrupt, dramatic onset of obsessive-compulsive disorder (OCD) or severely restricted food intake" coincident with the presence of two or more neuropsychiatric symptoms.[28] The new hypothesis resulted from studies on the previous hypothesis of PANDAS, and would be distinguished from traditional childhood onset OCD by the severity, abruptness and dramatic onset of symptoms.[28]

Children and adolescents hypothesized to have PANS would be identified by the following three criteria:

  1. Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake
  2. Concurrent presence of additional neuropsychiatric symptoms, with similarly severe and acute onset, from at least two of the following seven categories
    1. 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
  3. Symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham's chorea, systemic lupus erythematosus, Tourette disorder or others.[28]
There are other conditions that may have similar presentation; diagnostic workup of individuals suspected of PANS should exclude Sydenham's chorea, lupus erythematosus, acute disseminated encephalomyelitis, and Tourette syndrome. Evidence of acute rheumatic fever would exclude a PANS classification.[28] Depending on neuropsychiatric symptoms, diagnostic tests may include magnetic resonance imaging (MRI), lumbar puncture, and electroencephalography (EEG).[28]

[edit] See also

[edit] References

  1. ^ a b c d e f g h i j k l NIH. PANDAS. Retrieved 24 February 2012.
  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 c 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." 
  4. ^ a b c d e f g h i j k Pichichero ME (2009). "The PANDAS syndrome". Adv Exp Med Biol. Advances in Experimental Medicine and Biology (Springer) 634: 205–16. doi:10.1007/978-0-387-79838-7_17. ISBN 9780387798370. PMID 19280860. http://books.google.com/?id=CxfTmEAqdAoC&lpg=PR2&pg=PA205#v=onepage&q=pichichero. 
  5. ^ Maia TV, Cooney RE, Peterson BS (2008). "The neural bases of obsessive-compulsive disorder in children and adults". Dev. Psychopathol. 20 (4): 1251–83. doi:10.1017/S0954579408000606. PMC 3079445. PMID 18838041. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3079445. 
  6. ^ a b Singer HS, Williams PN (2006). "Autoimmunity and pediatric movement disorders". Adv Neurol 99: 166–78. PMID 16536363. 
  7. ^ 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. PMC 3181902. PMID 19432385. http://www.dialogues-cns.org/brochures/40/pdf/40.pdf. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ Singer HS, Hong JJ, Yoon DY, Williams PN (December 2005). "Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls". Neurology 65 (11): 1701–7. doi:10.1212/01.wnl.0000183223.69946.f1. PMID 16207842. 
    Loiselle CR, Wendlandt JT, Rohde CA, Singer HS (February 2003). "Antistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome". Pediatr. Neurol. 28 (2): 119–25. doi:10.1016/S0887-8994(02)00507-6. PMID 12699862. 
  11. ^ Loiselle CR, Lee O, Moran TH, Singer HS (April 2004). "Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes". Mov. Disord. 19 (4): 390–6. doi:10.1002/mds.10522. PMID 15077236. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ [unreliable medical source?] 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.
  16. ^ 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. 
  17. ^ Rullan E, Sigal L (2001). "Rheumatic fever". Curr Rheumatol Rep 3 (5): 445–52. doi:10.1007/s11926-996-0016-4. PMID 11564377. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ Dale RC (November 2005). "Post-streptococcal autoimmune disorders of the central nervous system". Dev Med Child Neurol 47 (11): 785–91. doi:10.1017/S0012162205001647. PMID 16225745. 
  23. ^ Johns Hopkins Medicine. A Strep - Tourette Connection? Brain Waves Fall 2004 Volume 16, Number 4. Retrieved 25 November 2006
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ a b c d e Swedo SE, Leckman JF, Rose NR (Feb 2012). "From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric acute-onset neuropsychiatric syndrome)" (PDF). Pediatr Therapeut. 2 (2). doi:10.4172/2161-0665.1000113. http://pandasnetwork.org/wp-content/uploads/2012/02/2161-0665-2-113.pdf. 

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