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PANDAS Article


Ronnas
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I have been reviewing some of the most recent medical journal articles regarding PANDAS. I thought this one had some good information. Although this forum is really focused on alternative therapies I think that parents need to be aware of PANDAS as well. My son straddles a dx of PANDAS and sydenham's chorea.

 

If someone wants the whole article they can contact me via lattitudes or braintalk. I have only included parts the Introduction and Discussion as the article is very long.

 

J Neuropsychiatry Clin Neurosci 16:252-260, August 2004

 

A Possible Association of Recurrent Streptococcal Infections and Acute Onset of Obsessive-Compulsive Disorder

 

 

INTRODUCTION

 

Rheumatic fever is an immunologically mediated disease that follows infection by group A ß-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.

 

Published evidence indicates a possible etiological link between GABHS infection and a subset of obsessive-compulsive disorder (OCD),13–16 Tourette's syndrome (TS),13,16–19 and autism,20 and suggests that antibodies that develop against a subgroup of Streptococcus pyogenes cross-react with human brain tissue in genetically susceptible children. Swedo et al. coined the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) to represent these disorders. The PANDAS criteria are: 1) presence of OCD or tic disorder, 2) onset between age 3 to puberty, 3) episodic course with dramatic symptom exacerbations, 4) association with GABHS infection, and 5) motoric hyperactivity.21 The PANDAS concept has recently been reviewed by Murphy et al.22 and Swedo et al.23,24 and challenged by others who conclude that currently there is insufficient evidence to establish an association between GABHS and PANDAS.25–28 These authors argue that there is not clear-cut evidence for concordance of acute rheumatic fever (ARF) and PANDAS, no evidence of an increased incidence of ARF among family members of PANDAS cases, and no clear-cut association of PANDAS with GABHS infections. Further, they argue that antineuronal antibodies have not been found in all TS cases and antineuronal antibodies have been found in a substantial number of control subjects. They also point out that majority of TS cases do not meet PANDAS criteria and doubted if there is room to implicate nongenetic factors as being significant in the pathogenesis of TS.

 

The mechanism for anti-GABHS antibody cross-reactivity to brain tissue is attributed to molecular mimicry. Susceptibility to instigating an autoimmune reaction in response to an environmental trigger (GABHS or possibly other infectious agents) has been ascribed to a genetic predisposition. Genetic and environmental influences involved in the pathophysiology of rheumatic fever (RF) and PANDAS have not been elucidated, however, recently published papers provide intriguing clues (see below) that suggest that streptococcal superantigens play a crucial role.

 

Although the significance has been disputed, elevated levels of a unique surface alloantigen on B lymphocytes have been suggested to be characteristic in RF and PANDAS subjects (see below). Zabriskie et al. raised monoclonal antibodies against this alloantigen by immunizing mice with B cells from a patient with RHD.8 One of these monoclonal antibodies, D8/17, has been isolated in an effort to detect individuals at risk as well as individuals who manifest active illnesses. Children who are susceptible to or who have early onset OCD, TS and autism appear to be vulnerable or tend to overexpress this lymphocyte marker in their B cell population.

 

 

The goal of the present paper is to review: 1) microbiologic characteristics of GABHS, 2) immune responses to GABHS as one of the possible etiologies of PANDAS and other neuropsychiatric disorders, and 3) the D8/17 antibody as a potential marker of disease and/or risk for development of PANDAS.

 

 

DISCUSSION

 

Although the significance of D8/17 testing for OCD is in question, the relationship between recurrent streptococcal infections and development of sudden onset of OCD in a subset appears firmly established.(44) Streptococcal antibodies from SC subjects (and by inference OCD) that bind to basal ganglia but not to the rest of the brain tissue71 support above findings. Currently, superantigens from a specific streptococcal strain or strains are believed to play a crucial role in the expansion of specific clones of T cells that target a specific epitope on the M protein as well as host tissue (molecular mimicry)48,49

 

Regarding the D7/18 monoclonal antibody, eight recent studies investigating D8/17 positivity on the surface of B cells demonstrated elevated D8/17-positive cases in a subset of neuropsychiatric disorders that includes PANDAS, SC, OCD, TS, trichotillomania, tics, autism, and anorexia nervosa .

 

The observation that obsessive compulsive (OC) symptoms from SC are indistinguishable from OC symptoms found in chronic childhood OCD cases72,73 has led Swedo et al. to hypothesize that SC and OCD share the same or similar pathophysiology or etiology.73 Sydenham's chorea (SC) has known pathologic findings (that date back nearly a century) in the corpus striatum,74 thus the etiology of OCD was presumed to follow corresponding anatomical and/or pathophysiological changes. Swedo et al. have subsequently conducted a series of studies that have redefined a subset of OCD, with an increased rate of OCD in first-degree relatives of PANDAS cases than those reported in the general population,75 which are distinct clinical characteristics21 and laboratory findings. Specifically, OCD children were found to have an expanded subset of B lymphocytes staining positive for the D8/17-specific antigen (Table 3), increased antineuronal antibody titers (Table 2), and enlarged corpus striatum.76 The increased basal ganglia size found in the study was similar to that found previously for subjects with SC compared with normal subjects.77

 

Regarding the relationship between PANDAS and GABHS infection, a recent study reported that an association between antistreptococcal antibodies and OCD/tics might have been confounded by the presence of attention deficit hyperactivity disorder (ADHD).27 The authors enrolled subjects ages 7 to 55 regardless of the status of GABHS infection. In this study, elevated antistreptolysin-O (ASO) and anti-DNase B titers were associated with ADHD but not with tics or OCD. Increased ASO and anti-DNase B titers, however, are nonspecific measurements of recent and repeated streptococcal infections, do not indicate immunity, and are not pathognomonic of complicated streptococcal infection. In the case of RF, when ASO and anti-DNase B levels are increased, the diagnosis of rheumatic fever has always been considered only presumptive.36 It is true that subjects in the above study were younger than the subjects in some OCD/tics studies, and thus may have affected the study outcomes.

 

Although OC symptoms from OCD and SC are similar, pathogenic strains responsible for SC may be different from serotypes associated with PANDAS. The PANDAS concept was introduced, in part, to allow for the characterization of particular strains of GABHS that are prone to the induction of PANDAS in the susceptible host.21

 

Additionally, if antineuronal antibody binds to basal ganglia tissue the manner through which it crosses the blood-brain barrier is not clear. Does an inflammatory process allow antineuronal antibodies to cross the blood-brain barrier? Swedo and Kiessling advanced several plausible possibilities that may allow such antibodies to cross the blood brain barrier.85

 

In SC, OCD, or TS, antineuronal antibody titers have been shown to correlate with symptom severity.16,17,73,85,86 Whether putative antineuronal antibody binding to brain tissue is associated with changes in underlying pathophysiology is unclear. Published reports also suggest that OC symptoms precede chorea and that OC symptoms resolve before SC symptoms.73 The temporal sequence of OC and SC symptom emergence and resolution as well as the ability of an underlying immune mechanism to effectuate clinical manifestation remains elusive.

 

In summary, emerging evidence strongly suggests an involvement of streptococcal superantigens in the pathogenesis of RF48 and Kawasaki disease.49 Changes in HLA class II alleles appear to affect superantigen functions, dramatically leading to the proliferation of specific T cell clones,46,47 which appear to target cardiac and vascular tissues.48,49 The pressing need at this time is to examine the role of superantigens from M18 strain (known to cause RF) in SC and PANDAS. We speculate that subsets of other psychiatric disorders such as anorexia nervosa, body dysmorphic disorder, and ADHD may also share pathophysiology similar to that of RF. Findings from these studies, if affirmative, would have a profound impact for the practicing physicians in psychiatry and pediatrics.

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Hi Ronnas,

 

That article looks facinating and the implicatons are amazing.

 

I work in a large Emergency Dept and we have a large amount of Psych patients come through to be medically cleared before they go to the mental health dept.

I would love a copy of this paper to give to the psych Drs.

 

Who knows, maybe we can change the outcome for a lot of these people that may have been misdiagnosed. I know it would be like as Shrek says" getting through layers of onions" as far as making mainstream medical people look at stuff like this, but Heh I've got the next 20yrs of my working life!!

 

Just the other day I had an adult who was embarrassed about her OCD, but when I told her my children had had it and now didn't (thanks to this site) she came out of her shell and talked about it. She described how they had put her on meds for it, but it didn't help, the OCD got worse then the side effects of the meds started.

The poor woman was now in a vicious cycle.

Studies like these may help to stop this, so thanks a heap.

 

LOL

Clare

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