ACQUIRED AUTISM IN ADHD

Of late there has been some correspondence about the occurrence of co-morbid Autistic Spectrum Disorder (ASD), and Attention Deficit Hyperactivity Disorder (ADHD). After more than 40 years of treating these populations intensively, I can assert that there is a relationship between ASD and ADHD. In some cases, it is clearly a genetic overlap. However in many cases the "ASD" is acquired. This will be elucidated below.

There is the difference in the evaluation of a child with ASD and the later diagnosis of ADHD in contradistinction to the evaluation of a child with ADHD, and the findings of symptoms of ASD. If one looks one often finds. The ADHD symptoms may not be florid and may not meet the unhelpful criteria of DSM-V but the child with ASD has many signs, symptoms and characteristics of a child with ADHD.

A large number of children with ADHD manifest ASD-like symptoms, but do not really have an Autistic Spectrum Disorder. The additional diagnosis of ASD in these patients is harmful because it's incorrect.

Children with ADHD have a totally different set of brain operations than children without ADHD. They perceive, process, and express differently. The majority of these children are alienated from the popular group of children who coalesce together. What is happening here?

The popular crowd, which of course is a majority of individuals who see things the same way, cognate the same way and express the same way. Children with ADHD just think differently. They tend to have an extremely high speed nonlinear processor. They often blurt out answers before the teacher has completed, asking the question. They cannot explain how they do it. Simultaneously they have difficulty trying to think and learn and respond the way a teacher wants because it makes absolutely no sense to them. This can be observed in preschoolers (which, as a parent and grandparent I have had my share of experience with that population).

Often these children are derided, chastised and marginalized. They have absolutely no idea why this happens. They can be very smart little kids at five or six or seven but they are still very concrete, without insight and self-awareness. They feel defective and do not know why.  But by the middle of first grade, they are outsiders. This contributes mightily to low self-esteem, depression, and other psychosocial problems.

Ostrasizem from the crowd dramatically impacts the child's ability to socialize. Besides being teased and taunted and made fun of they are excluded in painful ways. They are not invited to events.  They are not picked for teams and clubs.  No one wants to partner up with them for projects.  Then someone diagnoses them with ASD, which is a useful excuse to many teachers and counselors. They appear to be autistic-ish or Asperger’s-ish.  They are not.

This is a sort of acquired anaclitic ASD. Children with ASD have difficulty picking up social cues and developing relationships. Children with ADHD who have been deprived of the opportunity to learn social skills, interpersonal interactions and the like appear to be ASD. Many of them will succeed nonetheless, but will have paid a  price along the way. Many others are permanently affected. They are socially awkward and uncomfortable.  They misread cues, or are not even aware of them. They expect to be ignored, teased or taunted. These are symptoms and characteristics of ASD but they are not biological.  They are acquired.

Beside the intrinsic issues identified above, the problem is magnified exponentially by the anti-ADHD people. There are a series of mistakes made. First is the failure to make the diagnosis, or to deny the diagnosis. Second is the refusal to treat. Third is maltreatment. The vast majority of patients that I have seen who have been diagnosed at some point in their lives and treated in someway have had suboptimal outcomes. If the patient and family are not educated thoroughly about ADHD; if proper, age-appropriate, cognitive, behavioral therapy is not applied; and if prudent psycho-pharmacotherapy is not initiated and monitored closely the results are not great.

Indeed there is an association between ASD and ADHD that has  a genetic/biological basis. Yet it is very important to diagnose correctly acquired "autism" in ADHD children and help them properly. Another label does not mean a better outcome.

A CONNECTION BETWEEN OCD & PANDAS/PANS

 New finding in the PANDAS/PANS spectrum.

This is a report of three interesting patients with post-infectious, Obsessive, Compulsive Disorder (OCD), anxiety, and depression. Curious diagnostic findings and a novel and new effective treatment implemented.

PANDAS/PANS is not a single distinct entity. Indeed, it is a post infectious neuropsychiatric syndrome with a myriad of presentations. There is not a single diagnostic test for every patient with symptoms and problems of a post infectious problem. This lack of a single entity with a single symptom cluster, and a single metabolic profile is a source of great annoyance to those in a profession who require absolutism and who abhor the need to stop and think about the complexities of this syndrome.

In the past three months, I and a colleague have encountered three cases of individuals with severe OCD  coupled with anxiety, panic, and various degrees of depression. Two of the individuals could recall that their symptoms occurred directly after a significant infection. One was severe colitis another a strep infection.  All had been treated with a panoply of SSRI’s and atypicals.  None had been treated with Anafranil or other tricyclics or a benzodiazepine.  Nor had they been evaluated for PANDAS.

At my direction all three patients had a comprehensive metabolic survey for evidence of acute or chronic infection, as well as the status of their immune systems. All three patients showed evidence of acute inflamation. In all three cases, the immunologic survey showed inconsistent results. In all three cases, there were significant abnormalities of the Pneumococcal. Subtypes, 23 valent. The precise significance of these markers have not been established. Nonetheless, each patient received a standard dose of Pneumovax 23.

Within 36 hours each patient, showed dramatic improvement. The patients were told ahead of time that the vaccine could affect their OCD and other symptoms. They were advised that there was a deficiency in their pneumonia antibodies and vaccination was advised. All accepted that.

Patients and family members were amazed that patient's circumstances had turned around. There was dramatic improvement in physical and emotional manifestations of their problems. Obsessions and compulsions diminished by greater than 90% in each case. Anxiety diminished similarly. The one patient with profound depression for several years suddenly was able to smile, laugh and enjoy life.

This data is important in many ways. It suggests that true medical/metabolic evaluation of psychiatric patients who have many different complaints is actually a proper baseline for care and treatment. It suggests that while there is no one thing that can be called PANDAS/PANS it is, nonetheless a reality.

Naysayers may say that this information is meaningless, not from a controlled study nor by sycophants from  various “experts” at centers of supposed self-proclaimed excellence. It is old-fashioned, clinical empiricism that happens when the doctors actually examine the patients, diagnose and treat them, without external rules about what they can and cannot think, say, or do.

This information is presented as it is, and without the  review of those who have no idea and/or no belief in what we write about.

                                                     Jory F Goodman, MD

Dr. Jory Goodman Featured in New York Times Magazine

Dr. Jory Goodman featured in The New York Times Magazine

Adult PANDAS: Bare Facts

[Below is a paper a prepared recently for a juried journal. They did not find it pertinent.  They had no idea what this is about and the implications for our health and welfare. I've included the bibliography for patients and parents to take to their, and their children's physicians.  Feel free to critique.  I'll make a comment about this at the end.]

It has been known for more than a century that post-infectious autoimmune physical and neuropsychiatric symptoms can occur. Most well-known are the post-streptococcal infectious autoimmune processes which include rheumatic fever, glomerulonephritis, Sydnenham's Chorea and St. Vitus dance. That the central nervous system is vulnerable to such processes has been acknowledged and understood. 

Over the past 15 years the phenomenon of Pediatric Autoimmune Neurologic and Psychiatric Disorders Associated with Strep, (PANDAS), has been identified around the world1,2. Despite naysayers and nonbelievers the evidence-based clinical data in conjunction with laboratory evidence establishes the existence of this disorder beyond any reasonable doubt.2,3 There remains great confusion as to precisely what neuropsychiatric and/or physical symptoms may be associated with PANDAS4,10; whether or not agents other than Streptococcus cause PANDAS5,6, and what potential laboratory findings may make or support this diagnosis7,8. This leads to further confusion and consternation with respect to diagnostic evaluation, and of greater importance, when, how and what to do to treat the protean manifestations of this disorder.

The question of PANDAS in adults largely has been ignored with uninformed, erroneous comments and statements that adults cannot acquire PANDAS. Hence, they cannot have it.. This paper will present evidence-based clinical research data to prove that adults can have or acquire PANDAS. A broad range of neuropsychiatric and physical symptoms will be described [see table I]. Many of these have been diagnosed as primary problems and treated ineffectively as such. Others have been misdiagnosed and mistreated.  Some simply have been missed [see table II].

A brief discussion of clinical and laboratory diagnostic tools will occur7,9. Comments on the viable treatment options available will be made, again from the perspective of the author's evidence-based clinical research.11,12

Certainly adults can acquire PANDAS. However this would require exposure to a novel infectious agent for that adult. Adult acquisition would, for all intents and purposes, be similar to native Americans and Polynesians falling victim to diseases brought by European explorers. Most commonly adults have had PANDAS for many years but either it has not been considered or it has been misdiagnosed and typically poorly treated as some other neuropsychiatric or physical complaint.

Diagnosis in adults is a logical extension of the diagnosis in children. Thus far the majority of the diagnoses in children are made after the phenomenon has been present for some time. In adults the phenomena have been present for years or decades. Indeed there are an increasing number of reports of acute onset PANDAS in children: Obsessive Compulsive Disorder (OCD); Tourette's and Tics are the most frequent. One familiar with PANDAS immediately considers this diagnosis with acute onset and needs to look for it in patients with other symptomatology [see table III]. In the author's practice innumerable children and adolescents previously diagnosed with Anorexia Nervosa (AN), various anxiety disorders, OCD, Tics and Tourette's, body dysmorphic disorder and quite commonly bipolar disorder (BPD) have been diagnosed with PANDAS, undergone effective treatment and their prior diagnoses disappear. This is of particular importance in BPD, OCD and AN.

The tantrums, outbursts, lability, aggressiveness, ready anger and other symptomatology that leads to the diagnosis of BPD and the treatment thereof in children and adolescents repeatedly has turned out to be PANDAS induced Tourette's, with or without generalized anxiety disorder (GAD) and/or panic disorder (PD). In most of these cases removal of tonsils and adenoids has “cured” the bipolar disorder.11. Patient's have been removed from potent mood stabilizers and atypical antipsychotics as well as [Table II] SSRIs.13  In most cases the patients have Attention Deficit Hyperactivity Disorder (ADHD), usually undiagnosed, which has contributed materially to the overall problems.14 This is an important point which will be elaborated upon further below.

Similarly in adolescent girls with AN,7,15 most of whom have been through months and years of eating disorder treatment, in facilities and hospitals, careful clinical and laboratory examination reveals their true diagnoses to be PANDAS. Most patients with AN have significant symptoms of anxiety and OCD. The OCD symptoms are ego dystonic (OCD is misdiagnosed frequently in patients with ADHD who use obsessive-compulsive mechanisms to bind anxiety–of course this leads to ineffective treatment for the “OCD”). There is an obvious element of body dysmorphic disorder in their preoccupations with weight and image. Again the diagnosis and treatment of the underlying PANDAS which has been driving this constellation of symptoms leads to dramatic resolution of the “eating disorder”, much to the consternation of the devoted eating disorder therapists. And yes, most of these patients have  concurrent ADHD.

This experience with dozens of children and adolescents led the author to examine adults with the same group of diagnoses. It is important to remark at this time that most of the children, adolescents and adults had never done particularly well with any therapeutic intervention for their purported diagnoses [Table II]. Nonetheless examination of adult patients with: OCD; BPD; AN; body dysmorphic disorder; fibromyalgia; and all of the other diagnoses noted in Table I led to the diagnosis of PANDAS. And again, as with the children and adolescents, the putative diagnoses dissolved with proper treatment. Treatment of underlying or concurrent diagnoses of depression, anxiety, ADHD, sleep disorders and so forth then became simple and effective. Elevated anti-DNAase B antibodies plummeted. A 64-year-old woman with a long history of depression, anxiety, poor sleep, fibromyalgia and Systemic lupus erythematosus (SLE) who also had obvious ADHD and periodic limb movement disorder (PLMD) experienced a complete disappearance of her fibromyalgia symptoms after tonsillectomy. Aches and pains went away. Energy improved. Sleep became restorative and attention and mood improved with proper treatment. Anti-DNAase B antibody levels dropped. Her ANA, elevated for many years dropped to a normal level.

This evidence-based clinical research has seen complete resolution of Tics, OCD, GAD/PD/ Tourette's misdiagnosed as BPD and other problems “cured” by the diagnosis and treatment of PANDAS. The outcomes are not perfect. It is obvious that individuals susceptible to PANDAS have a genetic predisposition.16,17,18,19 Very few people with strep throats develop rheumatic fever, glomerulonephritis or the spectrum of neuropsychiatric and physical symptoms driven by an autoimmune response to strep. Those that do develop PANDAS remain susceptible to flares after treatment. This means that exposure to the precipitating agent may cause a brief recurrence of symptomatology. Dependent upon individual circumstances--active infection, exposure without apparent infection and intensity of symptoms--these flares variously are treated with antibiotics and/or corticosteroids or ignored in the knowledge that the flareup will resolve once the antibodies have eliminated the infectious agent and that the source of chronic, subacute infection previously present in the tonsils and adenoids, or sinuses, intestines… has been eradicated. One patient treated from middle school to adulthood knows that she has had a strep exposure when she develops compulsive hand washing again. She knows that this will last about 2 weeks and then stop.

PANDAS is not a single entity. There is no doubt that multiple genetic loci will be identified eventually in individuals susceptible to PANDAS. The variations make different individuals vulnerable to different infectious agents and different symptom clusters. Clearly there is one subgroup that develops a chronic presentation. The author infers that these patients have a chronic viral trigger and/or a genetic subtype wherein the inflamed neurologic tissue continues to generate an autoimmune response regardless of the eradication of the primary infectious agent.20,21,22,23,24

Thus far multiple agents have been identified as precipitants of PANDAS [Table III]. No doubt many others will be determined in the future. Definitive genetic subtypes have not been identified. No specific test is diagnostic of PANDAS. An elevated anti-DNAase B with symptoms is sufficient but not necessary. Elevated mycoplasma, streptozyme, Lyme and many others are also sufficient but not necessary. The fascinating relationship with fibromyalgia and low-level SLE and rheumatoid arthritis (RA) deserves extensive study exploration.

Treatment approaches are controversial. If an antibiotic suppresses symptoms but the symptoms recur after cessation of the antibiotic then, clearly, there is an internal source of chronic subacute infection. Steroids in the acute phase usually exacerbate PANDAS. Plasmapheresis and IVIG are both effective in acute symptomatic relief of symptoms but neither appears definitive or permanent. This suggests either a source of chronic subacute infection, a chronic virus, or inflamed neurologic tissue sufficient to continue to generate an antibody response. 

Many practitioners approach this situation incrementally with long-term antibiotics (which can result in antibiotic allergy, resistant organisms, and pseudomembranous colitis), repeated IVIG (which is not “curative” but provides symptomatic relief for a variable period of time), and plasmapheresis which yields about the same results as the IVIG.

The author has found an aggressive approach most effective. Once the diagnosis is considered, appropriate chemistries and serology must be obtained. Whether or not the chemistries and serology  are  positive a thorough examination for potential sources of chronic subacute infection is warranted. Tonsils and adenoids, sinuses, mastoids, appendix, intestines and colon are all potential nidi. Thus far two patients have been seen with obstipation and multiple symptoms of PANDAS who have improved subsequent to antibiotic therapy for the colonic infection and resolution of the obstipation. One of these patients is a young man who presented with GAD, PD, OCD, ADHD, body dysmorphic disorder and depression who improved subsequent to tonsillectomy only to have a relapse related to a G.I. source which then resolved after effective treatment of that. He truly had PANDAS from top to bottom.

Given the panoply of infectious agents which can precipitate PANDAS there is no single, simple approach to this problem. The most important thing is to think of it, look for it, find it and then treat it.

Adults can get and have PANDAS. More often than not they've had it since childhood. What must the psychiatrist do about this? First and foremost the psychiatrist must not behave as have our peers of prior generations. That means that when anything psychiatric takes on a medical aspect–syphilis, sleep disorders, pain management, seizure disorders, traumatic brain injuries–they turn it over to the “real” doctors. The psychiatrist must go down the list of psychiatric diagnoses extant with specific disregard to the artificial boundaries and parameters of DSM as one begins to look at the specifics of the patient.

Based upon extensive clinical experience there is an obvious overlap between ADHD and PANDAS. And again adult ADHD is not characterized in DSM-IV TR and will be poorly characterized in DSM-V. The psychiatrist must begin to look at each and every diagnosis as potentially symptomatic of something else. Something like PANDAS. Will this be proven correct in a in every case? Of course not.   Will this be proven correct in a startling number of cases? Yes. If you do not think of it you do not look for it and if you do not look for it you do not find it. The author has diagnosed 18 cases of porphyria. Is it contemplated in every case? No. Are there indicators for which to look? Yes.

Psychiatrists must familiarize themselves with all of the available literature on PANDAS which at this time is relatively scant. Never accept anyone else's diagnosis. Think for yourself and peruse the list of symptoms and diagnoses appended to this article and begin to question yourself every time you hear or contemplate these diagnoses.  Question whether or not these may be symptoms of an underlying autoimmune disorder related to  PANDAS.  Learn what labs to order and what history to take with respect to sore throats and ear infections and the timeline for the evolution of various symptoms. The correct diagnosis of PANDAS is a definitive intervention and transformative experience for patients heretofore tormented, disabled, overmedicated and miserable.

It is precisely in circumstances such as these that evidence-based clinical medicine is the determinant of diagnostic accuracy and definitive therapeutic intervention. If each of you were to review your past and present caseload from this perspective the database and knowledge of and this would grow exponentially in less than a year.

Autoimmune phenomena are responsible for a staggering number of NeuroPsychiatric and Medical problems.  With this knowledge the diagnoses, prognoses and lives of hundreds of thousands of patients can be altered and improved in a very short time.

[We've been told that the above does not meet the editorial "needs" of the journal.  I could submit it elsewhere.  But the experience that I and many of my colleagues in private practice have had is that our submissions are rarely published. Without academic affiliations and large bibliographies of our own (having worked their way up from 5th to 4th to 3rd to 2nd to 1st author) we are not credible. Yet, I and dozens of my colleagues with whom I have conferred over decades have had the same experience, usually to see their ideas and research pop up in another journal under the authorship of one of the “jurors” of the journal to which the work was submitted. That is why so many of us self publish. My book, 1st edition copyright 1998 was heavily plagiarized. Hence many of us now post our work on the Internet and self publish on the Internet. Hopefully this article and the appended bibliography will help patients, families and physicians get effective treatment now, rather than having to wait until goombahs at Harvard or the NIH come forward in 2 or 3 years with their startling discovery of the above.]

Table 1.

Tics	9      number of patients seen
Tourette's	6                        “
Obsessive Compulsive Disorder	6                        “
Anorexia Nervosa	2                        “
Generalized Anxiety Disorder	16                      “
Panic Disorder	4                        “
Phobias	4                        “
Hyperekplexia	1                        “
Spastic Dysphonia	1                        “
Myoclonus	2                        “
Hypertonicity	1                        “
Attention Deficit Hyperactivity Disorder	21                      “
Body Dysmorphic Disorder	5                        “
Fibromyalgia	4                        “
Low level Systemic Lupus Erythematosus & Rheumatoid Arthritis associated with Fibromyalgia	3                        “
Periodic Limb Movement Disorder	20                      “
Severe Halitosis	3                        “
Strange Body Odor (perceived by patient & others)--Colonic etiology	2                        “
Bipolar Disorder	7                        “
Intermittent Explosive Disorder (Tourette's)	2                        “
Torsion Dystonia/Spastic Torticollis	2                        “

Table 2.

Acute infection or reinfection (the latter includes acute “flares” with re-exposure after effective treatment)

Puberty

Corticosteroids

Stimulants

Noradrenergic/dopaminergic antidepressants

Selective serotonin reuptake inhibitors either by acute akathisia or tachyphylaxis to dopamine blockade

Dopamine blocking agents: atypical antipsychotics, neuroleptics, anti-emetics via acute akathisia, tachyphylaxis to dopamine blockade and exacerbation of extrapyramidal symptoms and dystonia's

Development of antibiotic resistance

Table 3.

Streptococcus, multiple subtypes

Haemophilus influenza

Staphylococcus aureus

Pneumococcus

Mycoplasma pneumonia

Lyme disease

Viruses

1

PANDAS 

(Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcus) 

J Child Adolesc Psychopharmacol. 2011 Apr;21 (2):177-82. Epub 2011 Apr 12. 

Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings.

Lewin AB, Storch EA, Murphy TK. 

Rothman Center for Neuropsychiatry, Department of Pediatrics, University of South Florida College of Medicine, St. Petersburg, Florida 33701, USA. 

ABSTRACT: 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. 

PMID: 21486169 [pubMed - indexed for MEDLINEJ 

Int J Pediatr Otorhinolaryngol. 2011 Jun;7S(6):872-3. Epub 2011 Apr 3. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an indication for tonsillectomy. 

Alexander AA, Patel NJ, Southammakosane CA, Mortensen MM. 

University of Virginia, Department of Radiology, Charlottesville, VA 22908, USA. 

ABSTRACT: 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 followup 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. 

PMID: 21466900 [pubMed - indexed for MEDLINEJ 

Neurology. 2011 Jan 18;76(3):294-300. 

Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Cortese I, Chaudhry V, So Yl', Cantor F, Cornblath DR, Rae-Grant A. 

National Institutes of Health, Bethesda, USA. 

Comment in 

Neurology. 2011 Oct 2S;77(17):el0l; author reply el03-4. Neurology. 2011 Oct 25;77(17):e103; author reply el03-4. Neurology. 2011 Oct 2S;77(17):e10S; author reply elOS. Neurology. 2011 Oct 2S;77(17):el01; author reply e103-4. Neurology. 2011 Oct 2S;77(17):el04-S; author reply el0S. Neurology. 2011 Oct 25;77(17):e101-2; author reply el03-4. Neurology. 2011 Oct 2S;77(17):el02-3; author reply el03-4. 

2 

Neurology. 2011 Oct 25;77(17):el05-6; author reply el06. 

OBJECTIVE: To reassess the role of plasmapheresis in the treatment of neurologic disorders. METHODS: 

We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since 

the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified. RESULTS AND RECOMMENDATIONS: Plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barre syndrome (GBS) and in the short-term management of chronic inflammatory demyelinating polyneuropathy (Class I studies, Level A). Plasmapheresis is established as ineffective and should not be offered for chronic or secondary progressive multiple sclerosis (MS) (Oass I studies, Level A). Plasmapheresis is probably effective and should be considered for mild AIDP /GBS, as second-line treatment of steroid-resistant exacerbations in relapsing forms ofMS, and for neuropathy associated with immunoglobulin A or immunoglobulin G gammopathy, based on at least one Class I or 2 Class II studies (Level B). Plasmapheresis is probably not effective and should not be considered for neuropathy associated with immunoglobulin M gammopathy, based on one Class I study (Level B).Plasmapheresis is possibly effective and may be considered for acute fulminant demyelinating CNS disease (Level C). There is insufficient evidence to support or refute the use of plasmapheresis for myasthenia gravis, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection, and Svdenham 

chorea (Oass III evidence, Level U). 

PMCID: PMC3034395 

PMID: 21242498 [pubMed - indexed for MEDLINEJ 

JAm Acad Child Adolesc Psychiatry. 2011 Feb;50(2):108-118.e3. Epub 2010 Dec 31. 

Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. 

Leckman]F, I<1ng RA, Gilbert DL, Coffey B], Singer HS, Dure LS 4th, Grantz H, Katsovich L, Lin H, 

Lombroso PJ, Kawikova I,Johnson DR, Kurlan RM, Kaplan EL. 

Child Study Center and the Yale Center for Clinical Investigation, Yale University School of Medicine, 230 

South Frontage Road, New Haven, CT 06520-7900, 

OBJECTIVE: The objective of this blinded, prospective, longitudinal study was to determine whether new group A ~ hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (nonPANDAS) group. METHOD: Consecutive clinical ratings of tic and OC symptom severity were obtained 

for 31 PANDAS subjects and 53 non- PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS: No group differences were observed in the number, of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/ or OC symptoms. In every instance, this association occurred in the non- PANDAS group. CONCLUSIONS: This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic 

criteria. 

PMCID: PMC3024577 [Available on 2012/2/1] PMID: 21241948 [pubMed - indexed for MEDLINEJ 

J Neuroimmunol. 2010 Dec 15;229(1-2):243-7. Epub 2010 Sep 22. 

Maternal history of autoimmune disease in children presenting with tics and/or obsessive- 

compulsive disorder. 

Murphy TK, Storch EA, Turner A, Reid]M, Tan], Lewin AB. 

Department of Pediatrics, University of South Florida, College of Medicine, St. Petersburg, FL 33701, USA. 

3 

OBJECTIVES: A commonality across a number of pediatric neuropsychiatric disorders is a higher than typical rate of familial _ and especially maternal - autoimmune disease. Of recent interest, a subtype of obsessive-compulsive disorder (OCD) and tic disorders known collectively as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (pANDAS) is believed to be secondary to 

central nervous system (CNS) autoimmunity that occurs in relation to group A streptococcal infection. Thus, we hypothesized that a sample of children with OCD and/or tics would have an increased maternal risk for an autoimmune response relative to population norms. We also expected maternal prevalence of various autoimmune diseases to be higher among those participants that met the putative criteria for PANDAS. METHODS: We examined, via structured interview, the medical history of the biological mothers of 107 children with OCD and/or tics. RESULTS: Autoimmune disorders were reported in 17.8% of study mothers, which is significantly greater than the general prevalence among women in the United States (approximately 5%). Further, study mothers were more likely to report having an autoimmune disease if their children were considered "likely PANDAS" cases versus "unlikely PANDAS" cases. CONCLUSIONS: The results offer preliminary support for hypothesized links between maternal autoimmune disease and both OCD / tics and PANDAS in youth. Further research is necessary to clarify these general associations; links to specific autoimmune disease; and relevance of autoimmune disease in other family members (e.g., fathers). 

PMCID: PMC2991439 

PMID: 20864184 [pubMed - indexed for MEDLINEJ 

J Child Adolesc Psychopharmacol. 2010 Aug;20(4):317-31. 

The immunobiology of Tourette's disorder. pediatric autoimmune neuropsychiatric disorders 

associated with Streptococcus. and related disorders: a way forward. 

Murphy TK, Kurlan R, Leckman J. 

Department of Pediatrics and Psychiatry, University of South Florida, St Petersburg, Florida 33701, USA. 

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 desctibed 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 ofTD, OCD, and 

PANDAS. 

PMID: 20807070 [PubMed - indexed for MEDLINEJ 

Autism Res. 2010 Aug;3(4):147-52. 

Role for antibodies in altering behavior and movement. 

Libbey JE, Fujinami RS. 

Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA. 

At the past meeting of INSAR, the role of autoimmunity was discussed in an educational session. This article summarizes this discussion. In immune-mediated diseases, antibodies can contribute to the pathogenesis of the disease and are sometimes the force that drives the disease process. This concept has not been established for autism. In autoimmune diseases, such as systemic lupus erythematosus (SLE), antibodies are found to react with double-stranded DNA. These antibodies also cross-react with N-methyl-D aspartate receptors. Many SLE patients suffer neurologic syndromes of the central nervous system (CNS). Similarly individuals 

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infected with Group A streptococcus (GAS) have antibodies against the GAS carbohydrate, which cross-react with tubulin and lysoganglioside GMl on neurons. During the acute stage of infection, GAS-infected patients develop Syndenham chorea where the disease process is driven in part by these cross-reactive antibodies. As the antibody levels decrease, the clinical features of Syndenham chorea resolve. In these two immunemediated diseases, antibodies clearly playa role in the pathogenesis of the diseases. There are reports that mothers of individuals with autism have antibodies that react with brain proteins and when these antibodies are passively transferred to pregnant non-human primates or rodents the offspring has behavioral and nervous system changes. It is still not clear whether the antibodies found in mothers of individuals with autism actually playa role in the disease. More studies need to be performed to identify the proteins recognized by the antibodies and to determine how these could affect development, behavior and changes within the CNS. 

PMID: 20589715 [pubMed - indexed for MEDLINEJ 

TurkJ Pediatr. 2009 Jul-Aug;51 (4):317-24. 

The relationship between group A beta hemolytic streptococcal infection and psychiatric symptoms: a pilot study. 

Cengel-Kiiltiir SE, Cop E, Kara A, Cengiz AB, Uludag AI<, Unal F. 

Department of Child and Adolescent Psychiatry, Hacettepe Universjty Faculty of Medicine, Ankara, Turkey. The aim of this study was to test if children with group A beta hemolytic streptococcal infection (GABHS) are more likely to develop neuropsychiatric symptoms or the syndrome of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) compared to children with GABHS-negative throat cultures. Children aged 8 to 12 years (n = 81) with upper respiratory tract infection were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version, Children's Yale Brown Obsession Compulsion Scale, Yale Global Tic 

Severity Scale, Child Behavior Checklist for Ages 4-18, Conners Parent Rating Scale, and State-Trait Anxiety Inventory for Children at baseline and six weeks later. One case of PANDAS was diagnosed and no other differences were observed between groups and time points. It was suggested that GABHS infection may be a triggering factor for PANDAS in some genetically prone individuals. 

PMID: 19950837 [pubMed - indexed for MEDLINE] 

I Psychosom Res. 2009 Dec;67(6):547-57. 

The PANDAS subgroup oftic disorders and childhood-onset obsessive-compulsive disorder. Martino D, Defazio G, Giovannoni G. 

Department of Neurological and Psychiatric Sciences, University of Bari, Italy. 

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 obsessivecompulsive 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. 

PMID: 19913659 [pubMed - indexed for MEDUNE] 

Mol Psychiatry. 2010 Jul;15(7):712-26. Epub 2009 Aug 11. 

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda], Baghban A, Villar G, Lipkin WI. 

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Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. 

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/ memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgGl subclass but are not attributable to differences in cytokine profiles. The mode of distupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders. 

PMID: 19668249 [pubMed - indexed for MEDLIN E) 

Curr Opin Pediatr. 2009 Feb;21 (1):127-30. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update. 

Shulman ST. 

The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. 

PURPOSE OF REVIEW: To review recent developments related to the proposed entity Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci (so-called 'PANDAS'). RECENT FINDINGS: The relationship between obsessive-compulsive disorder (OCD) or tics/Tourette's syndrome in childhood to antecedent group A streptococci (GAS) is unclear. One recent prospective cohort study found that more than 85% of clinical exacerbations in OCD / tic behavior in patients who met criteria for PANDAS had no relationship to GAS infection. Another study found no correlation between clinical exacerbations and changes in a variety of markers of brain autoimmunity, the proposed pathogenesis of PANDAS. A third recent study concluded that, compared with specialty clinic diagnoses, patients diagnosed with tics or Tourette's by physicians in the community were significantly more likely to be diagnosed with PANDAS without meeting the proposed criteria, most lacked supporting laboratory evidence of GAS infection, and they were more likely to be treated with unjustified short-term to chronic antibiotic and/ or immunomodulatory therapy. SUMMARY: Despite continued research in the field, the relationship between GAS and specific neuropsychiatric disorders (pANDAS) remains elusive. It is possible that GAS infection may be but one of the many stressors that can exacerbate tic/Tourette's or OCD in a subset of such patients. 

PMID: 19242249 [pubMed - indexed for MEDLINE] 

Pediatrics. 2009 Jan;123(1):e171; author reply e171-3. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus. 

Scolnick B. 

Comment on: Pediatrics. 2008 Aug;122(2):273-8. PMID: 19117840 [pubMed - indexed for MEDLINE] 

Pediatrics. 2008 Aug;122(2):273-8. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of 

diagnosis and treatment in the community and at a specialty clinic. 

Gabbay V, Coffey BJ, Babb JS, Meyer L, Wachtel C, Anam S, Rabinovitz B. 

Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. 

Comment in: Pediatrics. 2009 Jan;123(1):e171; author reply e171-3. 

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OBJECTIVES: This study aimed to examine whether pediatric autoimmune neuropsychiatric disorders associated with streptococcus were appropriately diagnosed in the community and to determine subsequent rates of unwarranted use of antibiotic treatment for tics and obsessive-compulsive symptoms without the identification of an infection. METHODS: The design was a retrospective, cross-sectional, observational study of 176 children and adolescents who were evaluated in a specialty program for tics, Tourette's disorder, and related problems. Previously published diagnostic criteria were used to establish the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus in our clinic. RESULTS: 

Subjects were significantly less likely to receive a diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus at the specialty clinic than in the community. In the community, subjects were significantly more likely to be treated with antibiotics or immunosuppressant medication if they received a diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus. Of the 27 subjects with a community diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus who were treated with antibiotics, 22 (82%) were treated without laboratory evidence of an infection; 2 were treated with immunomodulatory medications. CONCLUSIONS: Our results support our hypothesis that pediatric autoimmune neuropsychiatric disorders associated with streptococcus are frequently diagnosed in the community without the application of all working diagnostic criteria. This phenomenon has resulted in unwarranted use of antibiotic treatment for tics/ obsessive-compulsive disorder without evidence 

of laboratory infection. 

PMCID: PMC2770722 

PMID: 18676543 [pubMed - indexed for MEDLINE] 

Pediatrics. 2008 Jun;121(6):1188-97. 

Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a 

prospective blinded cohort study. 

Kurlan R,Johnson D, Kaplan EL; and the Tourette Syndrome Study Group. 

University of Rochester School of Medicine, Mt Hope Professional Building, 1351 Mt Hope Ave, Suite 100, Rochester, NY 14620, USA. roger_kurlan@urmc.rochester.edu 

Comment in: Pediatrics. 2008 Nov;122(5):1157; author reply 1157-8. 

OBJECTIVE: 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). PATIENTS AND METHODS: Subjects included 40 matched pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections casecontrol 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. RESULTS: 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. CONCLUSIONS: 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 betahemolytic 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 obsessivecompulsive disorder patients based on specific symptom precipitants. 

PMID: 18519489 [pubMed - indexed for MEDLINE] 

J Trop Pediatr. 2009 Feb;55(1):46-8. Epub 2008 May 22. 

Challenges in the identification and treatment of PANDAS: a case series. Mabrouk AA, Eapen V. 

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Department of Pediatrics, School Health Services, Al AID. 

Paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), is characterized by childhood-onset obsessive-compulsive disorder (OCD) and Tic disorder that has been found to have a post infectious autoimmune-mediated etiology, where the onset and subsequent exacerbations of symptoms is temporally related to group A beta-hemolytic streptococci (GABHS) infection. In addition to the use of anti-tic and antiobsessional agents, the use of Penicillin during the acute phase and for prophylaxis, tonsillectomy, immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin, etc. have all been reported to improve the symptoms. We describe five cases of neuropsychiatric symptoms triggered by streptococcal infection in an Arab population and highlight the challenges faced by clinicians in the identification and management of PANDAS. 

PMID: 18499734 [pubMed - indexed for MEDLINEJ 

Cardiac involvement in children with PANDAS. [References]. Segarra, Ana R; Murphy, Tanya K. 

Journal of the American Academy of Child & Adolescent Psychiatry. Vo1.47(5), May 2008, pp. 603-604. IT ournal; Peer Reviewed Journal) 

The clinical characteristics that define the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus) subgroup are the presence of obsessive-compulsive disorder (OeD) and! or tic disorder, prepubertal age at onset, abrupt onset, relapsing-remitting symptom course, association with neurological abnormalities during exacerbations and temporal association between symptom exacerbation and a GAS infection. We report here on 10 cases that we comprehensively evaluated as part of a prospective 

study examining the relationship of GAS to OCD and/or tic symptoms, in which color Doppler 

echo cardiography evaluation was completed in children meeting the PANDAS phenotype. Nine of the 10 children had one or more streptococcal titers that were elevated, and four of the 10 were in a neuropsychiatric exacerbation, and the rest were remitting or remitted. This correlation suggests an acquired or developmental, rather than a congenital, cause of valvular incompetence. The cardiac risk in this series of children with OCD and tics appears to be low and similar to that of the general population. (psycINFO Database Record (c) 

2010 APA, all rights reserved) 

Institution 

Segarra, Ana R.: Department of Psychiatry, University of Florida, FL, US Murphy, Tanya K.: Department of Psychiatry, University of Florida, FL, US 

What every psychiatrist should know about PANDAS: A review. [References]. 

Moretti, Germana; Pasquini, Massimo; Mandarelli, Gabriele; Tarsitani, Lorenzo; Biondi, Massimo. Clinical Practice and Epidemiology in Mental Health. Vol.4 May 2008, ArtID 13. 

[journal; Peer Reviewed Journal] 

The term Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS) was coined by Swedo et al. in 1998 to describe a subset of childhood obsessive-compulsive disorders (OCD) and tic disorders triggered by group-A beta-hemolytic Streptococcus pyogenes infection. Like adult OCD, PANDAS is associated with basal ganglia dysfunction. Other putative pathogenetic mechanisms of PANDAS include molecular mimicry and autoimmune-mediated altered neuronal signaling, involving calcium-calmodulin dependent protein (Ca.M) kinase II activity. Nonetheless the contrasting results from numerous studies provide no consensus on whether PANDAS should be considered as a specific nosological entity or simply a useful research framework. Herein we discuss available data that could provide insight into pathophysiology of adult OCD, or might explain cases of treatment-resistance. We also review the latest research findings on diagnostic and treatment. (psycINFO Database Record (c) 2010 APA, all rights reserved) (journal abstract) 

Institution: Department of Psychiatric Sciences and Psychological Medicine, "Sapienza" University of Rome, Rome, Italy 

PANDAS and paroxysms: A case of conversion disorder? [References]. Kuluva, Joshua; Hirsch, Scott; Coffey, Barbara. 

Journal of Child and Adolescent Psychopharmacology. Vol.18(1), Mar 2008, pp. 109-115. [journal; Peer Reviewed Journal] 

Presents a case study of a 16-year-old adolescent Caucasian boy,]. initially referred for consultation regarding Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). For 

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approximately nine months prior to presentation, J. had been experiencing frequent motor and vocal tics punctuated by episodes of violent behavior. These events became so distressful to the patient, his family, and his surroundings that he was forced to leave school and all of his other social activities. Many of J's paroxysmal events were of a violent nature with aggression directed towards other people. Not only does this suggest that these events were neither tics nor seizures, but it also suggests that J. has some difficulty with the modulation of aggression. In addition, given the acute onset of his symptoms and decline in adaptive functioning, one might question whether there had been some trauma that had precipitated the illness. 

Finally, from a developmental perspective, the timing ofJ's symptom onset cannot be ignored. As it appeared that he was on a trajectory to become a successful athlete and student, the onset of his symptoms put obstacles in his path of continuing with his accomplishments. One may question if, with all of his success, J was on some level quite anxious about responsibility that would come with his advancement in life. Institution: NYU Child Study Center, New York, NY, US Hirsch, Scott: NYU Child Study Center, New 

York, NY, US 

CNS Spectr. 2007 May;12(5):359-64, 367-375. Obsessive-compulsive disorder: boundary issues. Fineberg NA, Saxena S, Zohar J, Craig KJ. 

Postgraduate School of Medicine, University of Hertfordsrure, Gueen Elizabeth II Hospital, Welwyn Garden 

City, UK. kim.fox@hpt.nhs.uk 

The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain 

unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area. PMID: 17514081 [PubMed - indexed for MEDLIN E) 

BioI Psychiatry. 2007 Feb 1;61(3):279-84. Epub 2006 Nov 27. 

Relationship of movements and behaviors to Group A Streptococcus infections in elementary school 

children.

Murphy TK, Snider LA, Mutch PJ, Harden E, Zaytoun A, Edge PJ, Storch EA, Yang MC, Mann G, 

Goodman WK, Swedo SE. 

Department of Psychiatry, College of Medicine, Gainesville, Florida 32610, USA. 

BACKGROUND: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) research is based on the hypothesis that infections trigger changes in behavior and movement in children. METHODS: We enrolled 693 children (ages 3 to 12 years) into a systematic, longitudinal study. Data were collected monthly for 8 months (October-May) to determine point prevalence of Group A Streptococcal (GAS) infections, tics, behavior, and choreiform movements. Simultaneous throat cultures were obtained, and relational analyses were made between GAS and movement/observation ratings. RESULTS: 

Combined behavior/GAS associations (concurrent with or 3 subsequent months to GAS) revealed a strong relationship, relative risk (RR) of 1. 71 (p < .0001). Detailed analysis revealed that balance/ swaying and nontic grimacing were responsible for a significant proportion of this association (RR = 2.92, P < .0001). A strong seasonal pattern was found, with fall being more significant for GAS infections and observation ratings (p < .0001) compared with winter/spring. Children with repeated streptococcus (n = 64) showed higher rates of behavior and distal choreiform observations (p = .005). CONCLUSIONS: Motor/behavior changes were noted to occur in relationship to positive GAS culture with support that repeated GAS 

increases risk. 

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PMID: 17126304 [pubMed - indexed for MEDLINE] 

Tics. anxiety. and possible PANDAS in an adolescent. [References]. Coffey, Barbara; Wieland, Natalie. 

Journal of Child and Adolescent Psychopharmacology. Vol.17(4), Aug 2007, pp. 533-538. 

[J ournal; Peer Reviewed Journal) 

Presents a case of J, a 16-year-old boy with tics and anxiety symptoms referred by his pediatrician for 

consultation regarding the diagnosis of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (pANDAS). There is no history of hyperactivity or impulsivity in early childhood or currently. J. has always done all of his schoolwork and gets it in on time, including up to the present. However, there have been some problems with attentional functioning in the past, starting in middle school, about which his teachers have apparently been concerned. J. reports that it is difficult for him to concentrate at times now, although he relates this mostly to his tics. J. was evaluated by a child and adolescent psychiatrist 2 months ago. J. has had longstanding treatment with a child psychologist for approximately 5 years. J. describes primarily a supportive psychotherapy, although the mother reports that cognitive behavioral techniques are also used. Given J.'s multiple anxiety, mood, and tic symptoms, he would be a good candidate for more formal cognitive behavioral techniques, including exposure and response prevention, for his anxiety. In 

addition, strong efforts should be made to help J. return to high school. 

JAm Acad Child Adolesc Psychiatry. 2006 Oct;45(10):1171-8. 

Cognitive-behavioral therapy for PANDAS-related obsessive-compulsive disorder: findings from a 

preliminary waitlist controlled open trial. 

Storch EA, Murphy TK, Geffken GR, Mann G, Adkins J, Merlo LJ, Duke D, Munson M, Swaine Z, 

Goodman WK .. 

Department of Psychiatry, University of Florida, Gainesville, FL 32610, USA. 

OBJECTIVE: To provide preliminary estimates of the effectiveness of cognitive-behavioral therapy (CBT) in treating pediatric obsessive-compulsive disorder (OCD) of the pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) subtype. METHOD: Seven children with OCD of the PANDAS subtype (range 9-13 years) were treated in a 3-week intensive CBT program conducted at a university clinic. Six of seven children were taking selective serotonin reuptake inhibitor medication(s) upon presentation. Assessments were conducted at four time points: baseline, pretreatment approximately 4 weeks later, posttreatment, and 3-month follow-up. Raters were blind to the nature of the study treatment. RESULTS: Six of seven participants were classified as treatment responders (much or very much improved) at posttreatment, and three of six remained responders at follow-up. Clinician severity ratings, as measured by the Children's Yale-Brown Obsessive-Compulsive Scale and Anxiety Disorder Interview Schedule for DSMIV Child Interview Schedule-Parent version, decreased significantly following intervention, with effect sizes of 3.38 and 2.29, respectively. Self-reported general anxiety and depression symptoms were not significantly reduced. CONCLUSIONS: This study provides preliminary support for CBT in treating the PANDAS subtype of pediatric OCD. This approach is also considered a safe and minimally invasive treatment 

approach. 

PMID: 17003662 [pubMed - indexed for MEDLINEJ 

J Child Neurol. 2006 Sep;21(9):727-36. 

Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, 

PANDAS, and PANDAS variants. 

Pavone P, Parano E, Rizzo R, Trifiletti RR. 

Department of Pediatrics, Division of Clinical Pediatrics, University of Catania, Viale Andrea Doria 6, 95125 

Catania, Italy. ppavone@mbox.unict.it 

Streptococcal infection in children is usually benign and self-limited. In a small percentage of children, 

prominent neurologic and/ or psychiatric sequelae can occur. Sydenham chorea is the best defined and best recognized. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a well-defIned syndrome in which tics (motor and! or vocal) and! or obsessive-compulsive disorder consistently exacerbate in temporal correlation to a group A beta-hemolytic streptococcal infection. PANDAS constitutes a subset of children with tics, Tourette syndrome, and obsessive-compulsive disorder. In addition to strictly defined PANDAS, we and others have recognized several PANDAS variants, including adult-onset variant, a dystonic variant, a myoclonic variant, and a "chronic" PANDAS variant. The nosology and classification of these entities are rapidly evolving. The recognition that some pediatric neurobehavioral 

10 

syndromes have infectious and/or immunologic triggers points to important new avenues of disease treatment. In this review, we summarize this complex and rapidly evolving area of clinical research. PMID: 16970875 [pubMed - indexed for MEDLINEJ 

Selective Serotonin Reuptake Inhibitor-Induced Behavioral Activation in the PANDAS Subtype. [References) . 

Murphy, Tanya K; Storch, Eric A; Strawser, Melissa S. Primary Psychiatry. Vol.13(8), Aug 2006, pp. 87-89. Journal; Peer Reviewed Journal) 

Although selective serotonin reuptake inhibitors (SSRI) are an effective and commonly used treatment for pediatric obsessive-compulsive disorder (OCD), their use has come under close scrutiny following reports of adverse reactions. The authors of this case report believe that children with the OCD subtype, pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), may have increased vulnerability. The following report provides initial data on behavioral activation following SSRI use in 38 children with OCD of the PANDAS subtype. The authors use a particular case to highlight this issue and discuss treatment implications. 

Institution: Department of Psychiatry, University of Florida, Gainesville, FL, US 

Pediatrics. 2005 Jul;116(1);56-60. 

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

Mell LK, Davis RL, Owens D. 

Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA. 

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These findings lend epidemiologic evidence that PANDAS may arise as a result of a postinfectious autoimmune phenomenon induced by childhood streptococcal infection. 

PMID: 15995031 [pubMed - indexed for MEDLINE] 

Am Fam Physician. 2005 May 15;71(10):1949-54. Evaluation of poststreptococcal illness. 

Hahn RG, Knox LM, Forman TA. 

Department of Family Medicine, University of Southern California, Los Angeles, California, USA. 

Group A beta-hemolytic streptococcal pharyngitis, scarlet fever, and rarely asymptomatic carrier states are associated with a number of poststreptococcal suppurative and non suppurative complications. As in streptococcal pharyngitis,acute rheumatic fever, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and poststreptococcal glomerulonephritis most often occur in children. The hallmarks of rheumatic fever include arthritis, carditis, cutaneous disease, chorea, and subsequent acquired valvular disease. Pediatric autoimmune neuropsychiatric disorders encompass a subgroup of illnesses involving the basal ganglia in children with obsessive-compulsive disorders, tic disorders, dystonia, chorea encephalitis, and dystonic choreoathetosis. Poststreptococcal glomerulonephritis is most frequently encountered in children between two and six years of age with a recent history of pharyngitis and a rash in the setting of poor personal hygiene during the winter months. The clinical examination of a patient with possible 

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poststreptococcal complications should begin with an evaluation for signs of inflammation (i.e., complete blood count, erythrocyte sedimentation rate, C-reactive protein) and evidence of a preceding streptococcal infection. Antistreptolysin 0 titers should be obtained to confirm a recent invasive streptococcal infection. Other important antibody markers include antihyaluronidase, antideoxyribonuclease B, and antistreptokinase 

antibodies. 

PMID: 15926411 [pubMed - indexed for MEDLIN E) 

J Child Psychol Psychiatry. 2005 Mar;46(3):227-34. 

Annotation: PANDAS: a model for human autoimmune disease. Swedo SE, Grant PJ. 

National Institute of Mental Health, Bethesda, Maryland 20892-1255, USA. 

BACKGROUND: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS) is a recently recognized syndrome in which pre-adolescent children have abrupt onsets of tics and/or obsessive-compulsive symptoms, a recurring and remitting course of illness temporally related to streptococcal infections, and associated neurologic findings including adventitious movements, hyperactivity and emotional lability. METHODS: Inspired by observations of similar symptoms in children with Sydenham's chorea, a search was undertaken for clinical and laboratory evidence in support 

of the new syndrome. RESULTS: Consistent and predictable clinical findings have been described in a large case series. Magnetic resonance imaging has supported the postulated pathobiology of the syndrome with evidence of inflammatory changes in basal ganglia. Antibasal ganglia antibodies have been found in some acute cases, mimicking streptococcal antigen epitopes. CONCLUSIONS: While PANDAS remains a controversial diagnostic concept, it has stimulated new research endeavors into the possible links between bacterial pathogens, autoimmune reactions, and neuropsychiatric symptoms. 

PMID: 15755299 [pubMed - indexed for MEDLIN E) 

J Neuropsychiatry Clin Neurosci. 2004 Summer;16(3):252-60. 

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

disorder.

Kim SW, GrantJE, Kim SI, Swanson TA, Bernstein GA,Jaszcz WE, Williams KA, Schlievert PM. Department of Psychiatry, University of Minnesota Medical School, Minneapolis, Minnesota, USA. 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. 

PMID: 15377732 [pubMed - indexed for MEDLINE] 

Mol Psychiatry. 2004 Oct;9(10):900-7. 

PANDAS: current status and directions for research. Snider LA, Swedo SE. 

Pediatrics & Developmental Neuropsychiatry Branch, Department of Health and Human Services, National 

Institute of Mental Health, Bethesda, MD 20892, USA. 

The recognition of the five ctiteria 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 (OeD) 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 

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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. 

PMID: 15241433 [pubMed - indexed for MEDLINEJ 

J Child Neurol. 2004 May;19(5):387-90. 

Functional brain imaging in Sydenham's chorea and streptococcal tic disorders. Citak EC, Cucuyener K, Karabacak NI, Serdaroglu A, Okuyaz C, Aydin K. Department of Pediatric Neurology, Gazi University Medical Faculty, Ankara, Turkey. Comment in: J Child Neurol. 2006 Jun;21 (6):544-5. 

Group A streptococcal infections cause a wide range of neuropsychiatric disorders, such as Sydenham's chorea, tics, obsessive-compulsive disorders, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography, single-photon emission computed tomography) imaging studies in patients with Sydenham's chorea have suggested reversible striatal abnormalities. The objective of this study was to investigate the cerebral perfusion patterns of the subcortical structures by using hexamethylpropylenamine oxime single-photon emission computed tomography (HMP AO-SPEC1j in seven cases of Sydenham's chorea and two cases of streptococcal tic disorder. HMP AO-SPECT studies revealed a hyperperfusion pattern in two and a hypoperfusion pattern in five of the chorea patients and in two patients with tic disorder. The results are discussed in relation to the duration and severity of the symptoms and the response to therapy. Functional imaging findings can be variable in Sydenham's chorea, and hyperperfusion of the striatum and thalamus could be an indicator of the response to therapy and the severity of symptoms. However, the number of cases so far investigated by either SPECT or positron emission tomography is still too limited to draw any firm conclusions. 

PMID: 15224712 [pubMed - indexed for MEDLIN E) 

Pediatrics. 2004 Apr;113(4):907-11. 

The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. 

Swedo SE, Leonard HL, Rapoport JL. 

Pediatrics and Developmental Neuropsychiatry Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892, USA. swedos@mail.nih.gov 

Comment on: Pediatrics. 2004 Apr;113(4):883-6. 

PMID: 15060242 [pubMed - indexed for MEDLINEJ 

Pediatrics. 2004 Apr;113(4):883-6. 

The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? Practical considerations for the clinician. 

Kurlan R, Kaplan EL. 

Cognitive and Behavioral Neurology Unit, Department of Neurology, University of Rochester School of Medicine, Rochester, New York 14642-8673, USA. roger_kurlan@urmc.rochester.edu 

Comment in: Pediatrics. 2004 Apr;113(4):907-11. 

Clinicians have been faced with much publicity and contradictory scientific evidence regarding a recently described condition termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). It has been proposed that children with PANDAS experience tics, obsessivecompulsive behavior, and perhaps other neuropsychiatric symptoms as an autoimmune response to streptococcal infection. We review current scientific information and conclude that PANDAS remains a yetunproven hypothesis. Until more definitive scientific proof is forthcoming, there seems to be insufficient evidence to support 1) routine microbiologic or serologic testing for group A streptococcus in children 

.. 

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who present with neuropsychiatric symptoms or 2) the clinical use of antibiotic or immune-modifying therapies in such patients. The optimum diagnostic and therapeutic approach awaits the results of additional research studies. 

PMID: 15060240 [pubMed - indexed for MEDLINEJ 

Pediatr Neurol. 2004 Feb;30(2):1 07-10. 

Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pavone P, Bianchini R, Parano E, Incorpora G, Rizzo R, Mazzone L, Trifiletti RR. Division of Pediatric Neurology, University of Catania, Catania, Italy. 

The objective of this study was to assess brain involvement through the presence of antineuronal antibodies in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and in uncomplicated active Group A streptococcal infection. We compared serum anti brain antibody to human basal ganglia sections assessed by indirect tissue immunofluorescence in two groups: a PANDAS group, comprised of 22 patients (mean age 10.1 years; 20 male, 2 female) who met strict National Institutes of Mental Health diagnostic criteria for PANDAS and had clinically active tics or obsessive-compulsive disorder, or both; and a GABHS control group consisting of 22 patients (mean age 9.1 years; 15 mol/L, 7 female) with clinical evidence of active Group A beta-hemolytic streptococcal (GABHS) infection confirmed by throat culture and elevated antistreptolysin 0 titers but without history or clinical evidence of tics or obsessivecompulsive disorder. We observed positive anti-basal ganglia staining (defined as detectable staining at 1:10 serum dilution) in 14/22 patients in the PANDAS group (64%) but only 2/22 (9%) in the GABBS control group (P < 0.001, Fisher's exact test). These results suggest that antibrain antibodies are present in children with PANDAS that cannot be explained merely by a history of GABBS infection. 

PMID: 14984902 [pubMed - indexed for MEDLINE] 

BioI Psychiatry. 2004 Jan 1;55(1):61-8. 

Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. 

Murphy TK, Sajid M, Soto 0, Shapira N, Edge P, Yang M, Lewis MH, Goodman WK Department of Psychiatry, University of Florida, Gainesville, Florida 32610-0256, USA. 

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 0, 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). Comovements 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. 

PMID: 14706426 [pubMed - indexed for MEDLIN E) 

J Child Adolesc Psychopharmacol. 2003 Fall;13(3):209-12. 

Obsessive-Compulsive disorder. Tourette's disorder. or pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in an adolescent? Diagnostic and therapeutic challenges. Gabbay V, Coffey B. 

New York University Child Study Center, New York University School of Medicine, New York, New York PMID: 14642008 [pubMed - indexed for MEDLIN E) 

Int J Pediatr Otorhinolaryngol. 2003 Aug;67(8):837-40. 14 

PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections--an uncommon. but important indication for tonsillectomy. 

Heubi C, Shott SR. 

Department of Pediatric Otolaryngology, Cincinnati Children's Hospital Medical Center, 3333 Burnet 

Avenue, Cincinnati, OH 45229, USA. 

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. 

PMID: 12880661 [pubMed - indexed for MEDLIN E) 

Curr Opin Neurol. 2003 Jun;16(3):359-65. 

Post-streptococcal autoimmune disorders of the central nervous system. 

Snider LA, Swede SE. 

Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA. 

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. 

PMID: 12858074 [pubMed - indexed for MEDLINE] 

AmJ Psychiatry. 2002 Aug;159(8):1430-2. 

D8/}7 expression on B lymphocytes in anorexia nervosa. 

Sokol MS, Ward PE, Tamiya H, Kondo DG, Houston D, Zabriskie JB. 

Creighton University School of Medicine and Children's Hospital, Omaha, NE 68114, Comment in: Am J Psychiatry. 2003 Jun;160(6):1193-4; author reply 1194. 

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%). 

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CONCLUSIONS: A larger study is needed to determine whether D8/17 serves as a marker for susceptibility to a type of anorexia nervosa. 

PMID: 12153841 [PubMed - indexed for MEDLINEJ 

Mol Psychiatry. 2002;7 Suppl2:S24-5. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections 

(PANDAS).

Swedo SE. 

Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, Bethesda, MD 

PMID: 12142939 [pubMed - indexed for MEDLINE] 

Ann Neurol. 2001 Nov;50(5):588-95. 

Posrstreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto- 

reactive antibasal ganglia antibodies. 

Dale RC, Church AJ, Cardoso F, Goddard E, Cox TC, Chong WI(, Williams A, Klein NJ, Neville BG, 

Thompson EJ, Giovannoni G. 

Department of Neurology, Great Ormond Street Hospital National Health Service Trust and Institute of 

Child Health, University of London, UK 

Antibasal ganglia antibodies (ABGA) are associated with Sydenham's chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. We present 10 patients with acute disseminated encephalomyelitis (ADEM) associated with Group A beta hemolytic streptococcal infection. The clinical phenotype was novel, with 50% having a dystonic extrapyramidal movement disorder, and 70% a behavioral syndrome. None of the patients had rheumatic fever or Sydenham's chorea. Enzyme-linked imrnunosorbent assay, Western immunoblotting, and immunohistochemistry were used to detect ABGA. Neurological (n = 40) and streptococcal (n = 40) controls were used for comparison. Enzyme-linked immunosorbent assay results showed significandy elevated ABGA in the patients with poststreptococcal ADEM. Western immunoblotting demonstrated ABGA reactivity to three dominant protein bands of 60,67, or 80 kDa; a finding not reproduced in controls. Fluorescent immunohistochemistry demonstrated specific binding to large striatal neurones, which was not seen in controls. Streptococcal serology was also 

significandy elevated in the poststreptococcal ADEM group compared with neurological controls. Magnetic resonance imaging studies showed hyperintense basal ganglia in 80% of patients with poststreptococcal ADEM, compared to 18% of patients with nonstreptococcal ADEM. These findings support a new subgroup of postinfectious autoimmune inflammatory disorders associated with Group A beta hemolytic streptococcus, abnormal basal ganglia imaging, and elevated ABGA. 

PMID: 11706964 [pubMed - indexed for MEDLIN E) 

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Semin Clin Neuropsychiatry. 2001 Oct;6(4):266-76. 

Obsessive compulsive disorder: is there an association with childhood streptococcal infections and 

altered immune function? 

Murphy TK, Petitto JM, Voeller KIZ, Goodman WI(. 

Child Anxiety and Tic Disorder Clinic, McKnight Brain Institute, University of Florida, Department of 

Psychiatry, Gainesville, FL 32610, USA. 

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. 

PMID: 11607922 [pubMed - indexed for MEDLIN E) 

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37. Laryngoscope. 2001 Sep;l11 (9):1515-9. 

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Pediatric autoimmune neuropsychiatric disorders and streptococcal infections: role of otolaryngologist.

Orvidas LJ, Slattery MJ. 

Department of Otorhinolaryngology, Mayo Clinic, Rochester, Minnesota 55905, USA. 

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 obsessivecompulsive 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. 

PMID: 11568599 [pubMed - indexed for MEDLINE] 

J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1120-6. 

Psychiatric disorders in ftrst-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Lougee L, Perlmutter SJ, Nicolson R, Garvey MA, Swedo SE. 

Pediatrics and Developmental Neuropsychiatry Branch, NIMH, Bethesda, MD 20892-1255, USA. 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 atleast 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 

OeD. Further study is warranted to determine the nature of the relationship between genetic and environmental factors in PANDAS. 

PMID: 10986808 [pubMed - indexed for MEDLINE] 

J Child Adolesc Psychopharmacol. 2000 Summer;10(2):133-45. 

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

Eating Disorders Program, The Menninger Clinic, Topeka, Kansas 66601, USA. 

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 0 (ASO) titers. The "rheumatic" marker D8/17 was also measured. This B-cell 

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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. 

PMID: 10933123 [pubMed - indexed for MEDLINE] 

BioI Psychiatry. 2000 May 15;47(10):851-7. 

On defining Sydenham's chorea: where do we draw the line? Murphy TK, Goodman WK, Ayoub EM, Voeller KlZ. 

Department of Psychiatry, University of Florida, College of Medicine, Gainesville 32610-0256, USA. 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 playa 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. PMID: 10807957 [pubMed - indexed for MEDLIN E) 

Pediatr Infect Dis J. 1999 Mar;18(3):281-2. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). 

Shulman ST. 

Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL, USA. 

PMID: 10093955 [pubMed - indexed for MEDLINE) 

AmJ Psychiatry. 1998 Feb;155(2):264-71. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical 

description of the first 50 cases. 

Swedo SE, Leonard HL, Garvey M, Mittleman B, AllenAJ, Perlmutter S, Lougee L, Dow S, ZamkoffJ, 

DubbertBK 

Section on Behavioral Pediatrics, NIMH, Rockville Pike, Bethesda, MD 20892-1381, USA. 

Erratum in: Am J Psychiatry 1998 Apr;155(4):578. 

Comment in: Am J Psychiatry. 2002 Feb;159(2):320. 

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 comorbiclity 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 

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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. 

PMID: 9464208 [pubMed - indexed for MEDUNE] 

JAm Acad Child Adolesc Psychiatry. 1996 Jul;35(7):913-5. 

Case study: acute basal ganglia enlargement and obsessive-compulsive symptoms in an adolescent 

boy. 

GieddJN, RapoportJL, Leonard HL, Richter D, Swedo SE. 

Child Psychiatry Branch, NIMH, Bethesda, MD 20892-1600, USA. 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAs) may arise when antibodies directed against invading bacteria cross-react with basal ganglia structures, resulting in exacerbations of obsessive-compulsive disorder (OCD) or tic disorders. This is a report of severe worsening of obsessive-compulsive symptoms in an adolescent boy following infection with group A beta-hemolytic streptococci for whom serial magnetic resonance imaging scans of the brain were acquired to assess the relationship between basal ganglia size, symptom severity, and treatment with plasmapheresis. These data provide further support for basal ganglia-mediated dysfunction in OeD and the potential for immunological treatments in PANDAs patients. 

PMID: 8768351 [pubMed - indexed for MEDLIN E) 

BOOK CHAPTERS (from PsycInfor search) 

We do not have any of the books in the Medical Library collection. 

Immune and endocrine function in child and adolescent obsessive compulsive disorder. [References] . 

Murphy, Tanya K; Yokum, Kelley. 

McKay, Dean [Ed]; Storch, Eric A [Ed]. (2011). Handbook of child and adolescent anxiety disorders. (pp. 505-520). xix, 532 pp. New York, NY, US: Springer Science + Business Media; US. 

(create) This chapter discusses immune and endocrine function in child and adolescent obsessive compulsive disorder (OCD). It begins by examining L. Selling's theory for autoimmune and infection triggered causes of anxiety. It then questions what the pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) phenotype looks like. Next, it looks at the role of Group A Strep (GAS) in causing infections. This chapter then explores the links between GAS and OCD /Tics. Support for infection triggered pediatric neuropsychiatric disorders is discussed. Controversies in establishing an infectious trigger are considered. Other topics covered include the best evaluation and treatment options; antibiotics; neurological and cardiac concerns; and, endocrine dysregulation in anxiety. (psycINFO Database Record (c) 2012 AP A, all rights reserved) 

Obsessive-compulsive disorder: Boundary issues. [References]. Fineberg, Naomi A; Saxena, Sanjaya; Zohar, Joseph; Craig, Kevin J. PsycINFO 

Hollander, Eric [Ed); Zohar,Joseph [Ed); Sirovatka, PaulJ [Ed); Regier, Darrel A [Ed). (2011). Obsessive- 

compulsive spectrum disorders: Refining the research agenda for DSM-V. (pp. 1-32). xxiv, 233 pp. Washington, DC, US: American Psychiatric Association; US. 

(from the book) This reprinted article originally appeared in CNS Spectrums, May 2007, Vol. 12(5),359- 375. (The following abstract of the original article appeared in record 2008-15917-004). The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests 

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substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area. (psycINFO Database Record (c) 2010 APA, all rights reserved) 

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. [References] . 

Larson, MichaelJ; Storch, Eric A; Murphy, Tanya K. PsycINFO 

Storch, Eric A [Ed]; Geffken, Gary R [Ed]; Murphy, Tanya K. (2007). Handbook of child and adolescent obsessive-compulsive disorder. (pp. 163-174). xvi, 415 pp. Mahwah, NJ, US: Lawrence Erlbaum Associates Publishers; US. 

(from the chapter) Clinicians and researchers have recently encountered conflicting views and increasing publicity regarding the diagnosis and treatment of a subset of children that present with symptoms of obsessive-compulsive disorder (OeD) and/ot tic disorders as an immune response to a Group A Streptococcus (GAS) infection. Known as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS), symptoms include an abrupt onset following a GAS infection (e.g., strep throat or scarlet fever), a relapsing-remitting course of illness, and include new onset psychiatric symptoms (e.g., irritability, sudden mood changes, and separation anxiety) in addition to motor/vocal tics and/or obsessions/ compulsions. The prevalence of PANDAS is currently unknown although some estimates suggest that 11 % to 33% of patients with OCD / tics report onset associated with an infection. Difficulties in identification of base-rates and probabilities for encountering the disorder will persist until definitive criteria are established and the validation of PANDAS occurs. This chapter reviews the history, potential etiology, clinical features and the currently accepted treatments for PANDAS. Controversies regarding this disorder are discussed in an effort to encourage critical thought and discussion regarding the potential of infectiontriggered OCD. (psycINFO Database Record (c) 2010 APA, all rights reserved) 

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