There is a large literature on this subject. It never ceases to amaze us the strange ways of biology and that the axiom "the longest is the right one" is fulfilled in this case.

There is a large literature on this subject. It never ceases to amaze us the strange ways of biology and that the axiom "the longest is [HIDDEN]" is fulfilled in this case.

Faced with sudden-onset obsessive-compulsive disorder (OCD) in a 9-year-old boy who also presents with tics and chorea as neurological manifestations, infection by:

Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study.

If pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is a unique clinical entity, we hypothesized that children meeting diagnostic criteria would have more clinical exacerbations temporally linked to bona fide group A beta-hemolytic streptococcus infection than matched control subjects (chronic tic and/or obsessive-compulsive disorder with no known temporal relationship to group A beta-hemolytic streptococcus infection). Subjects included 40 matched pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections case-control pairs who were prospectively evaluated with intensive laboratory testing for group A beta-hemolytic streptococcus and clinical measures for an average of 2 years. Additional testing occurred at the time of any clinical exacerbations or illness. Laboratory personnel were blinded to case or control status and clinical (exacerbation or not) condition. Clinical raters were blinded to the results of laboratory tests. The cases had a higher clinical exacerbation rate and a higher bona fide group A beta-hemolytic streptococcus infection rate than the control group. Only 5 of 64 exacerbations were temporally associated (within 4 weeks) with a group A beta-hemolytic streptococcus infection, and all occurred in cases. The number (5.0) was significantly higher than the number that would be expected by chance alone (1.6). Yet, >/=75% of the clinical exacerbations in cases had no observable temporal relationship to group A beta-hemolytic streptococcus infection. Patients who fit published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections seem to represent a subgroup of those with chronic tic disorders and obsessive-compulsive disorder who may be vulnerable to group A beta-hemolytic streptococcus infection as a precipitant of neuropsychiatric symptom exacerbations. Group A beta-hemolytic streptococcus infection is not the only or even the most common antecedent event associated with exacerbations for these patients. Additional intensive studies are needed to determine whether there is clinical or scientific evidence to support separating out subgroups of tic disorder and/or obsessive-compulsive disorder patients based on specific symptom precipitants.

Association between streptococcal infection and obsessive-compulsive disorder, Tourette's syndrome, and tic disorder.

Reports have suggested that streptococcal infection may be etiologically related to pediatric autoimmune neuropsychiatric disorders (PANDAS), but there are few good epidemiologic studies to support this theory. Using population-based data from a large West-Coast health maintenance organization, we assessed whether streptococcal infection was associated with increased risk for obsessive-compulsive disorder (OCD), Tourette's syndrome (TS), or tic disorder. This is a case-control study of children 4 to 13 years old receiving their first diagnosis of OCD, TS, or tic disorder between January 1992 and December 1999 at Group Health Cooperative outpatient facilities. Cases were matched to controls by birth date, gender, primary physician, and propensity to seek health care. Patients with OCD, TS, or tic disorder were more likely than controls to have had prior streptococcal infection (OR: 2.22; 95% CI: 1.05, 4.69) in the 3 months before onset date. The risk was higher among children with multiple streptococcal infections within 12 months (OR: 3.10; 95% CI: 1.77, 8.96). Having multiple infections with group A beta-hemolytic streptococcus within a 12-month period was associated with an increased risk for TS (OR: 13.6; 95% CI: 1.93, 51.0). These associations did not change appreciably when limited to cases with a clear date of onset of symptoms or with tighter matching on health care behavior. These findings lend epidemiologic evidence that PANDAS may arise as a result of a postinfectious autoimmune phenomenon induced by childhood streptococcal infection.

Pediatric autoimmune neuropsychiatric disorders after streptococcus infection.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) is a group of disorders recently recognized as a clinical entity. A case of PANDAS is described here, which remitted after 1 month of treatment. Recent Group A beta-hemolytic streptococcus infection should be considered in a child who presents with a sudden explosive onset of tics or obsessive compulsive symptoms.

The evaluation of relationship between group A streptococcal infection with tic disorders in children.

To evaluate the relationship between group A beta hemolytic streptococcus infection (GABHS) and tic disorders in children. This is a case-control study that was conducted in Child and Adolescent Psychiatric Clinic, Isfahan, Iran, between May 2008 and February 2009. Thirty-six children (aged 5-15) with tic and 36 children without tic and obsessive-compulsive disorder (OCD) were investigated for clinical and laboratory signs of GABHS. The tools utilized in this research were clinical interview according to the DSM IV-TR and laboratory tests (throat culture, rapid antigen detection test [RADT], anti streptolysin O [ASO] and yale global tics severity scale [YGTSS]). The control group was of the same gender and age as the tic group who had come to the clinic for other illnesses and was in need of blood test. None of the subjects in the case and control groups had a clinical history of GABHS infection. The relationship between tic disorder and GABHS infection (if any of these laboratory tests takes place: throat culture, RADT, ASO > or = 250) in the tic group was 16 (44.4%) and in the control group was 9 (25%), there were significant differences (p<0.05). No significant correlation was found between ASO titer and YGTSS scores. The specificity of RADT was 100%. The result showed correlation between GABHS infection and tic disorder, but it does not mean that GABHS infection caused tic disorder.

[Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A report of two cases].

To critically review the past years of research on paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in children and adolescents. Literature on PANDAS published from 1995 onward was systematically reviewed. The review focuses on definition and diagnostic consideration aetiological and therapeutical issues. To illustrate the clinical characteristic of PANDAS authors present two cases of children with a severe course of obsessive-compulsive disorder and Tourette's syndrome. Post-streptococcal autoimmunity has been postulated as an aetiologic factor in the development of childhood-onset obsessive-compulsive disorder, tic disorders including Tourette's disorder. This hypothesis arose from a series of clinical observations including the documentation of obsessive-compulsive symptoms of children affected by Sydenham's chorea, a variant of rheumatic fever characterised by neurological dysfunction and also by concomitant investigations of childhood-onset OCD and Tourette's syndrome. Results of these studies led to the identification of children whose clinical course is characterised by abrupt and dramatic symptom exacerbations which are temporally related to group A beta-hemolytic streptococcal infections. The identification of such a subgroup will allow for testing of the model of pathogenesis as well as development of novel treatment and prevention strategies. Future research are needed to explore the nature of PANDAS and their relationship with different psychiatric disorders in children and adolescents.

Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function?

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.

Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome.

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.

[PANDAS: a possible model for adult OCD pathogenesis].

Obsessive-compulsive disorder is a disabling disorder. Genetic predisposing factors may have an important role in the onset of the symptoms, but is not been individualized any specific gene yet. In the last years it has been demonstrated that obsessive-compulsive disease and/or tic syndromes may be triggered by an antecedent infection especially with group A beta-hemolytic streptococci. On the basis of recent studies has been postulated that in genetically predisposed individuals, certain streptococcal antigens trigger antibodies which, through a process of molecular mimicry, cross-react with epitopes on the basal ganglia. According to such hypothesis, the acronym PANDAS has been used to describe a subset of children with abrupt onset or exacerbations of OCD or tics, or both, following streptococcal infections. Neuroimaging studies reveal increased basal ganglia volumes, and the proposed cause involves the cross-reaction of streptococcal antibodies with basal ganglia tissue. The hypothesis of a possible involvement of the immunitary system seems justified from quantitative alterations of TNF-alpha, IL-6 and IL-1 in the patients' serum with such syndrome. Echotomographic studies on cardiac valves have not yet demonstrated the parallels between PANDAS and Sydenham's chorea. The use of treatment strategies, such as therapeutic plasmapheresis or intravenous immunoglobulin, has been proposed to explain the autoimmune process responsible for the pathogenesis of PANDAS. Further research is still necessary in order to understand the role of streptococcal infection in the pathogenesis of PANDAS.

The immunobiology of Tourette's disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward.

Obsessive-compulsive disorder (OCD) and related conditions including Tourette's disorder (TD) are chronic, relapsing disorders of unknown etiology associated with marked impairment and disability. Associated immune dysfunction has been reported and debated in the literature since the late 80s. The immunologic culprit receiving the most interest has been Group A Streptococcus (GAS), which began to receive attention as a potential cause of neuropsychiatric symptoms, following the investigation of the symptoms reported in Sydenham's chorea (SC) and rheumatic fever, such as motor tics, vocal tics, and both obsessive-compulsive and attention deficit/hyperactivity symptoms. Young children have been described as having a sudden onset of these neuropsychiatric symptoms temporally associated with GAS, but without supporting evidence of rheumatic fever. This presentation of OCD and tics has been termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS). Of note, SC, OCD, and TD often begin in early childhood and share common anatomic areas--the basal ganglia of the brain and the related cortical and thalamic sites--adding support to the possibility that these disorders might share a common immunologic and/or genetic vulnerability. Relevant manuscripts were identified through searches of the PsycINFO and MedLine databases using the following keywords: OCD, immune, PANDAS, Sydenham chorea, Tourette's disorder Group A Streptococcus. Articles were also identified through reference lists from research articles and other materials on childhood OCD, PANDAS, and TD between 1966 and December 2010. Considering the overlap of clinical and neuroanatomic findings among these disorders, this review explores evidence regarding the immunobiology as well as the relevant clinical and therapeutic aspects of TD, OCD, and PANDAS.

Childhood-onset obsessive-compulsive disorder and tic disorders: case report and literature review.

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.

[Obsessive-compulsive disorders in children. Subtypes of OCD and their relation to infection with group A streptococci].

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.

A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections.

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. 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. 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. 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.

A possible association of recurrent streptococcal infections and acute onset of obsessive-compulsive disorder.

Rheumatic fever is an immunologically mediated disease that follows infection by group A beta-hemolytic Streptococcus (GABHS). In rheumatic fever, antibodies generated against GABHS cross-react with the heart, joints, skin, and other sites, inducing an inflammatory, multisystem disease. Brain tissue-specific antibodies have been demonstrated in a subset of children with Sydenham chorea (a component of the Jones criteria for the diagnosis of rheumatic fever), and most Sydenham chorea patients manifest obsessive-compulsive symptoms very similar to those in traditional obsessive-compulsive disorder. The parallels drawn from the paradigm of Sydenham's chorea to Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is an area of active controversy. Newly emerging information on the role of GABHS superantigens in the pathogenesis of rheumatic fever is of particular interest. In this article, we review the microbial characteristics of GABHS and the subsequent immune responses to GABHS as a possible etiology of PANDAS.

Is parental report of upper respiratory infection at the onset of obsessive-compulsive disorder suggestive of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection?

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.

[Acute rheumatic fever, Sydenham's chorea and psychopathology].

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 chorea. Antibodies against group A beta-hemolytic streptococcus 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.

Importance of Streptococci Infections in Childhood Neuropsychiatric Disorders.

Paediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS) are important neuropsychiatric disorders in childhood. Streptococcus pyogenes infection associated with tics, obsessive-compulsive disorders, and chorea co-occurrence is important. Swedo et al. have increased the awareness of this situation since 1998. How streptococcal infections give rise to this condition is not clear yet, but the severity of the symptoms is reduced by the treatment of streptococcal infections is important. Eight-year- nine-month-old girl presented with complaints of a 2-year history of upper respiratory tract infections and increased severity of blinking of eyes, throat cleaning, tic disorder and obsession with hand cleaning. In addition, choreiform movements were present and fluoxetine did not improve the symptoms. The patient was followed-up and treated with PANDAS pre-diagnosis. Streptococcus treatment and prophylaxis decreased the patient's complaints. A six-year-four months old boy, admitted with abnormal hand and body movements, which increased severity after the school period, and causing deteriorated fine motor skills during infectious periods for two years. There were also complaints with vocal tics and obsessive-compulsive disorder in the form of throat cleaning. Treatment of S. pyogenes was administered in throat culture. After the penicillin prophylaxis, the complaints decreased. In this study, two patients were presented with choreiform movements, obsessive-compulsive disorder and tic disorder due to follow-up PANDAS diagnosis. PANDAS should be considered in children with neuropsychiatric disorders, especially symptoms associated with infection periods.

Delayed-maturation theory of obsessive-compulsive disorder

Childhood-Onset Obsessive-Compulsive Disorder and Tic Disorders was another experiment that supported the delayed-maturation theory regarding OCD. It was conducted by Snider and Swedo in 2003. Research included the diagnosis of pediatric autoimmune neuropsychiatric disorder, associated with streptococcal infection, also known as PANDAS. Thus, requiring a prospectively determined association between group A beta-hemolytic streptococcal infection, GABHS, and obsessive-compulsive disorder or tic disorder. Screening for a 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,

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: an overview.

The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been used to describe a syndrome characterized by various obsessions, compulsions, tics, hyperactivity, motor stereotypies, and paroxysmal movement disorders that are correlated with prior infection by group A beta-hemolytic Streptococcus pyogenes (GABHS) infections. Five clinical criteria can be used to diagnose PANDAS: (1) the presence of obsessive-compulsive disorder (OCD) and/or any other tic disorders; (2) prepuberal onset (between 3 years of age and the start of puberty); (3) abrupt onset and relapsing-remitting symptom course; (4) a distinct association with GABHS infection; and (5) association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity). The exact pathogenesis of PANDAS remains unclear, and several theories that focus on multiple etiologic or contributive factors have emerged. PANDAS appears to be a neurobiological disorder that potentially complicates GABHS infections in genetically susceptible individuals. The current standard of care for PANDAS patients remains symptomatic, and cognitive behavioral therapy, such as exposure and response prevention, combined with family counseling and psychoeducation, should be the first approach for treating PANDAS. This review examines current theories of PANDAS pathogenesis, identifies possible treatments for managing this complex condition, and highlights areas for future research. Moving forward, developing more standardized diagnostic criteria and identifying specific laboratory markers to facilitate PANDAS diagnoses are crucial.

PANDAS: current status and directions for research.

The recognition of the five criteria for PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) by Swedo et al established a homogenous subgroup of children with childhood onset obsessive-compulsive disorder (OCD) and/or tic disorders. The five clinical characteristics that define the PANDAS subgroup are the presence of OCD and/or tic disorder, prepubertal age of onset, abrupt onset and relapsing-remitting symptom course, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and a temporal association between symptom exacerbations and a Group-A beta-hemolytic streptococcal (GAS) infection. These five criteria have been used for the purpose of systematic research on the phenomenology and unique therapies for the PANDAS subgroup as well as studies of the pathophysiology of post-streptococcal OCD and tic disorders. The etiology of OCD and tics in the PANDAS subgroup is unknown, but is theorized to occur as a result of post-streptococcal autoimmunity in a manner similar to that of Sydenham's chorea. The working hypothesis for the pathophysiology begins with a GAS infection in a susceptible host that incites the production of antibodies to GAS that crossreact with the cellular components of the basal ganglia, particularly in the caudate nucleus and putamen. The obsessions, compulsions, tics, and other neuropsychiatric symptoms seen in these children are postulated to arise from an interaction of these antibodies with neurons of the basal ganglia.

Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings.

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.

PANDAS

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a controversial hypothetical diagnosis for a subset of children with rapid onset of obsessive-compulsive disorder (OCD) or tic disorders. Symptoms are proposed to be caused by group A streptococcal (GAS), and more specifically, group A beta-hemolytic streptococcal (GABHS) infections. OCD and tic disorders are hypothesized to arise in a subset of children as a result of a post-streptococcal autoimmune process. The proposed link between infection and these disorders is that an autoimmune reaction to infection produces antibodies that interfere with basal ganglia function, causing symptom exacerbations, and this autoimmune response results in a broad range of neuropsychiatric symptoms.

No Cases of PANDAS on Follow-Up of Patients Referred to a Pediatric Movement Disorders Clinic.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) remains a controversial diagnosis and it is unclear how frequently it is encountered in clinical practice. Our study aimed to determine how many children with acute-onset tics and/or Obsessive-Compulsive Disorder (OCD) met criteria for PANDAS. A retrospective review was performed on 39 children who presented to a movement disorders clinic with acute-onset tics or OCD from 2005 to 2012. Out of 284 patients seen over the course of 7 years, only 39 had acute-onset tics and/or OCD symptoms. None of the 39 children who presented to us acutely met full criteria for PANDAS. Thirty-eight percent had no association between their symptoms and group A beta-hemolytic streptococcal infection, while 54% had prior inconclusive laboratory testing done and no exacerbations during the course of the study. Only 8% of patients had an acute exacerbation after their initial visit; however, testing for GAHBS in these patients was negative Discussion: Our results support the notion that PANDAS, if it exists, is an exceedingly rare diagnosis encountered in a pediatric movement disorder clinic. While none of our patients met criteria for PANDAS, two with acute-onset OCD would have met criteria for pediatric acute-onset neuropsychiatric syndrome (PANS) indicating that PANS may be a more appropriate diagnosis.

The PANDAS subgroup of tic disorders and childhood-onset obsessive-compulsive disorder.

Diagnosis and treatment of the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) variant of Gilles de la Tourette syndrome (GTS) and childhood-onset obsessive-compulsive disorder (OCD) are still controversial issues. Most cross-sectional studies confirm a significant association between GTS and the development of an immune response against group A beta-hemolytic streptococcus (GABHS). Moreover, longitudinal retrospective studies suggest that a recent exposure to GABHS might be a risk factor for the onset of tics and obsessive-compulsive symptoms. However, further evidence from longitudinal prospective research is needed to verify whether a temporal association between GABHS infections and symptom exacerbations is a useful and reliable criterion for the diagnosis of PANDAS. In addition, preliminary results suggest that the PANDAS spectrum might be enlarged to include attention deficit/hyperactivity disorder. Although a number of immunological biomarkers have been proposed as markers of the PANDAS variant, at present, none of these has been conclusively proved useful to diagnose and monitor disease course in children with a suspicion of PANDAS. Finally, despite their empirical use in community settings, we still lack conclusive, evidence-based data regarding the usefulness of antibiotic and immunomodulatory treatments in children with PANDAS. Given the relevance of this topic for general pediatric health, additional research efforts to solve all the pending issues and the hottest points of debate are warranted.

MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection.

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. 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. 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. 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.

The PANDAS subgroup: recognition and treatment.

A subgroup of patients with childhood-onset obsessive-compulsive disorder (OCD) has been identified who share a common clinical course characterized by dramatic symptom exacerbations following Group A beta-hemolytic streptococcal (GABHS) infections. The term PANDAS has been applied to the subgroup, to indicate the postulated etiology of their symptoms: 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 (sawtooth course), association with neurological abnormalities (presence of adventitious movements or motoric hyperactivity during exacerbations), and temporal association between symptom exacerbations and GABHS infections. Post-streptococcal symptom exacerbations are typically quite dramatic, with patients reporting that their symptoms "...came on overnight" or "...appeared all of a sudden a few days after I had a sore throat." The post-streptococcal inflammatory nature of the neuropsychiatric symptoms provides novel opportunities for treatment and prevention, including immunomodulatory therapies such as therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG). A recently completed placebo-controlled trial revealed that both IVIG and TPE were effective in reducing neuropsychiatric symptom severity (40% to 55% reductions, respectively) for a group of severely ill children with OCD and/or tic disorders. Further research is required to determine why the treatments are helpful, as well as to ascertain whether or not antibiotic prophylaxis can help prevent post-streptococcal symptom exacerbations.

Obsessive-Compulsive Disorder -- Etiology

The earlier onset of sudden OCD that is preceded by a Streptococcus infection has been known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections). Just as Sydenham chorea can present as a sequela from Streptococcus infections, the theory behind OCD is similar in that the strep infection, through molecular mimicry, causes autoimmune antibodies against the basal ganglia leading to obsessive thoughts and compulsive habits. [3] However, the term PANDAS is falling out of favor in lieu of childhood acute neuropsychiatric symptoms (CANS), which allows the development of OCD in the pediatric population to be attributable to other sources than Strep, such as metabolites and toxins. [1]

Case series: increased vulnerability to obsessive-compulsive symptoms with repeated episodes of Sydenham chorea.

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.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.

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). 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. 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. 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.

Infection-triggered anorexia nervosa in children: clinical description of four cases.

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. 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. 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. There may be a link between infectious disease and some cases of AN, which raises the possibility of new treatment.

Basal ganglia disease

Tourette syndrome/obsessive–compulsive disorder Tourette syndrome is a disorder that is characterized by behavioral and motor tics, OCD and attention deficit hyperactivity disorder (ADHD). For this reason, it is commonly believed that pathologies involving limbic, associative and motor circuits of the basal ganglia are likely. Since the realization that syndromes such as Tourette syndrome and OCD are caused by dysfunction of the non-motor loops of basal ganglia circuits, new treatments for these disorders, based on treatments originally designed to treat movement disorders are being developed. Sydenham's chorea Sydenham's chorea is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. It is a result of an autoimmune response that occurs following infection by group A β-hemolytic streptococci (GABHS) that destroys cells in the corpus striatum of the basal ganglia. PANDAS

Streptococcal upper respiratory tract infections and psychosocial stress predict future tic and obsessive-compulsive symptom severity in children and adolescents with Tourette syndrome and obsessive-compulsive disorder.

One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity. Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity. Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity. Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

[Autoimmune neuropsychiatric disorders associated to infection by streptococcus in the paediatric age: PANDAS].

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. 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). We reviewed the medical records at the Instituto Neurológico 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. 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. The obtained are similar to those reported in the literature. Only 5.2% of the cases were linked to a prior streptococcus infection.