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Arnold, Paul D., Richter, Margaret A.
Is obsessive-compulsive disorder an autoimmune disease?
CMAJ 2001 165: 1353-1358
"OBSESSIVE-COMPULSIVE DISORDER (OCD) IS A COMMON and debilitating neuropsychiatric disorder. Although it is widely believed to have a genetic basis, no specific genetic factors have been conclusively identified as yet, leading researchers to look for environmental risk factors that may interact with an underlying genetic susceptibility in affected individuals. Recently, there has been increasing interest in a possible link between streptococcal infections and the development of OCD and tic disorders in children. It has been suggested that OCD in some susceptible individuals may be caused by an autoimmune response to streptococcal infections, that is, a similar biological mechanism to that associated with Sydenham's chorea. The term "pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections" (PANDAS) has been used to describe a subset of children with abrupt onset or exacerbations of OCD or tics, or both, following streptococcal infections. Affected children have relatively early symptom onset, characteristic comorbid symptoms and subtle neurological dysfunction. Neuroimaging studies reveal increased basal ganglia volumes, and the proposed cause involves the cross-reaction of streptococcal antibodies with basal ganglia tissue. Vulnerability to developing PANDAS probably involves genetic factors, and elevated levels of D8/17 antibodies may represent a marker of susceptibility to PANDAS. Prophylactic antibiotic treatments have thus far not been shown to be helpful in preventing symptom exacerbations. Intravenous immunoglobulin therapy may be an effective treatment in selected individuals. Further understanding of the role of streptococcal infections in childhood-onset OCD will be important in determining alternative and effective strategies for treatment, early identification and prevention of this common and debilitating psychiatric disorder." [Full Text]

Hoekstra PJ, Kallenberg CG, Korf J, Minderaa RB.
Is Tourette's syndrome an autoimmune disease?
Mol Psychiatry. 2002;7(5):437-45.
"We provide a review of recent research findings which support the involvement of autoimmunity in childhood-onset tic disorders, in particular the presence of antineuronal autoantibodies, D8/17 B lymphocyte overexpression, a marker of chorea associated with streptococcal infection, and possible beneficial effects of immunomodulatory intervention. One of the most controversial areas in this field is the validity of the proposed PANDAS concept. Some researchers have delineated a putatively unique subgroup of patients, from the spectrum of illness encompassing Tourette's syndrome and obsessive-compulsive disorder (OCD), whose tics and obsessive-compulsive symptoms are shown to arise in response to beta-hemolytic streptococcal infections. They designated it by the term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Herein we additionally present pros and cons concerning the concept of PANDAS. Finally, recommendations for future research directions are given." [Abstract]

Snider LA, Swedo SE.
Post-streptococcal autoimmune disorders of the central nervous system.
Curr Opin Neurol. 2003 Jun;16(3):359-65.
"PURPOSE OF REVIEW: Autoimmune disease has long been intertwined with investigations of infectious causes. Antibodies that are formed against an infectious agent can, through the process of molecular mimicry, also recognize healthy cells. When this occurs, the immune system erroneously destroys the healthy cells causing autoimmune disease in addition to appropriately destroying the offending infectious agent and attenuating the infectious process. The first infectious agent shown to cause a post-infectious autoimmune disorder in the central nervous system was Streptococcus pyogenes in Sydenham's chorea. The present review summarizes the most recent published findings of central nervous system diseases that have evidence of a post-streptococcal autoimmune etiology. RECENT FINDINGS: Sydenham's chorea and other central nervous system illnesses that are hypothesized to have a post-streptococcal autoimmune etiology appear to arise from targeted dysfunction of the basal ganglia. PANDAS (pediatric autoimmune disorders associated with streptococcal infections) is the acronym applied to a subgroup of children with obsessive-compulsive disorder or tic disorders occurring in association with streptococcal infections. In addition, there are recent reports of dystonia, chorea encephalopathy, and dystonic choreoathetosis occurring as sequelae of streptococcal infection. Investigators have begun to isolate and describe antistreptococcal-antineuronal antibodies as well as possible genetic markers in patients who are susceptible to these illnesses. SUMMARY: Clinical and research findings in both immunology and neuropsychiatry have established the existence of post-streptococcal neuropsychiatric disorders and are beginning to shed light on possible pathobiologic processes." [Abstract]

Murphy TK, Sajid M, Soto O, Shapira N, Edge P, Yang M, Lewis MH, Goodman WK.
Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics.
Biol Psychiatry. 2004 Jan 1;55(1):61-8.
"BACKGROUND: A subgroup of children with obsessive-compulsive and tic disorders are proposed to have an infectious trigger. The purpose of this study was to investigate the relationship between group A streptococcal titers and symptom fluctuations in children with a clinical course resembling that described for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. METHODS: Twenty-five children with obsessive-compulsive disorder and/or tic disorder were evaluated for neuropsychiatric severity and group A streptococcal antibody titers (streptolysin O, deoxyribonuclease B, and carbohydrate A) at 6-week intervals for > or = six consecutive evaluations (total visits=277). RESULTS: Children with large symptom fluctuations (n=15) were compared with children without dramatic fluctuations (n=10). Co-movements of obsessive-compulsive/tic severity and group A streptococcal antibodies were assessed. In subjects with large symptom changes, positive correlations were found between streptococcal titers and obsessive-compulsive severity rating changes (p=.0130). These subjects were also more likely to have elevated group A streptococcal titers during the majority of observations (p=.001). Tic symptom exacerbations occurred more often in the fall/winter months than spring/summer months (p=.03). CONCLUSIONS: Patients with marked obsessive-compulsive/tic symptom changes may be characterized by streptococcal titer elevations and exhibit evidence of seasonal tic exacerbations." [Abstract]

Murphy TK, Benson N, Zaytoun A, Yang M, Braylan R, Ayoub E, Goodman WK.
Progress toward analysis of D8/17 binding to B cells in children with obsessive compulsive disorder and/or chronic tic disorder.
J Neuroimmunol. 2001 Nov 1;120(1-2):146-51.
"BACKGROUND: Previous research has suggested that a subgroup of children with obsessive compulsive disorder (OCD) have neuropsychiatric sequelae of streptococcal pharyngitis, similar to that seen in the neurological manifestation of rheumatic fever (RF). Monoclonal antibody D8/17 demonstrates increased binding to B cells in patients with RF and in patients with neuropsychiatric disorders using immunofluorescent microscopy. OBJECTIVE: The aim of this study was to determine if an earlier immunofluorescent microscopy study of monoclonal antibody D8/17 in childhood-onset OCD and/or chronic tic disorder (CTD) could be replicated using the more objective method of flow cytometric analysis. METHOD: D8/17 binding to B cells was determined in patients with OCD and or CTD (N=32), and healthy controls (N=12) by flow cytometric analysis. RESULTS: Subjects with OCD/CTD showed increased mean cell binding (26.0%) of monoclonal antibody compared with healthy controls (9.1%) (p<0.001). When using the threshold of greater than 19% binding (95% upper confidence interval) as a measure of positivity, 65.6% of patients compared with 8.3% of controls showed increased antibody binding to B cells (p=0.01). CONCLUSIONS: Although this study reports positive results, many methodological issues will need to be addressed before generalized use of assay for diagnostic purposes." [Abstract]

Murphy, TK, Goodman, WK, Fudge, MW, Williams, RC, Jr, Ayoub, EM, Dalal, M, Lewis, MH, Zabriskie, JB
B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette's syndrome?
Am J Psychiatry 1997 154: 402-407
"OBJECTIVE: It has been hypothesized that Sydenham's chorea, a major manifestation of rheumatic fever, may provide a medical model for obsessive-compulsive disorder and associated conditions, such as Tourette's syndrome. Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to this complication of group A streptococcal infection. The authors investigated whether D8/17 expression is greater than normal in some forms of obsessive-compulsive disorder and Tourette's syndrome. METHOD: By immunofluorescence techniques, 31 patients with childhood-onset obsessive-compulsive disorder and/or Tourette's syndrome or chronic tic disorder and 21 healthy comparison subjects were evaluated for percentage of D8/17-positive B cells. None had rheumatic fever or Sydenham's chorea. Levels of antineuronal antibodies and streptococcal antibodies were also determined. RESULTS: The average percentage of B cells expressing the D8/17 antigen was significantly higher in the patients (mean = 22%, SD = 5%) than in the comparison subjects (mean = 9%, SD = 2%). When classified categorically, all patients but only one comparison subject were D8/17 positive. No difference between groups in the presence of antineuronal antibodies or high streptococcal titers was found. CONCLUSIONS: Patients with childhood-onset obsessive-compulsive disorder or Tourette's syndrome had significantly greater B cell D8/17 expression than comparison subjects despite the absence of documented Sydenham's chorea or rheumatic fever. These findings suggest that D8/17 may serve as a marker for susceptibility among some forms of childhood-onset obsessive-compulsive disorder and Tourette's syndrome, as well as rheumatic fever or Sydenham's chorea." [Abstract]

Swedo, SE, Leonard, HL, Mittleman, BB, Allen, AJ, Rapoport, JL, Dow, SP, Kanter, ME, Chapman, F, Zabriskie, J
Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever
Am J Psychiatry 1997 154: 110-112
"OBJECTIVE: The authors' goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). METHOD: Blood samples obtained from 27 children with PANDAS, nine children with Sydenham's chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. RESULTS: The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham's chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. CONCLUSIONS: These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette's syndrome, rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity." [Abstract]

Swedo, Susan E., Leonard, Henrietta L., Garvey, Marjorie, Mittleman, Barbara, Allen, Albert J., Perlmutter, Susan, Dow, Sara, Zamkoff, Jason, Dubbert, Billinda K., Lougee, Lorraine
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases
Am J Psychiatry 1998 155: 264-271
"OBJECTIVE: The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). METHOD: The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. RESULTS: The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. CONCLUSIONS: The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies." [Abstract]

Murphy ML, Pichichero ME.
Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS).
Arch Pediatr Adolesc Med. 2002 Apr;156(4):356-61.
"BACKGROUND: The current diagnostic criteria for pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS) are pediatric onset, neuropsychiatric disorder (obsessive-compulsive disorder [OCD]) and/or tic disorder; abrupt onset and/or episodic course of symptoms; association with group A beta-hemolytic streptococcal (GABHS) infection; and association with neurological abnormalities (motoric hyperactivity or adventitious movements, including choreiform movements or tics). OBJECTIVE: To assess new-onset PANDAS cases in relation to acute GABHS tonsillopharyngitis. DESIGN: Prospective PANDAS case identification and follow-up. RESULTS: Over a 3-year period (1998-2000), we identified 12 school-aged children with new-onset PANDAS. Each patient had the abrupt appearance of severe OCD behaviors, accompanied by mild symptoms and signs of acute GABHS tonsillopharyngitis. Throat swabs tested positive for GABHS by rapid antigen detection and/or were culture positive. The GABHS serologic tests, when performed (n = 3), showed very high antideoxyribonuclease antibody titers. Mean age at presentation was 7 years (age range, 5-11 years). In children treated with antibiotics effective in eradicating GABHS infection at the sentinel episode, OCD symptoms promptly disappeared. Follow-up throat cultures negative for GABHS were obtained prospectively after the first PANDAS episode. Recurrence of OCD symptoms was seen in 6 patients; each recurrence was associated with evidence of acute GABHS infection and responded to antibiotic therapy, supporting the premise that these patients were not GABHS carriers. The OCD behaviors exhibited included hand washing and preoccupation with germs, but daytime urinary urgency and frequency without dysuria, fever, or incontinence were the most notable symptoms in our series (58% of patients). Symptoms disappeared at night, and urinalysis and urine cultures were negative. CONCLUSION: To our knowledge, this is the first prospective study to confirm that PANDAS is associated with acute GABHS tonsillopharyngitis and responds to appropriate antibiotic therapy at the sentinel episode." [Abstract]

Trifiletti RR, Packard AM.
Immune mechanisms in pediatric neuropsychiatric disorders. Tourette's syndrome, OCD, and PANDAS.
Child Adolesc Psychiatr Clin N Am. 1999 Oct;8(4):767-75.
"The authors have reviewed recent data supporting the presence of immune abnormalities in several neuropsychiatric disorders (TS, OCD, and PANDAS). Several groups agree that there is a subset of patients with TS and OCD (perhaps about 10%) for whom there is a clear streptococcal trigger, validating the PANDAS concept. Also, evidence of biochemical markers for TS and OCD have begun to emerge, namely D8/17 and antibrain antibodies, which suggest the presence of similar immune abnormalities, even in idiopathic cases. If this line of research reveals definable, and relatively specific, immune abnormalities in at least some cases of TS and OCD, it will likely have important implications for the diagnosis and treatment of these common neuropsychiatric disorders, particularly in children who respond poorly to conventional therapies. Child psychiatrists are encouraged to stay tuned." [Abstract]

Kochman F, Hantouche EG, Karila L, Bayart D, Bailly D.
[Obsessive-compulsive disorder in children induced by streptococcal infection]
Presse Med. 2001 Nov 24;30(35):1747-51.
"FROM OBSESSIVE-COMPULSIVE DISORDER TO PANDAS: Obsessive-compulsive disorder (OCD) represents a potentially severe and handicapping disorder that affects several hundreds of thousands of children in France. OCD has, for many years, been considered as a neurosis resulting from mental conflicts. It is currently seen as a neurobiological disorder, the etiological substratum of which is more organic than mental. Recently a sub-type of OCD was isolated in children following infection by Group A b-hemolytic streptococci. This sub-type has been described as Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS). A NEW PHYSIOPATHOLOGICAL APPROACH: The putative dysimmune relationship between bacterial infection and neurotic disorder has led to the development of an original etiopathogenic model that may lead to new therapeutic strategies. The clinical case report of an adolescent presenting with trichotillomania associated with recurrent pharyngitis is a good illustration of this. PUBLISHED DATA: Data published in medical literature over the last 10 years indicates a 10% prevalence in the young suffering from OCD, i.e. 0.1 to 0.3% of the young population." [Abstract]

Leonard HL, Swedo SE.
Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).
Int J Neuropsychopharmacol. 2001 Jun;4(2):191-8.
"The evidence to date, both published and unpublished, which addresses the validity of the proposed unique subgroup of children with early and abrupt onset of obsessive--compulsive disorder (OCD) and/or tic disorders subsequent to streptococcal infections was reviewed. The aetiology of OCD and tic disorders is unknown, although it appears that both disorders may arise from a variety of genetic and environmental factors. Post-streptococcal autoimmunity has been postulated as one possible mechanism for some. The acronym PANDAS (for paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been given to a subgroup of paediatric patients who meet five inclusionary criteria: presence of OCD and/or tic disorder, pre-pubertal symptom onset, sudden onset or episodic course of symptoms, temporal association between streptococcal infections and neuropsychiatric symptom exacerbations, and associated neurological abnormalities. The proposed model of pathophysiology provides for several unique treatment strategies, including the use of antibiotic prophylaxis to prevent streptococcal-triggered exacerbations, and the use of immunomodulatory interventions (such as intravenous immunoglobulin or therapeutic plasma exchange) in the treatment severe neuropsychiatric symptoms. For the latter study group, long-term (2--5 yr) follow-up revealed continued symptom improvement for the majority of patients, particularly when antibiotic prophylaxis had been effective in preventing recurrent streptococcal infections. In addition, the episodic nature of the subgroup's illness provides for opportunities to study brain structure and function during health and disease, as well as allowing for investigations of the aetiologic role of anti-neuronal antibodies and neuroimmune dysfunction in both OCD and tic disorders. Although much research remains to be done, an increasing body of evidence provides support for the postulate that OCD and tic disorders may arise from post-streptococcal autoimmunity. The unique clinical characteristics of the PANDAS subgroup, the presence of volumetric changes in the basal ganglia, and the dramatic response to immunomodulatory treatments, suggest that symptoms arise from a combination of local, regional and systemic dysfunction. Ongoing research is directed at understanding the nature of the abnormal immune response, as well as identifying at-risk children, in order to provide for novel strategies of prevention and treatment." [Abstract]

Nicolson R, Swedo SE, Lenane M, Bedwell J, Wudarsky M, Gochman P, Hamburger SD, Rapoport JL.
An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations.
J Am Acad Child Adolesc Psychiatry. 2000 Oct;39(10):1313-5.
"Patients with childhood-onset obsessive-compulsive disorder (OCD) with symptom exacerbations following streptococcal infections benefit from treatment with plasma exchange. In this study, 5 patients with treatment-refractory OCD without a history of streptococcus-related exacerbations underwent an open 2-week course of therapeutic plasma exchange. Behavioral ratings, completed at baseline and 4 weeks after the initial treatment, included the Clinical Global Impressions Scale and the Yale-Brown Obsessive Compulsive Scale. All 5 patients completed the trial with few side effects, but none showed significant improvement. Plasma exchange does not benefit children and adolescents with OCD who do not have streptococcus-related exacerbations." [Abstract]

Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE.
Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood.
Lancet. 1999 Oct 2;354(9185):1153-8.
"BACKGROUND: In children, exacerbations of tics and obsessive symptoms may occur after infection with group A beta-haemolytic streptococci. If post-streptococcal autoimmunity is the cause of the exacerbations, then children might respond to immunomodulatory treatments such as plasma exchange or intravenous immunoglobulin (IVIG). We studied whether plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms. METHODS: Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function. FINDINGS: 30 children entered the study and 29 completed the trial. Ten received plasma exchange, nine IVIG, and ten placebo. At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45%] and 13 [58%], respectively), anxiety (2.1 [31%] and 3.0 [47%] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33%] and 2.8 [35%] improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49%). Treatment gains were maintained at 1 year, with 14 (82%) of 17 children "much" or "very much" improved over baseline (seven of eight for plasma exchange, seven of nine for IVIG). INTERPRETATION: Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies." [Abstract]

Allen AJ, Leonard HL, Swedo SE.
Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome.
J Am Acad Child Adolesc Psychiatry. 1995 Mar;34(3):307-11.
"A review of clinical observations and literature reports leads to the hypothesis that, via a process analogous to Sydenham's chorea, infections with group A beta-hemolytic streptococci, among others, may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourette's syndrome). If this hypothesis is correct, then immunological treatments should lead to decreased symptoms in some cases. Four cases with abrupt, severe onset or worsening of OCD or tics are presented from an open treatment study. All were boys aged 10 to 14 years. One had OCD, one had Tourette's syndrome, and two had both OCD and Tourette's syndrome. Clinically and on standardized rating scales, their symptoms were in the moderate to very severe range. Two had evidence of recent group A beta-hemolytic streptococci infections, and the others had histories of recent viral illnesses. Two were treated with plasmapheresis, one with intravenous immunoglobulin, and one with immunosuppressive doses of prednisone. All had a clinically significant response immediately after treatment. Diagnostic criteria are provided that describe these cases of pediatric, infection-triggered, autoimmune neuropsychiatric disorders (PITANDs). Suggestions are made regarding the evaluation and management of patients who may have this condition." [Abstract]

Muller N, Riedel M, Erfurth A, Moller HJ.
[Immunoglobulin therapy in Gilles de la Tourette syndrome]
Nervenarzt. 1997 Nov;68(11):914-6.
"It has known for a long time that Sydenham's chorea and tics, as seen in Gilles de la Tourette's syndrome (GTS), are phenomenologically very similar. Tics may occur as symptoms of acute Sydenham's chorea or persist over years as residual symptoms. Investigating of children suffering from GTS, including obsessive-compulsive symptoms, have provided signs of a poststreptococcal autoimmune process but also shown that treatment based on immunological interventions has been effective. We treated a 14-year-old boy showing all diagnostic criteria of GTS, familial susceptibility, and an increase in the antibody titer of streptococcal antigens with 75 immunoglobulins i.v. over 5 days. Response to this therapy was good regarding motor tics, vocal tics, and behavioral symptoms such as disturbed impulse control which still persisted after 9 months. These findings and the successful therapy underline reports of the literature and point to a pathogenetic mechanism of an immunologically triggered disturbance of the striatal dopaminergic system, at least in a subgroup of GTS." [Abstract]

Garvey MA, Perlmutter SJ, Allen AJ, Hamburger S, Lougee L, Leonard HL, Witowski ME, Dubbert B, Swedo SE.
A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections.
Biol Psychiatry. 1999 Jun 15;45(12):1564-71.
"BACKGROUND: Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenham's chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations. METHODS: Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained. RESULTS: There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases. CONCLUSIONS: Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size." [Abstract]

Dinn WM, Harris CL, McGonigal KM, Raynard RC.
Obsessive-compulsive disorder and immunocompetence.
Int J Psychiatry Med. 2001;31(3):311-20.
"OBJECTIVE: A postinfectious, autoimmune response may be associated with the development of pediatric obsessive-compulsive disorder (OCD). According to this model, antistreptococcal antibodies cross-react with basal ganglia neurons following streptococcus infection. This autoimmune reaction disrupts a basal ganglia-thalamocortical circuit and generates obsessive-compulsive symptoms. One implication of this model is that prolonged immunologic stress may be a risk factor for OCD. That is, immunologic stress may compromise the blood-brain barrier and permit the influx of antistriatal antibodies into the central nervous system. This article explores one part of this putative relationship by investigating whether adult OCD patients, compared to members of other psychiatric groups, demonstrate a higher incidence of recurrent infections and other conditions suggestive of compromised immune function. METHOD: To test this hypothesis, we conducted a medical records review of 100 consecutive patients evaluated at a private psychiatric clinic specializing in the treatment of anxiety disorders. Sixty-five patients met diagnostic criteria for an Axis-I syndrome. Primary diagnoses included OCD, posttraumatic stress disorder, social anxiety disorder, generalized anxiety disorder, panic disorder with agoraphobia, and dysthymic disorder. Each medical record was reviewed for the presence of target syndromes or presenting symptoms suggestive of compromised immune function. RESULTS: Chart review revealed an increased rate of immune-related symptoms and syndromes among OCD patients in comparison to other anxiety and mood disorder groups. Groups did not differ significantly in the incidence of non-immune symptoms and syndromes. CONCLUSION: Adult OCD patients appear to have an increased rate of immune-related diseases above and beyond that seen in other psychiatric disorders." [Abstract]

Black JL, Lamke GT, Walikonis JE.
Serologic survey of adult patients with obsessive-compulsive disorder for neuron-specific and other autoantibodies.
Psychiatry Res. 1998 Dec 14;81(3):371-80.
"A subset of patients with pediatric onset obsessive-compulsive disorder (OCD) and tic syndromes (e.g. Tourette's syndrome) have symptom onset or exacerbation associated with infection. Some of these patients have been demonstrated to have antineuronal antibodies reactive with nuclei of the basal ganglion. It has been hypothesized that these patients have an immune process initiated by infection that affects the basal ganglion and causes obsessive-compulsive symptoms. The term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) has been coined to describe those patients with evidence of recent group A beta hemolytic streptococcal infection. We tested the serum from 13 adult patients with obsessive-compulsive disorder for panels of autoantibodies that serve as markers of autoimmunity in the practice of neurology and internal medicine. We investigated the frequency of neuron-specific autoantibodies [N-type and P/Q-type voltage-gated calcium channel antibodies, type 1 Purkinje cell antibodies, types 1 and 2 antineuronal nuclear antibodies, amphiphysin antibodies, and glutamic acid decarboxylase (65 kDa) antibodies], other organ-specific autoantibodies (muscle acetylcholine receptor-binding antibodies, striated muscle antibodies, thyroid microsomal and thyroglobulin antibodies), and non-organ-specific autoantibodies (antinuclear antibodies, antimitochondrial antibodies, and smooth muscle antibodies) to determine if any of these antibodies might serve as a serological marker for adult OCD or yield evidence of an autoimmune diathesis. Although most of our subjects had onset of OCD before 19 years of age (N=8) or before puberty (N=4), the study revealed no humoral evidence of autoimmunity involving the neuron-, organ-, and non-organ-specific antibodies that we assayed." [Abstract]

Dale, R.C.
Autoimmunity and the basal ganglia: new insights into old diseases
QJM 2003 96: 183-191
"Sydenham's chorea (SC) occurs weeks or months after Group A streptococcal infection, and is characterized by involuntary, purposeless movements of the limbs, in addition to behavioural alteration. There is a body of evidence which suggests that SC is an immune-mediated brain disorder with regional localization to the basal ganglia. Recent reports have suggested that the spectrum of post-streptococcal CNS disease is broader than chorea alone, and includes other hyperkinetic movement disorders (tics, dystonia and myoclonus). In addition, there are high rates of behavioural sequelae, particularly emotional disorders such as obsessive-compulsive disorder, anxiety and depression. These findings have lead to the hypothesis that similar immune-mediated basal ganglia processes may be operating in common neuropsychiatric disease such as tic disorders, Tourette syndrome and obsessive-compulsive disorder. This review analyses the historical aspects of post-streptococcal CNS disease, and the recent immunological studies which have addressed the hypothesis that common neuropsychiatric disorders may be secondary to basal ganglia autoimmunity." [Abstract]

Murphy TK, Goodman WK, Ayoub EM, Voeller KK.
On defining Sydenham's chorea: where do we draw the line?
Biol Psychiatry. 2000 May 15;47(10):851-7.
"Sydenham's chorea (SC) is a major manifestation of rheumatic fever characterized by an array of neuropsychiatric symptoms that vary in severity, timing, and character. Some of the same symptoms are seen in Tourette's syndrome and childhood-onset obsessive-compulsive disorder. Genetic vulnerability appears to play a role in all three conditions. The term PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) has been introduced to describe a putative subset of obsessive-compulsive disorder and Tourette's syndrome that bears some resemblance to Sydenham's chorea. This article discusses whether PANDAS should be subsumed under Sydenham's chorea, thus expanding the diagnostic boundaries of Sydenham's chorea to include primarily neuropsychiatric presentations now classified as cases of obsessive-compulsive disorder or Tourette's syndrome. We conclude that PANDAS is a useful construct, but that it would be premature to view it as a subset of Sydenham's chorea-whether defined narrowly or broadly." [Abstract]

Asbahr FR, Ramos RT, Negrao AB, Gentil V.
Case series: increased vulnerability to obsessive-compulsive symptoms with repeated episodes of Sydenham chorea.
J Am Acad Child Adolesc Psychiatry. 1999 Dec;38(12):1522-5.
"The association between obsessive-compulsive symptoms (OCS) and Sydenham chorea (SC) supports the hypothesis of a common neuroimmunological dysfunction in basal ganglia associated with group A beta-hemolytic streptococcal infection underlying both conditions. Four children with 2 distinct SC episodes were evaluated to assess the course of OCS. All patients developed OCS during their second episodes (3 met criteria for obsessive-compulsive disorder [OCD]), but not in their first episodes (2 developed OCS and met criteria for OCD). These data suggest that the recurrence of SC episodes may result in a cumulative effect, thus increasing the risk of appearance and intensification of OCS." [Abstract]

Gimzal A, Topcuoglu V, Yazgan MY.
[Acute Rheumatic Fever, Sydenham's Chorea and Psychopathology]
Turk Psikiyatri Derg. 2002 Summer;13(2):137-41.
"Acute rheumatic fever (ARF) is an autoimmune disorder that is triggered by group A beta-hemolytic streptococcal infections. ARF consists of several combinations of carditis, polyarthritis and Sydenham's chorea, and rarely seen erythema marginatum and subcutaneous nodules. Sydenham's chorea is seen in about 20% of patients with ARF. As a late symptom of ARF, Sydenham's chorea usually occurs 3 months or longer after the streptococcal infection. Sydenham's chorea is a neuropsychiatric disorder that may present with emotional lability, anxiety, obsessive compulsive symptoms, attention deficit and hyperactivity symptoms or tics. Obsessive-compulsive symptoms occur in 70% of patients with Sydenham's chorea. The role of the autoimmune mechanisms and the dysfunction of the basal ganglia have been demonstrated in Sydenham's chroea. Antibodies against group A beta-hemolytic streptococs cross-react with basal ganglia. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) shares the same mechanism with Sydenham's chorea, but PANDAS has not been shown to require penicillin prophylaxis. Thus it is important to distinguish between them. Sydenham's chorea is associated with adulthood OCD, Tourette syndrome and schizophrenia. These features make Sydenham's chorea an explanatory model for obsessive-compulsive disorder (OCD) and related disorders. This poststreptococcal disorder provides a treatment opportunity with new therapies like antibiotic therapy, plasma exchange and intravenous immunoglobulin therapy for psychiatric disorders. In this paper we summarize the phenomenological and treatment studies of OCD, attention deficit and hyperactivity disorder (ADHD), and tic disorders in subjects with ARF, with or without Sydenham's chorea." [Abstract]

Kiessling LS, Marcotte AC, Culpepper L.
Antineuronal antibodies in movement disorders.
Pediatrics. 1993 Jul;92(1):39-43.
"OBJECTIVE. To determine whether children with recent onset of movement disorders (Tourette syndrome, motor and/or vocal tics, chorea, choreiform movements) show evidence of serological antibodies directed against the human central nervous system as previously documented in research on Sydenham's chorea. METHODS. Serum antibodies against previously frozen human caudate nucleus sections were analyzed using a blinded design and immunofluorescent staining methods. The sera of one group of 50 children referred for evaluation of attention deficit hyperactivity disorder, behavior disorders, and learning disabilities (24 with an associated movement disorder) seen between June 1989 and June 1990 were analyzed. The study was replicated in 33 children (21 with an associated movement disorder) seen between June 1990 and November 1990. RESULTS. In the original sample of 50 children, those with movement disorders were significantly more likely to have evidence of antineuronal antibodies than were those without movement disorders (odds ratio [OR] 4.80, 95% confidence interval [CI] 2.58 to 8.93). Results of the replication were similar (OR 6.00, 95% CI 2.56 to 14.03). For the total group, the OR was 5.50, (95% CI 3.54 to 8.99), which is highly significant. The percentage of children with a movement disorder whose sera were strongly positive for antineuronal antibodies (44%) was very similar to that previously found in children with Sydenham's chorea (46%). Children with movement disorders were also more likely than children without movement disorders to have at least one antistreptococcal titer elevated. CONCLUSIONS. The data strongly suggest an association between antecedent group A beta-hemolytic streptococcal infection as inferred from elevated antistreptococcal titers and the presence of serum antineuronal antibodies, which may, in turn, be linked to childhood movement disorders." [Abstract]

Snider LA, Swedo SE.
Childhood-onset obsessive-compulsive disorder and tic disorders: case report and literature review.
J Child Adolesc Psychopharmacol. 2003;13 Suppl 1:S81-8.
"A subgroup of childhood-onset obsessive-compulsive disorder (OCD) and tic disorders has been found to have a postinfectious autoimmune-mediated etiology. Clinical observations and systematic investigations have shown that a subgroup of children with OCD and/or tic disorders have the onset and subsequent exacerbations of their symptoms following infections with group A beta-hemolytic streptococci (GABHS). This subgroup has been designated by the acronym PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Five clinical characteristics define the PANDAS subgroup: presence of OCD and/or tic disorder, prepubertal symptom onset, sudden onset or abrupt exacerbations, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and the temporal association between symptom exacerbations and GABHS infections. The proposed poststreptococcal inflammatory etiology provides a unique opportunity for treatment and prevention, including immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin. A placebo-controlled trial revealed that both intravenous immunoglobulin and plasma exchange were effective in reducing neuropsychiatric symptom severity (40 and 55% reductions, respectively) for a group of severely ill children in the PANDAS subgroup. Further research is required to determine why the treatments are helpful and to ascertain whether or not antibiotic prophylaxis can help prevent poststreptococcal symptom exacerbations." [Abstract]

Giulino L, Gammon P, Sullivan K, Franklin M, Foa E, Maid R, March JS.
Is parental report of upper respiratory infection at the onset of obsessive-compulsive disorder suggestive of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection?
J Child Adolesc Psychopharmacol. 2002 Summer;12(2):157-64.
"The diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) requires a prospectively determined association between group A beta-hemolytic streptococcal (GABHS) infection and obsessive-compulsive disorder (OCD) or tic disorder. Screening for GABHS infection imposes a significant burden on both patient and clinician. To heighten the index of suspicion for PANDAS, it would be useful to know if parent-reported upper respiratory infection (URI) is associated with PANDAS symptoms or associated characteristics. Eighty-three consecutive, clinically referred patients aged 6 to 17 years with a primary diagnosis of OCD and their primary caregivers were asked about URI signs and symptoms at the time of OCD onset, PANDAS symptoms, OCD and tic symptoms, comorbidity, and putative PANDAS risk factors. Specific inquiry regarding URI symptoms proved more informative than general inquiry. In the URI present versus URI absent group, more patients experienced a sudden rather than insidious onset of symptoms. Additionally, more patients with a URI plus sudden onset exhibited a comorbid tic disorder. Until validated biomarkers permit retrospective diagnosis, a history that OCD began around the time of a URI should clue the clinician to look prospectively for PANDAS. Additional research is required to define the boundaries of PANDAS and to develop psychometrically reliable and valid diagnostic strategies." [Abstract]

Orvidas LJ, Slattery MJ.
Pediatric autoimmune neuropsychiatric disorders and streptococcal infections: role of otolaryngologist.
Laryngoscope. 2001 Sep;111(9):1515-9.
"OBJECTIVE: To increase awareness and understanding of the putative role of streptococcal infection in the development of neuropsychiatric disorders in children and to discuss therapeutic options in this group of patients. METHODS: Case illustration and literature review. RESULTS: Two siblings, one with obsessive-compulsive disorder (OCD) and one with a tic disorder, had tonsillectomy for recurrent streptococcal pharyngitis. At the latest follow-up visit (11 mo postoperatively), both patients exhibited significant improvement in their psychiatric illnesses. We discuss these cases as well as the diagnosis, pathophysiology, and treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). CONCLUSION: PANDAS is an active area of research investigating the relationship between streptococcal infections and the development of obsessive-compulsive disorder or tic disorders (or both) in children. The etiopathogenesis of PANDAS is thought to reflect autoimmune mechanisms and involvement of the basal ganglia of susceptible hosts. Because otolaryngologists evaluate a large portion of pediatric patients with recurrent streptococcal pharyngitis, it is important to be aware of this association and to manage these patients appropriately." [Abstract]

Heubi C, Shott SR.
PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections--an uncommon, but important indication for tonsillectomy.
Int J Pediatr Otorhinolaryngol. 2003 Aug;67(8):837-40.
"Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, also know as "PANDAS," is well described in the neurologic and psychiatric literature. PANDAS is associated with obsessive compulsive disorders (OCD) and tic disorders. The streptococcal infections may trigger an autoimmune reaction that exacerbates these conditions. Recurrent streptococcal tonsillitis is one of the recurrent infections associated with PANDAS. This paper reviews the case reports of two brothers, one with OCD and the other with a tic disorder, both of whom improved significantly after undergoing adenotonsillectomy for treatment of their recurrent tonsillitis. A review of the pathophysiology and current understanding of PANDAS is presented." [Abstract]

Lougee L, Perlmutter SJ, Nicolson R, Garvey MA, Swedo SE.
Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).
J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1120-6.
"OBJECTIVE: To determine the rates of psychiatric disorders in the first-degree relatives of children with infection-triggered obsessive-compulsive disorder (OCD) and/or tics (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; PANDAS). METHOD: The probands of this study were 54 children with PANDAS (n = 24 with a primary diagnosis of OCD; n = 30 with a primary diagnosis of a tic disorder). One hundred fifty-seven first-degree relatives (100 parents [93%] and 57 siblings [100%]) were evaluated for the presence of a tic disorder. One hundred thirty-nine first-degree relatives (100 parents [93%] and 39 of 41 siblings over the age of 6 [95%]) were evaluated with clinical and structured psychiatric interviews to determine the presence of subclinical OCD, OCD, and other DSM-IV Axis I disorders. RESULTS: Twenty-one probands (39%) had at least one first-degree relative with a history of a motor or vocal tic; 6 mothers (11%), 9 fathers (19%), and 8 siblings (16%) received this diagnosis. Fourteen probands (26%) had at least one first-degree relative with OCD; 10 mothers (19%), 5 fathers (11%), and 2 siblings (5%), received this diagnosis. An additional 8 parents (8%) and 3 siblings (8%) met criteria for subclinical OCD. Eleven parents (11%) had obsessive-compulsive personality disorder. CONCLUSIONS: The rates of tic disorders and OCD in first-degree relatives of pediatric probands with PANDAS are higher than those reported in the general population and are similar to those reported previously for tic disorders and OCD. Further study is warranted to determine the nature of the relationship between genetic and environmental factors in PANDAS." [Abstract]

Giedd, Jay N., Rapoport, Judith L., Garvey, Marjorie A., Perlmutter, Susan, Swedo, Susan E.
MRI Assessment of Children With Obsessive-Compulsive Disorder or Tics Associated With Streptococcal Infection
Am J Psychiatry 2000 157: 281-283
"OBJECTIVE: The authors assessed selective basal ganglia involvement in a subgroup of children with obsessive-compulsive disorder (OCD) and/or tics believed to be associated with streptococcal infection. METHOD: Using computer-assisted morphometric techniques, they analyzed the cerebral magnetic resonance images of 34 children with presumed streptococcus-associated OCD and/or tics and 82 healthy comparison children who were matched for age and sex. RESULTS: The average sizes of the caudate, putamen, and globus pallidus, but not of the thalamus or total cerebrum, were significantly greater in the group of children with streptococcus-associated OCD and/or tics than in the healthy children. The differences were similar to those found previously for subjects with Sydenham’s chorea compared with normal subjects. CONCLUSIONS: These results support the hypothesis that there is a distinct subgroup of subjects with OCD and/or tics who have enlarged basal ganglia. These findings are consistent with the hypothesis of an autoimmune response to streptococcal infection." [Full Text]

Church, A J, Dale, R C, Lees, A J, Giovannoni, G, Robertson, M M
Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis
J Neurol Neurosurg Psychiatry 2003 74: 602-607
"BACKGROUND: The classical neurological disorder after group A beta haemolytic streptococcal infection is Sydenham's chorea. Recently a tic disorder occurring after group A streptococcal infection has been described and termed PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). It is proposed that antibodies induced after group A streptococcal infection react with basal ganglia neurones in Sydenham's chorea and PANDAS. Anti-basal ganglia antibodies (ABGA) are present in most cases of acute Sydenham's chorea, but rarely in controls. OBJECTIVE: To investigate the hypothesis that Tourette's syndrome may be associated with group A streptococcal infection and ABGA. METHODS: 100 patients with Tourette's syndrome (DSM-IV-TR) were enrolled in a cross sectional study. Children with neurological disease (n = 50) and recent uncomplicated streptococcal infection (n = 40), adults with neurological disease (n = 50), and healthy adults (n = 50) were studied as controls. Recent group A streptococcal infection was defined using antistreptolysin O titre (ASOT). ABGA were detected using western immunoblotting and indirect immunofluorescence. RESULTS: ASOT was raised in 64% of children with Tourette's syndrome compared with 15% of paediatric neurological disease controls (p < 0.0001), and in 68% of adults with Tourette's syndrome compared with 12% of adult neurological controls and 8% of adult healthy controls (p < 0.05). Western immunoblotting showed positive binding in 20% of children and 27% of adults with Tourette's syndrome, compared with 2-4% of control groups (p < 0.05). The most common basal ganglia binding was to a 60 kDa antigen, similar to the proposed antigen in Sydenham's chorea. Indirect immunofluorescence revealed autoantibody binding to basal ganglia neurones. Serological evidence of recent group A streptococcal infection, assessed by a raised ASOT, was detected in 91% (21/23) of Tourette's syndrome patients with positive ABGA compared with 57% (44/77) with negative ABGA (p < 0.01). CONCLUSIONS: The results support a role of group A streptococcal infection and basal ganglia autoimmunity in a subgroup of patients with Tourette's syndrome and suggest a pathogenic similarity between Sydenham's chorea and some patients with Tourette's syndrome." [Abstract]

Muller N, Riedel M, Straube A, Gunther W, Wilske B.
Increased anti-streptococcal antibodies in patients with Tourette's syndrome.
Psychiatry Res. 2000 Apr 24;94(1):43-9.
"Infection or postinfectious phenomena have been postulated to play a role in the pathogenesis of children afflicted with the typical symptoms of Tourette's syndrome (TS). We investigated whether an increase of titers of antistreptococcal antibodies can be reproduced in our children with TS, and whether this increase is restricted to children. We examined the titers of two different antistreptococcal antibodies, antistreptolysin (ASL) and anitDNase B, both in children and adults. Titer s of ASO and antiDNase B were measured (1) in 13 children/adolescents suffering from TS and in an aged-matched comparison group;(2) in 23 adult patients, a comparison group of 23 aged-matched controls, and in another group of 17 aged-matched, non-medicated acute schizophrenics. ASO and antiDNase B titers were determined by laser nephelometry using a commercially available kit. Two antistreptococcal cut-off levels were compared (> 250 U/ml and 400 U/ml). As expected, increases ASO titers (>400 IU/ml) were found in a higher portion of children/adolescents with TS compared to controls. Regarding adults, titers >250 U/ml for both antistreptococcal antigens were found in significantly more TS patients than in schizophrenic patients or healthy control subjects. The mean values of ASO and antiDNase titers were significantly higher in both groups of TS patients compared to control children/adolescents, to the comparison groups of healthy adults and to schizophrenics. No difference in antistreptococcal titers was found between schizophrenics and the group of healthy adults. TS patients exhibited higher antistreptococcal titers than age-matched comparison groups of both children/adolescents and adults using different types of calculation. Our findings support the theory that a postinfectious immune mechanism may play a role in the pathogenesis of TS. The mechanism still needs to be elucidated." [Abstract]

Morshed SA, Parveen S, Leckman JF, Mercadante MT, Bittencourt Kiss MH, Miguel EC, Arman A, Yazgan Y, Fujii T, Paul S, Peterson BS, Zhang H, King RA, Scahill L, Lombroso PJ.
Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders.
Biol Psychiatry. 2001 Oct 15;50(8):566-77.
"BACKGROUND: Some cases of Tourette's syndrome (TS) are hypothesized to be caused by autoantibodies that develop in response to a preceding group A beta hemolytic streptococcal infection. METHODS: To test this hypothesis, we looked for the presence ot total and IgG antibodies against neural, nuclear, cytoskeletal and streptococcal epitopes using indirect immunofluorescent assays and Western blot techniques in three patient groups: TS (n = 81), SC (n = 27), and a group of autoimmune disorders (n = 52) and in normal controls (n = 67). Subjects were ranked after titrations of autoantibodies from 0 to 227 according to their level of immunoreactivity. RESULTS: TS patients had a significantly higher mean rank for total antineural and antinuclear antibodies, as well as antistreptolysin O titers. However, among children and adolescents, only the total antinuclear antibodies were increased in TS patients compared to age matched controls. Compared to SC patients, TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, significantly lower IgG class anticytoskeletal antibodies, and a significantly higher rank for total antinuclear antibodies. Compared to a mixed group of autoimmune disorders, the TS patients had a significantly lower mean rank for total and IgG class antineural antibodies, total and IgG class antinuclear antibodies, IgG class anticytoskeletal antibodies, and a significantly higher rank for antistreptococcal antibodies. CONCLUSIONS: TS patients had significantly higher levels of total antineural and antinuclear antibodies than did controls. Their relation to IgG class antineural and antinuclear antibodies, markers for prior streptococcal infection, and other clinical characteristics, especially chronological age, was equivocal." [Abstract]

Muller N, Kroll B, Schwarz MJ, Riedel M, Straube A, Lutticken R, Reinert RR, Reineke T, Kuhnemund O.
Increased titers of antibodies against streptococcal M12 and M19 proteins in patients with Tourette's syndrome.
Psychiatry Res. 2001 Mar 25;101(2):187-93.
"It has been suggested that a post-streptococcal autoimmune process may be involved in the pathogenesis of a subgroup of children with tics and obsessive-compulsive symptoms (PANDAS). Elevated antibody titers against streptococcal antigens have also been described in adult patients suffering from Tourette's syndrome (TS). In order to characterise further streptococcal antigens, we focussed on M proteins. M proteins are a major virulence factor of group A streptococci and known to evoke an immunologic cross-reaction with diverse epitopes of human tissue including brain tissue. Therefore, antibodies against M proteins may play a role in the pathophysiology of at least a subgroup of TS patients. Antibodies against M proteins were studied in 25 adult patients suffering from TS and 25 healthy controls after careful medical examination. The antibody titers against the peptides M1, M4, M6, M12 and M19 were estimated by ELISA. Our results show increased titers of antibodies against the streptococcal M12 and M19 proteins in TS patients as compared with controls, while antibody titers against M1, M4 and M6 did not differ between the TS and control groups. Elevated serum titers of antibodies against M12 and M19 proteins support the view that a streptococcus-induced autoimmune process may be involved in TS. The finding of a possible autoimmune origin of TS has implications for both pathophysiology and future therapeutic strategies." [Abstract]

Singer HS, Loiselle CR, Lee O, Minzer K, Swedo S, Grus FH.
Anti-basal ganglia antibodies in PANDAS.
Mov Disord. 2004 Apr;19(4):406-15.
An autoimmune-mediated mechanism involving molecular mimicry has been proposed for a variety of pediatric movement disorders that occur after a streptococcal infection. In this study, anti-basal ganglia antibodies (ABGA) were measured in 15 children with the diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and compared with those in 15 controls. ELISA and Western immunoblotting (WB) methods were used to detect ABGA against supernatant (S1), pellet (P2), and synaptosomal preparations from adult postmortem caudate, putamen, and globus pallidus. ELISA optical density values did not differ between PANDAS patients and controls across all preparations. Immunoblotting identified multiple bands in all subjects with no differences in the number of bands or their total density. Discriminant analysis, used to assess mean binding patterns, showed that PANDAS patients differed from controls only for the caudate S1 fraction (Wilks' lambda = 0.0236, P < 0.0002), with PANDAS-primarily tic subjects providing the greatest discrimination. Among the epitopes contributing to differences between PANDAS and control in the caudate S1 fraction, mean binding to the epitope at 183 kDa was the most different between groups. In conclusion, ELISA measurements do not differentiate between PANDAS and controls, suggesting a lack of major antibody changes in this disorder. Further immunoblot analyses using a caudate supernatant fraction are required to completely exclude the possibility of minor antibody repertoire differences in PANDAS subjects, especially in those who primarily have tics. [Abstract]

Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M, Kiessling LS.
Antibodies against human putamen in children with Tourette syndrome.
Neurology. 1998 Jun;50(6):1618-24.
"BACKGROUND: Similar to the model for Sydenham's chorea, antineuronal antibodies, which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). METHODS: Serum antibodies against human caudate, putamen, and globus pallidus (interna and externa) were assayed by enzyme-linked immunosorbent assay (ELISA) and Western blot techniques and results were correlated with clinical characteristics and markers of streptococcal infection. SUBJECTS: A total of 41 children with TS (mean age, 11.3 years) and 39 controls (mean age, 12.1 years) were included. RESULTS: Compared with controls, TS subjects had a significant increase in the mean (p=0.006) and median (p=0.002) ELISA optical density (OD) levels of serum antibodies against putamen, but not caudate or globus pallidus. Western blots on 20 control and 20 TS serum samples showed that specific antibodies to caudate/putamen occurred more frequently in TS subjects at 83, 67, and 60 kDa; antigens were present in a synaptosomal fraction. TS subjects with a positive family history of tics had higher OD values (p < or = 0.04), but no association was shown with age of tic onset, tic severity, sudden onset of tics, or presence of attention-deficit hyperactivity disorder or obsessive-compulsive disorder. Risk ratio calculations in TS and control groups and in study subjects dichotomized for high and low putamen OD values were similar for titers of antistreptolysin O > or = 166 or antideoxyribonuclease B > or = 170. A subgroup analysis limited to subjects with elevated streptococcal titers, however, showed a significantly (p < or = 0.004) larger number of TS subjects with elevated OD levels. CONCLUSION: Children and adolescents with TS had significantly higher serum levels of antineuronal antibodies against putamen than did controls, but their relation to clinical characteristics and markers for streptococcal infection remains equivocal." [Abstract]

Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M, Kiessling LS.
Antibodies against a neuron-like (HTB-10 neuroblastoma) cell in children with Tourette syndrome.
Biol Psychiatry. 1999 Sep 15;46(6):775-80.
"BACKGROUND: Similar to the model for Sydenham's chorea, antineuronal antibodies (ANAb), which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). METHODS: Serum antibodies against the neuron-like HTB-10 neuroblastoma cell were assayed by ELISA methods and Western blot analysis on 41 children with TS (mean age 11.3 years) and 39 control subjects (mean age 12.1 years). RESULTS: Group comparisons of ELISA assay optical density (OD) showed that mean OD values for serum antibodies were not different [control (mean +/- SEM), .506 +/- .076; and TS, .584 +/- .053 (p = .38)]. In contrast, median values [.353 in control subjects and .477 in TS subjects (p = .012)] were significantly different. Western blots identified numerous bands in all TS and control sera with no difference in identified HTB-10 antigens. There was no relationship between the presence of ANAb and age of tic onset, family history, tic severity, attention deficit hyperactivity disorder, or obsessive compulsive disorder. No relationship existed between positive strep titers (ASO > or = 166 and/or antiDNAaseB > or = 170) and ANAb determinations or the severity of tics. CONCLUSIONS: Children with TS have higher median, but not mean, levels of ANAb, as measured by the HTB-10 neuroblastoma cell membrane assay. This assay system identified antibodies in both control and clinical groups and failed to identify a relationship between antibodies and clinical phenotype or one-time markers for streptococcal infection. Further studies are required to define a possible immune-mediated hypothesis for TS." [Abstract]

Singer HS, Giuliano JD, Zimmerman AM, Walkup JT.
Infection: a stimulus for tic disorders.
Pediatr Neurol. 2000 May;22(5):380-3.
"The object of this study was to investigate the potential association of infections, especially group A hemolytic streptococcal infection, with the abrupt onset/exacerbation of tics or obsessive-compulsive behaviors. A structured clinical interview was used to evaluate 80 consecutive children, 5-17 years of age, with a diagnosis of tic disorder. Forty-two patients (53%) described a sudden, explosive onset or worsening of tic symptoms; 15 of these 42 had their exacerbation historically associated with an infection, nine of the 15 specifically with a streptococcal infection. Comparisons between those nine individuals and the remainder of the study population are presented. The results of this study reveal that descriptions of an abrupt tic onset or exacerbation are not uncommon in children with tic disorders; approximately 11% of children with tic disorders described abrupt changes of tic behavior within a 6-week period after a streptococcal infection." [Abstract]

Loiselle CR, Wendlandt JT, Rohde CA, Singer HS.
Antistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome.
Pediatr Neurol. 2003 Feb;28(2):119-25.
"Previous studies have suggested associations between Tourette syndrome and attention-deficit-hyperactivity disorder and antistreptococcal antibodies and between Tourette syndrome and antinuclear antibodies. In this study, antistreptolysin O, antideoxyribonuclease B, antinuclear, and antineuronal antibodies were measured in 41 children with Tourette syndrome and 38 controls, selected without regard to history of streptococcal infection. Results revealed that mean antistreptococcal titers did not differ between diagnostic groups. In addition, multiple regression analysis was unable to predict antistreptococcal antibody titers according to age and diagnosis. The frequency of elevated antistreptolysin O titers, based on a cutoff of 1:240, was significantly higher (P = 0.04) in patients with attention-deficit-hyperactivity disorder (64%) than in the group without attention-deficit-hyperactivity disorder (34%) but not when dichotomized according to age-matched normal values. No analysis of antideoxyribonuclease B titers identified any differences between groups. Antinuclear antibody titers were at least 1:160 in three of 33 Tourette syndrome patients; only one subject manifested a homogeneous staining pattern. Multiple regression analyses were unable to predict antinuclear, antineuronal, or anti-HTB-10 antibody titers according to the combination of age, diagnosis, and antistreptococcal titer. We suggest that longitudinal rather than single-point-in-time laboratory measurements be evaluated before definitive conclusions are drawn on associations between the diagnosis of Tourette syndrome, attention-deficit-hyperactivity disorder, or obsessive-compulsive disorders and antistreptococcal or antinuclear antibody titers." [Abstract]

Peterson BS, Leckman JF, Tucker D, Scahill L, Staib L, Zhang H, King R, Cohen DJ, Gore JC, Lombroso P.
Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders.
Arch Gen Psychiatry. 2000 Apr;57(4):364-72.
"BACKGROUND: Previous studies have provided preliminary serological evidence supporting the theory that symptoms of tic disorders or obsessive-compulsive disorder (OCD) may be sequelae of prior streptococcal infection. It is unclear, however, whether previously reported associations with streptococcal infection were obscured by the presence of diagnostic comorbidities. It is also unknown whether streptococcal infection is associated in vivo with anatomical alterations of the brain structures that have been implicated in the pathophysiology of these disorders. METHODS: Antistreptococcal antibody titers were measured in 105 people diagnosed as having CTD, OCD, or attention-deficit/hyperactivity disorder (ADHD) and in 37 community controls without a disorder. Subjects were unselected with regard to their history of streptococcal exposure. Basal ganglia volumes were measured in 113 of these subjects (79 patients and 34 controls). RESULTS: A DSM-IV diagnosis of ADHD was associated significantly with titers of 2 distinct antistreptococcal antibodies, antistreptolysin O and anti-deoxyribonuclease B. These associations remained significant after controlling for the effects of CTD and OCD comorbidity. No significant association was seen between antibody titers and a diagnosis of either CTD or OCD. When basal ganglia volumes were included in these analyses, the relationships between antibody titers and basal ganglia volumes were significantly different in OCD and ADHD subjects compared with other diagnostic groups. Higher antibody titers in these subjects were associated with larger volumes of the putamen and globus pallidus nuclei. CONCLUSIONS: These findings suggest that the prior reports of an association between antistreptococcal antibodies and either CTD or OCD may have been confounded by the presence of ADHD. They also support the hypothesis that in susceptible persons who have ADHD or OCD, chronic or recurrent streptococcal infections are associated with structural alterations in basal ganglia nuclei." [Abstract]

Sokol, Mae S., Ward, Pamela E., Tamiya, Hiroko, Kondo, Douglas G., Houston, Douglas, Zabriskie, John B.
D8/17 Expression on B Lymphocytes in Anorexia Nervosa
Am J Psychiatry 2002 159: 1430-1432
"OBJECTIVE: The authors' goal was to determine whether D8/17, a rheumatic fever susceptibility trait marker, identifies a possible type of anorexia nervosa: pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) anorexia nervosa. METHOD: Using immunofluorescence, the authors measured the percentage of D8/17-positive B lymphocytes in the peripheral blood of 16 subjects 7-21 years old who had not had rheumatic fever but who had possible PANDAS anorexia nervosa. The comparison subjects were 17 psychiatric patients with no eating disorder and no PANDAS characteristics. Subjects were considered D8/17 positive if they had 12% or more D8/17+ cells. RESULTS: There were more D8/17-positive individuals among those with PANDAS anorexia nervosa (81%) than among the comparison subjects (12%). The subjects with PANDAS anorexia nervosa had a higher percentage of D8/17+ cells (mean=27.1%, SD=17%) than the comparison subjects (mean=5.3%, SD=7.4%). CONCLUSIONS: A larger study is needed to determine whether D8/17 serves as a marker for susceptibility to a type of anorexia nervosa." [Abstract]

Sokol MS.
Infection-triggered anorexia nervosa in children: clinical description of four cases.
J Child Adolesc Psychopharmacol. 2000 Summer;10(2):133-45.
"BACKGROUND: Anorexia nervosa (AN) is a serious illness with no definitive treatment. Clinical and research evidence led to the hypothesis that some children with AN may have a pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS), similar in pathogenesis to other hypothesized PANDAS disorders. METHODS: Four youngsters (ages, 11-15 years) with PANDAS AN were treated with an open trial of antibiotics, in addition to conventional treatment. They were evaluated for eating disorder and obsessive-compulsive symptoms, and for weight gain. Evidence of streptococcal infection came from clinical evaluation, throat cultures, and two serological tests: anti-deoxyribonuclease B (anti-DNase B) and anti-streptolysin O (ASO) titers. The "rheumatic" marker D8/17 was also measured. This B-cell alloantigen is associated, in several publications, with poststreptococcal autoimmunity: Rheumatic fever (RF), Sydenham's chorea (SC), and possibly PANDAS obsessive compulsive disorder (OCD) and tic disorders. RESULTS: There was clinical evidence of possible antecedent streptococcal infection in all four patients, two of whom had comorbid OCD, with possible infection-triggered AN. All four had the rheumatic marker: A percentage of D8/17-positive B cells of 28-38%, with a mean of 33% (12% or more is considered positive for the marker). The patients responded to conventional treatment plus antibiotics with weight restoration and decreased eating disorder and obsessive-compulsive symptoms. Three needed to gain weight and did so. CONCLUSIONS: There may be a link between infectious disease and some cases of AN, which raises the possibility of new treatment." [Abstract]

Sokol MS, Gray NS.
Case study: an infection-triggered, autoimmune subtype of anorexia nervosa.
J Am Acad Child Adolesc Psychiatry. 1997 Aug;36(8):1128-33.
"OBJECTIVE: Certain cases of anorexia nervosa (AN) may be similar to the recently described subtype of childhood-onset obsessive-compulsive disorder hypothesized to be one of the pediatric infection-triggered autoimmune neuropsychiatric disorders (PITANDs). METHOD: Three clinical cases are reported. The first patient is a 12-year-old boy whose AN worsened acutely after a group A beta-hemolytic streptococcal (GABHS) infection. His symptoms were alleviated after antibiotic treatment. Two other patients with possible PITANDs-related AN are described. RESULTS: An infection-triggered process may contribute to the pathogenesis of a subtype of AN. CONCLUSIONS: Future research is needed to explore the nature of PITANDs and their relationship with AN." [Abstract]

Hollander E, DelGiudice-Asch G, Simon L, Schmeidler J, Cartwright C, DeCaria CM, Kwon J, Cunningham-Rundles C, Chapman F, Zabriskie JB.
B lymphocyte antigen D8/17 and repetitive behaviors in autism.
Am J Psychiatry. 1999 Feb;156(2):317-20.
"OBJECTIVE: Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in rheumatic fever, Sydenham's chorea, and subgroups of obsessive-compulsive disorder and Tourette's syndrome with repetitive behaviors. The authors examined the rate of D8/17 expression in children with autism and its correlation with severity of repetitive behaviors. METHOD: Blood samples from 18 patients with autism and 14 comparable medically ill children were evaluated for percentage of D8/17-positive B cells by immunofluorescence and for streptococcal antibodies. Severity of repetitive behaviors was also determined. RESULTS: The frequency of individuals with > or =11% D8/17-positive cells was significantly higher in the autistic patients (78%) than the comparison subjects (21%), severity of repetitive behaviors significantly correlated with D8/17 expression, and D8/17-positive patients had significantly higher compulsion scores than D8/17-negative patients. CONCLUSIONS: D8/17 expression is high in patients with autism and may serve as a marker for compulsion severity within autism." [Abstract]

Bodner SM, Morshed SA, Peterson BS.
The question of PANDAS in adults.
Biol Psychiatry. 2001 May 1;49(9):807-10.
"BACKGROUND: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a well-defined cause of obsessive-compulsive disorder in children. However, they have not been described or fully investigated in adults newly diagnosed with obsessive-compulsive disorder. METHODS: We describe an adult with onset of obsessive-compulsive disorder at 25 years of age after a severe antibiotic-responsive pharyngitis. He was evaluated with multiple psychiatric rating scales for obsessive-compulsive disorder and Tourette's syndrome, as well as with serologic assays and radiologic studies. RESULTS: In all respects except age our patient fulfilled established criteria for PANDAS. Assays for antibodies to group A beta-hematolytic streptococci, serum D8,17 lymphocytes, antistriatal (neuronal) antibodies, and anticytoskeletal antibodies all supported the hypothesis that a poststreptococcal process was active. Magnetic resonance imaging was abnormal and is described. CONCLUSIONS: The findings suggest that this patient's illness is similar to PANDAS in presentation and that poststreptococcal disease may result in adult-onset obsessive-compulsive disorder." [Abstract]

Kurlan R.
Tourette's syndrome and 'PANDAS': will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.
Neurology. 1998 Jun;50(6):1530-4. [Abstract]

Mary M. Robertson
Tourette syndrome, associated conditions and the complexities of treatment
Brain 123: 425-462. [Full Text]

Garvey MA, Giedd J, Swedo SE.
PANDAS: the search for environmental triggers of pediatric neuropsychiatric disorders. Lessons from rheumatic fever.
J Child Neurol. 1998 Sep;13(9):413-23. [Abstract]

Thomsen PH, Leckman J.
[Obsessive-compulsive disorders in children. Subtypes of OCD and their relation to infection with group A streptococci]
Ugeskr Laeger. 2002 Aug 5;164(32):3763-7.
"The present review describes the theory of a spectrum of obsessive-compulsive disorders (OCD). This spectrum includes such disorders as trichotillomania, eating disorders, body dysmorphic disorder, and possibly pervasive developmental disorders. OCD with an onset in childhood is presented as a specific subtype, with more boys affected and frequently co-morbid with tics and Tourette's syndrome. Furthermore, it seems to be more genetically determined and have more significant deviations, as measured by neuro-imaging studies, than has OCD with an adult onset. The PANDAS theory (paediatric autoimmune neuropsychiatric disorder associated with streptococcal infections) is described. This subtype of OCD is, still on a speculative basis, connected to infections with beta-haemolytic streptococci. The obsessive-compulsive symptoms are characterised by a sudden onset, "sawtoothed" course with relapses and remissions, and are associated with neurological abnormalities. There are still no clinical consequences in terms of penicillin treatment of this PANDAS subtype of OCD." [Abstract]

Dale RC.
[Streptococcus pyogenes and the brain: living with the enemy]
Rev Neurol. 2003 Jul 1-15;37(1):92-7.
"Streptococcus pyogenes (or group A beta hemolytic streptococcus) is a pathogenic bacterium that can give rise to a range of invasive and autoimmune diseases, although it is more widely known as the cause of tonsillitis. It is particularly interesting to note that this germ only causes disease in humans. For many years it has been acknowledged that it can cause an autoimmune brain disease (Sydenham s chorea). Yet, the spectrum of post streptococcal brain disorders has recently been extended to include other movement disorders such as tics or dystonia. A number of systematic psychiatric studies have shown that certain emotional disorders generally accompany the movement disorder (particularly, obsessive compulsive disorder). The proposed pathogenetic mechanism is that of a neuronal dysfunction in which antibodies play a mediating role. The antibodies that are produced after the streptococcal infection cross react with neuronal proteins, and more especially so in individuals with a propensity. This represents a possible model of immunological mimicry and its potential importance with respect to certain idiopathic disorders such as Tourette syndrome and obsessive compulsive disorder." [Abstract]

Murphy TK, Petitto JM, Voeller KK, Goodman WK.
Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function?
Semin Clin Neuropsychiatry. 2001 Oct;6(4):266-76.
"During the last few years, an increased interest in the possibility of immune mediated pathophysiology of obsessive compulsive disorder (OCD) and related disorders has been seen. In the late 1980s, the National Institute of Mental Health reported an increase of obsessive compulsive symptoms in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCD symptoms but no chorea led to the coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus).This association has furthered interest in studying immune parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and its association with SC, and a review of the existing studies that have assessed immunologic measures in patients with OCD and TS." [Abstract]

Singer HS, Loiselle C.
PANDAS. A commentary.
J Psychosom Res. 2003 Jul;55(1):31-9.
"PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection. As defined, the criteria include prepubertal children with either a tic or obsessive-compulsive disorder in whom a Group A beta-hemolytic streptococcal infection (GABHS) triggers the abrupt onset or exacerbation of tics/obsessive-compulsive behaviors. Pathophysiologically, it is proposed that antibodies produced against GABHS cross-react with neuronal cells, in a process involving molecular mimicry. Although PANDAS has received widespread notoriety, the existence of this condition has been questioned. This commentary reviews clinical and laboratory issues pertinent to the diagnosis of this entity. We conclude that PANDAS is an intriguing hypothesis that requires further confirmation." [Abstract]

Betancourt YM, Jimenez-Leon JC, Jimenez-Betancourt CS, Castillo VE.
[Autoimmune neuropsychiatric disorders associated to infection by streptococcus in the paediatric age: PANDAS]
Rev Neurol. 2003 Feb;36 Suppl 1:S95-107.
"INTRODUCTION: The acronym PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus) describes the neuropsychiatric disorders resulting from an autoimmune response to an infection by streptococcus in children. AIMS: The aim of this study was to clinically analyse 38 patients under the age of 16 with tics, Tourette syndrome (TS) or obsessive compulsive disorder (OCD) and their possible association to an infection caused by group A beta-haemolytic streptococcus (GABHS). METHOD: We reviewed the medical records at the Instituto Neurologico in Valencia (Venezuela) over a 12 year period (1988-2000). All the patients met the inclusion criteria set out by the National Institute of Mental Health in Bethesda (1997) and the DSM-IV. RESULTS: Onset of the symptoms was higher in the group of schoolchildren (n=24), followed by the group of preschool children (n=8) and adolescents (n=6). Males were predominant (n=33) (86.8%). 17 patients presented chronic tics (44.7%), 13 had transitory tics (34.2%) and there were eight cases of TS (21.1%). The most frequently related comorbid disorders were: difficulties in learning (n=30) (78.9%), ADHD (n=27) (71.1%), OCD 14 (36.8%), sleep disorders (n=14) (36.8%), behavioural disorders (n=12) (31.6%), language disorders (n=11) (28.9%), psychomotor disorders (n=10) (26.3%) and nocturnal enuresis (n=7) (18.4%). Electroencephalogram patterns were abnormal in 72.4% (n=12), and the disorganised pattern was the most frequently observed (n=12) (41.4%), followed by a slow diffuse pattern (n= 7) (24.1%) and the left centro-parieto-temporal focal paroxysmal specific pattern (n=7) (24.1%). Less frequently we found unspecific generalised paroxysmal patterns, in four cases (13.8%), and asymmetrical patterns (n=1) (3.4%). The association with an infection by streptococcus was shown in two cases, which amounted to 5.2% of the sample. CONCLUSIONS: The obtained are similar to those reported in the literature. Only 5.2% of the cases were linked to a prior streptococcus infection." [Abstract]

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Recent PANDAS Research

1) Willesen JL, Meyland-Smith F, Wiinberg B, Monrad J, Bertelsen MF
Clinical implications of infection with a novel metastrongyloid species in the red panda (Ailurus fulgens).
J Zoo Wildl Med. 2012 Jun;43(2):283-8.
In a recent survey, 30% of the European red panda (Ailurus fulgens) population was found to be infected with a newly discovered metastrongyloid nematode. In a following prospective study, four naturally infected captive-bred red pandas infected with this parasite were examined and compared with two uninfected control animals. On clinical examination, no abnormalities were detected with respect to vital parameters and cardiovascular system in all six examined animals. Similarly, few and nonspecific changes were recorded on serum biochemistry. No changes on pulmonary pattern were noted on thoracic radiographs. Vertebral heart scores were between 7.2 to 8.6, and no difference was noted between infected and control animals. Two animals had slightly prolonged clotting time and reaction time on thromboelastography but not likely to be of clinical relevance. In conclusion, infection with the newly identified metastrongyloid nematode in the red pandas seems to have little or no clinical importance. [PubMed Citation] [Order full text from Infotrieve]

2) Milewski AV, Dierenfeld ES
Supplemental iodine as a key to reproduction in pandas?
Integr Zool. 2012 Jun;7(2):175-82.
Pandas are endemic to iodine-poor environments and appear to be specialized for a goitrogenic staple diet. In particular, the importance of thiocyanate in bamboos might possibly have been overlooked in captive breeding programs. Although excreted in urine, thiocyanate first antagonizes absorption of iodine by the thyroid (of parent, fetus and suckling juveniles) and the mammary glands. In livestock and humans, subclinical deficiency of iodine is known to result in reproductive problems (including retardation of the fetus and suckling infant) even where the mother appears to be unaffected beyond slight hyperplasia of the thyroid and subtle hypothyroidism as reflected by levels of thyroid hormones. We suggest that the possibilities of iodine deficiency or excess should be carefully considered wherever the reproductive rates of pandas are unsatisfactory. [PubMed Citation] [Order full text from Infotrieve]

3) Rhee H, Cameron DJ
Lyme disease and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an overview.
Int J Gen Med. 2012;5:163-74.
Lyme disease (LD) is a complex, multisystemic illness. As the most common vector- borne disease in the United States, LD is caused by bacterial spirochete Borrelia burgdorferi sensu stricto, with potential coinfections from agents of anaplasmosis, babesiosis, and ehrlichiosis. Persistent symptoms and clinical signs reflect multiorgan involvement with episodes of active disease and periods of remission, not sparing the coveted central nervous system. The capability of microorganisms to cause and exacerbate various neuropsychiatric pathology is also seen in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), a recently described disorder attributed to bacterium Streptococcus pyogenes of group A beta-hemolytic streptococcus in which neurologic tics and obsessive-compulsive disorders are sequelae of the infection. In the current overview, LD and PANDAS are juxtaposed through a review of their respective infectious etiologies, clinical presentations, mechanisms of disease development, courses of illness, and treatment options. Future directions related to immunoneuropsychiatry are also discussed. [PubMed Citation] [Order full text from Infotrieve]

4) Chen X, Lupi F, An L, Sheely R, Viña A, Liu J
Agent-based modeling of the effects of social norms on enrollment in payments for ecosystem services.
Ecol Modell. 2012 Mar 24;229:16-24.
Conservation investments are increasingly being implemented through payments for ecosystem services (PES) for the protection and restoration of ecosystem services around the world. Previous studies suggested that social norms have substantial impacts on environmental behaviors of humans, including enrollment of PES programs. However, it is still not well understood how social norms are affected by the design of PES programs and how the evolution of social norms may affect the efficiency of conservation investments. In this paper, we developed an agent-based simulation model to demonstrate the evolution and impacts of social norms on the enrollment of agricultural land in a PES program. We applied the model to land plots that have been enrolled in China's Grain-to-Green Program (GTGP) to examine reenrollment in an alternative payment program when the current payments ceased. The study was conducted in Wolong Nature Reserve where several thousand plant and animal species, including giant pandas, may benefit from the reenrollment. We found that over 15% more GTGP land can be reenrolled at the same payment if social norms were leveraged by allowing more than ten rounds of interactions among landholders regarding their reenrollment decisions. With only three rounds of interactions, an additional 7.5% GTGP land was reenrolled at the same payment due to the effects of social norms. In addition, the effects of social norms were largest at intermediate payments and were smaller at much higher or much smaller payments. Even in circumstances where frequent interactions among landholders about their enrollment decisions are not feasible, policy arrangements that divide households into multiple waves for sequential enrollment can enroll over 11% more land at a given payment level. The approach presented in this paper can be used to improve the efficiency of existing PES programs and many other conservation investments worldwide. [PubMed Citation] [Order full text from Infotrieve]

5) Du Y, Huang Y, Zhang H, Li D, Yang B, Wei M, Zhou Y, Liu Y
Innate predator recognition in giant pandas.
Zoolog Sci. 2012 Feb;29(2):67-70.
Innate predator recognition confers a survival advantage to prey animals. We investigate whether giant pandas exhibit innate predator recognition. We analyzed behavioral responses of 56 naive adult captive giant pandas (Ailuropoda melanoleuca), to urine from predators and non-predators and water control. Giant pandas performed more chemosensory investigation and displayed flehmen behaviors more frequently in response to predator urine compared to both non-predator urine and water control. Subjects also displayed certain defensive behaviors, as indicated by vigilance, and in certain cases, fleeing behaviors. Our results suggest that there is an innate component to predator recognition in captive giant pandas, although such recognition was only slight to moderate. These results have implications that may be applicable to the conservation and reintroduction of this endangered species. [PubMed Citation] [Order full text from Infotrieve]

6) Das A, Radhakrishnan A
A case of PANDAS with Kleine-Levin type periodic hypersomnia.
Sleep Med. 2012 Mar;13(3):319-20.
We report on an 11-year-old girl, presenting with clinical features suggesting both pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and Kleine-Levin syndrome (KLS), who was successfully treated with penicillin prophylaxis. KLS is a sleep disorder characterized by recurrent episodes of hypersomnia and at least one of the following symptoms: (1) cognitive or mood disturbances, (2) megaphagia with compulsive eating; (3) hypersexuality with inappropriate behaviors; and (4) abnormal behavior. The etiopathogenesis is still unclear and there is no effective treatment other than symptomatic therapies. This intriguing case report suggests novel insight into the pathogenesis of this rare and enigmatic syndrome. [PubMed Citation] [Order full text from Infotrieve]

7) Redondo-Granado MJ, García-Saseta P, Vizcaíno-López I, Palencia-Luaces R
[Successful treatment with benzathine penicillin of two patients suspected of suffering from PANDAS].
Rev Neurol. 2012 Jan 16;54(2):125-7.
[PubMed Citation] [Order full text from Infotrieve]

8) Snyder RJ, Perdue BM, Powell DM, Forthman DL, Bloomsmith MA, Maple TL
Behavioral and hormonal consequences of transporting giant pandas from China to the United States.
J Appl Anim Welf Sci. 2012;15(1):1-20.
Zoological institutions strive to ensure the welfare of nonhuman animals in captivity. Part of this effort involves reducing the level of distress experienced by an animal to the greatest extent possible. However, some necessary zoo management practices such as transportation induce stress responses. An extensive literature exists concerning the animal welfare implications of road transportation for farm and laboratory animals. There has, however, been little focus on the effects of air transportation on wild animals in captivity. Because many endangered species are transported by air for breeding purposes, it is especially important to study the effects of stress on these species. This study investigated the behavioral and hormonal consequences of transporting 4 giant pandas (2 male-female pairs) by air from China to the United States. An autoregressive test revealed that urinary cortisol measures were highest for 2 subjects, Lun Lun and Tian Tian, during the flight than during the remainder of the 30-day period posttransport (p < .01). No long-term behavioral changes or problems emerged as a result of the transport. The study found that more research is needed to develop a complete understanding of transportation stress and welfare in captive wildlife. [PubMed Citation] [Order full text from Infotrieve]

9) Lewin AB, Storch EA, Mutch PJ, Murphy TK
Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus.
J Neuropsychiatry Clin Neurosci. 2011;23(4):391-8.
This study evaluated neurocognitive functioning in 26 youth with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and primarily obsessive-compulsive disorder (OCD) symptoms. Marked impairment in visuospatial recall memory (as assessed using the Rey-Osterrieth Complex Figure Test) was observed in spite of average to above-average performance on academic and other neurocognitive measures. Group A beta-hemolytic Streptococcus titer elevations were associated with worse performance on tasks of neurocognitive and executive ability (Stroop Color-Word Interference Test), visuospatial memory, and fine motor speed (finger tapping) as well as elevated obsessive-compulsive symptom severity. [PubMed Citation] [Order full text from Infotrieve]

10) Singer HS, Gilbert DL, Wolf DS, Mink JW, Kurlan R
Moving from PANDAS to CANS.
J Pediatr. 2012 May;160(5):725-31.
[PubMed Citation] [Order full text from Infotrieve]

11) Hutchinson JR, Delmer C, Miller CE, Hildebrandt T, Pitsillides AA, Boyde A
From flat foot to fat foot: structure, ontogeny, function, and evolution of elephant "sixth toes".
Science. 2011 Dec 23;334(6063):1699-703.
Several groups of tetrapods have expanded sesamoid (small, tendon-anchoring) bones into digit-like structures ("predigits"), such as pandas' "thumbs." Elephants similarly have expanded structures in the fat pads of their fore- and hindfeet, but for three centuries these have been overlooked as mere cartilaginous curiosities. We show that these are indeed massive sesamoids that employ a patchy mode of ossification of a massive cartilaginous precursor and that the predigits act functionally like digits. Further, we reveal clear osteological correlates of predigit joint articulation with the carpals/tarsals that are visible in fossils. Our survey shows that basal proboscideans were relatively "flat-footed" (plantigrade), whereas early elephantiforms evolved the more derived "tip-toed" (subunguligrade) morphology, including the predigits and fat pad, of extant elephants. Thus, elephants co-opted sesamoid bones into a role as false digits and used them for support as they changed their foot posture. [PubMed Citation] [Order full text from Infotrieve]

12) Dorji S, Vernes K, Rajaratnam R
Habitat correlates of the red panda in the temperate forests of Bhutan.
PLoS One. 2011;6(10):e26483.
Anthropogenic activities and associated global climate change are threatening the biodiversity in the Himalayas against a backdrop of poor knowledge of the region's threatened species. The red panda (Ailurus fulgens) is a threatened mammal confined to the eastern Himalayas, and because of Bhutan's central location in the distributional range of red pandas, its forests are integral to the long-term viability of wild populations. Detailed habitat requirements of the red panda are largely speculative, and there is virtually no ecological information available on this species in Bhutan. Between 2007 and 2009, we established 615 presence/absence plots in a systematic sampling of resident habitat types within Jigme Dorji and Thrumshingla National Parks, Bhutan, to investigate broad and fine-scale red panda habitat associations. Additional locality records of red pandas were obtained from interviewing 664 park residents. Red pandas were generally confined to cool broadleaf and conifer forests from 2,110-4,389 m above sea level (asl), with the majority of records between 2,400-3,700 m asl on south and east-facing slopes. At a finer scale, multivariate analysis revealed that red pandas were strongly associated with old growth Bhutan Fir (Abies densa) forest dominated by a dense cover of Yushania and Arundanaria bamboo with a high density of fallen logs and tree stumps at ground level; a high density of trees, dead snags, and rhododendron shrubs in the mid-storey; and locations that were close to water. Because Bhutan's temperate forests that encompass prime red panda habitat are also integral to human subsistence and socio-economic development, there exists an inadvertent conflict between the needs of people and red pandas. As such, careful sustainable management of Bhutan's temperate forests is necessary if a balance is to be met between the socioeconomic needs of people and the conservation goals for red pandas. [PubMed Citation] [Order full text from Infotrieve]

13) Sun J, Fu F, Gu W, Yan R, Zhang G, Shen Z, Zhou Y, Wang H, Shen B, Zhang X
Origination of new immunological functions in the costimulatory molecule B7-H3: the role of exon duplication in evolution of the immune system.
PLoS One. 2011;6(9):e24751.
B7-H3, a recently identified B7 family member, has different isoforms in human and mouse. Mouse B7-H3 gene has only one isoform (2IgB7-H3) with two Ig-like domains, whereas human B7-H3 has two isoforms (2IgB7-H3 and 4IgB7-H3). In this study a systematic genomic survey across various species from teleost fishes to mammals revealed that 4IgB7-H3 isoform also appeared in pigs, guinea pigs, cows, dogs, African elephants, pandas, megabats and higher primate animals, which resulted from tandem exon duplication. Further sequence analysis indicated that this duplication generated a new conserved region in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membrane and soluble forms. Through three-dimensional (3D) structure modeling and fusion-protein binding assays, we discovered that the duplicated isoform had a different structure and might bind to another potential receptor on activated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3) and mouse B7-H3 (mB7-H3) both increased T cell proliferation and IL-2, IFN-? production, whereas human 4IgB7-H3 (h4IgB7-H3) reduced cytokine production and T cell proliferation compared to control. Furthermore, both h2IgB7-H3 and mB7-H3 upregulated the function of lipopolysacharide (LPS)-activated monocyte in vitro. Taken together, our data implied that during the evolution of vertebrates, B7-H3 exon duplication contributed to the generation of a new 4IgB7-H3 isoform in many mammalian species, which have carried out distinct functions in the immune responses. [PubMed Citation] [Order full text from Infotrieve]

14) Jin Y, Lin W, Huang S, Zhang C, Pu T, Ma W, Lin D
Dental abnormalities in eight captive giant pandas (Ailuropoda melanoleuca) in China.
J Comp Pathol. 2012 May;146(4):357-64.
Dental data from eight adult giant pandas (Ailuropoda melanoleuca) (four females and four males) were collected at the Beijing Zoo from February 2009 to July 2010. Examination findings were recorded in dental charts. All the pandas had different degrees of tooth wear. Incisors, canines and second premolars had the most abnormalities. Five animals had caries; molars were the most affected. Chip fractures were found in seven teeth (incisor, canine and premolar) of five pandas; two had complicated fractures of their canines. Premolars and other teeth were missing in three pandas. Different degrees of dental plaque and calculus were found in all animals. Two pandas had mild gingivitis; the depth of periodontal pockets in all pandas was normal (0-2 mm). Five pandas had abnormal tooth mobility. Samples of dental plaque were collected for microbial culture. Two hundred and fifty-three bacterial strains belonging to 48 species of 23 genera were isolated. Streptococcus, Moraxella, Peptostreptococcus and Porphyromonas were the dominant genera. Further research with larger sample sizes of free-ranging and captive giant pandas will be required in order to demonstrate the absence of the premolar tooth, tooth fractures and the relatively low prevalence of periodontal disease in captive giant pandas. [PubMed Citation] [Order full text from Infotrieve]

15) Murphy TK, Storch EA, Lewin AB, Edge PJ, Goodman WK
Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.
J Pediatr. 2012 Feb;160(2):314-9.
[PubMed Citation] [Order full text from Infotrieve]

16) Hu Y, Guo Y, Qi D, Zhan X, Wu H, Bruford MW, Wei F
Genetic structuring and recent demographic history of red pandas (Ailurus fulgens) inferred from microsatellite and mitochondrial DNA.
Mol Ecol. 2011 Jul;20(13):2662-75.
Clarification of the genetic structure and population history of a species can shed light on the impacts of landscapes, historical climate change and contemporary human activities and thus enables evidence-based conservation decisions for endangered organisms. The red panda (Ailurus fulgens) is an endangered species distributing at the edge of the Qinghai-Tibetan Plateau and is currently subject to habitat loss, fragmentation and population decline, thus representing a good model to test the influences of the above-mentioned factors on a plateau edge species. We combined nine microsatellite loci and 551?bp of mitochondrial control region (mtDNA CR) to explore the genetic structure and demographic history of this species. A total of 123 individuals were sampled from 23 locations across five populations. High levels of genetic variation were identified for both mtDNA and microsatellites. Phylogeographic analyses indicated little geographic structure, suggesting historically wide gene flow. However, microsatellite-based Bayesian clustering clearly identified three groups (Qionglai-Liangshan, Xiaoxiangling and Gaoligong-Tibet). A significant isolation-by-distance pattern was detected only after removing Xiaoxiangling. For mtDNA data, there was no statistical support for a historical population expansion or contraction for the whole sample or any population except Xiaoxiangling where a signal of contraction was detected. However, Bayesian simulations of population history using microsatellite data did pinpoint population declines for Qionglai, Xiaoxiangling and Gaoligong, demonstrating significant influences of human activity on demography. The unique history of the Xiaoxiangling population plays a critical role in shaping the genetic structure of this species, and large-scale habitat loss and fragmentation is hampering gene flow among populations. The implications of our findings for the biogeography of the Qinghai-Tibetan Plateau, subspecies classification and conservation of red pandas are discussed. [PubMed Citation] [Order full text from Infotrieve]

17) Lewin AB, Storch EA, Murphy TK
Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings.
J Child Adolesc Psychopharmacol. 2011 Apr;21(2):177-82.
Termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS), these cases of childhood-onset obsessive compulsive disorder and tic disorders resemble the presentation of Sydenham chorea, in that they have an acute onset following a group A beta-hemolytic streptococcal infection (group A Streptococcus), with accompanying neurological signs, and an episodic or sawtooth course. Familial associations of this subgroup of patients remain understudied. This report provides phenotypic descriptions of three youth with PANDAS as well as their genetically identical siblings (in two cases of twins and one case of triplets). These cases highlight the potential for environmental influences for discordant presentations in genetically identical siblings. Despite identical genetics, presentations showed marked variation across siblings (from a full PANDAS presentation to asymptomatic). Further research into environmentally driven influences such as postinfectious molecular mimicry and epigenetic factors that may influence the manifestation of these pediatric neuropsychiatric disorders will promote our understanding of their prevention and treatment. [PubMed Citation] [Order full text from Infotrieve]

18) Alexander AA, Patel NJ, Southammakosane CA, Mortensen MM
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an indication for tonsillectomy.
Int J Pediatr Otorhinolaryngol. 2011 Jun;75(6):872-3.
Children with obsessive compulsive disorder or tic disorders that are associated with streptococcal infections (Group A beta-hemolytic) in the oro-pharyngeal region are given the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Tonsillectomy has been reported to resolve the neuro-psychiatric symptoms in these children. We have a case of a 9-year-old boy who was seen in our clinic with multiple recurrent streptococcal infections of the oro-pharyngeal cavity. He also exhibited neuro-psychiatric symptoms including agitation, hyperactivity, and tics. These symptoms followed his recurrent infections. Tonsillectomy was performed and in one year follow-up the patient did not have any recurrent streptococcal infections, and his neuro-psychiatric symptoms resolved completely. Guidelines for medical and surgical management of recurrent strep infections in the face of PANDAS are reviewed. [PubMed Citation] [Order full text from Infotrieve]

19) Li Y, Xu X, Zhang L, Zhang Z, Shen F, Zhang W, Yue B
An ARMS-based technique for sex determination of red panda (Ailurus fulgens).
Mol Ecol Resour. 2011 Mar;11(2):400-3.
Molecular sexing is a key component in the investigation of wild populations. In this study, we developed a fast, accurate and reliable amplification refractory mutation system (ARMS) technique for sex determination of red panda based on the exon 4 of the ZFX/ZFY gene. The amplicons were distinguished simply by agarose gel electrophoresis, exhibiting one fragment in females (X: 300 bp) and two in males (X: 300 bp, Y: 166 bp). Robustness of this ARMS system was confirmed by testing both 43 captive red pandas using DNA samples with known-sex and 10 wild red pandas using faecal DNA samples with unknown sex. [PubMed Citation] [Order full text from Infotrieve]

20) Brilot F, Merheb V, Ding A, Murphy T, Dale RC
Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome.
Neurology. 2011 Apr 26;76(17):1508-13.
[PubMed Citation] [Order full text from Infotrieve]