tourett's an autoimmune disease-interferon-gamma and neoptrin cytokines and quinolinic acid, a marker for autism?

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2002, Volume 7, Number 5, Pages 437-445

Table of contents Previous Article Next [PDF]

Perspective

Is Tourette's syndrome an autoimmune disease?

P J Hoekstra1, C G M Kallenberg2, J Korf3 and R B

Minderaa1

1Child and Adolescent Psychiatry Center, Hanzeplein 1,

9713 GZ Groningen, Netherlands

2Department of Clinical Immunology, University Hospital

Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands

3Department of Biological Psychiatry, University

Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands

Correspondence to: Dr P J Hoekstra, Child and Adolescent

Psychiatry Center, Hanzeplein 1, 9713 GZ Groningen, Netherlands. E-mail:

pieter.hoekstra@...

Abstract

We provide a review of recent research findings which

support the involvement of autoimmunity in childhood-onset tic disorders, in

particular the presence of antineuronal autoantibodies, D8/17 B lymphocyte

overexpression, a marker of chorea associated with streptococcal infection, and

possible beneficial effects of immunomodulatory intervention. One of the most

controversial areas in this field is the validity of the proposed PANDAS

concept. Some researchers have delineated a putatively unique subgroup of

patients, from the spectrum of illness encompassing Tourette's syndrome and

obsessive-compulsive disorder (OCD), whose tics and obsessive-compulsive

symptoms are shown to arise in response to beta-hemolytic streptococcal

infections. They designated it by the term pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections (PANDAS). Herein we

additionally present pros and cons concerning the concept of PANDAS. Finally,

recommendations for future research directions are given.

Molecular Psychiatry (2002) 7, 437-445.

doi:10.1038/sj.mp.4000972

Keywords

tics; Streptococcus pyogenes; autoimmunity; intravenous

immunoglobulins; autoantibodies; plasmapheresis; tryptophan; childhood

Introduction

Gilles de la Tourette's disorder, or Tourette's syndrome

(TS), as it is mostly simply referred to, is a neuropsychiatric disorder,

characterized by the presence of both motor and vocal tics. A tic is a sudden,

rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization

(DSM-IV). Common examples of motor tics include excessive eye blinking, nose

twitching, head jerks and tensing the abdomen, whereas throat clearing, coughing

and sniffing are the most prevalent vocalizations. Tics typically occur in bouts

during the day,1 whereas the course of tics over a period of months to years

often waxes and wanes with regard to their severity.2 Furthermore, the type of

tics in an individual patient is typically changing, with some tics disappearing

and new ones appearing in the course of time. With increasing age, however,

symptoms tend to decrease in intensity and to show less variation over time

regarding both severity and type of tics.3 The age of onset of tics is mostly

between 2 and 15 years with a median of 7.3 Facial tics are normally the initial

symptom. Tics are rather common in childhood, but are most often transient.4

Males are more commonly affected than females.5 Movements generally decrease

during sleep and may be suppressed for short periods while the patient is

awake.6 Transient tic disorders are estimated to affect at least 5% of children

between 7-11 years; population studies estimate prevalence rates for full blown

TS between 2.9 and 5.2 cases per 10 000.5 Transient tic disorder, in which

symptoms are required to last less than one year, and chronic motor or chronic

vocal tic disorder, in which only one type of tics (either motor or vocal) is

involved, are all thought to be etiologically closely related to TS, thus making

this DSM-IV based subclassification of tics into separate categories rather

artificial.

One interesting feature of TS is its well known

association with a wide range of behavioral disorders and psychopathology.7

Attention deficit hyperactivity disorder (ADHD) is known to affect 50% of

referred patients.8 Obsessive-compulsive symptoms constitute another common

cophenomenon of the spectrum of tic disorders.9 Finally, many children show

significant problems with social functioning.10

Currently, tics are diagnosed on clinical grounds alone.

Though tic disorders are no longer regarded as psychogenic, the pathogenesis is

poorly understood. Circumstantial evidence from neurochemical and imaging

studies stresses the importance of basal ganglia and

cortico-striato-thalamocortical circuits.11

A high degree of heritability is characteristic of tic

disorders. Several investigators found that the pattern of vertical transmission

within families fitted best to a mode of inheritance of TS involving a single

autosomal dominant locus with varying penetrance. No such single gene defect has

been found though, despite extensive linkage studies covering most of the

genome.12 Associations for markers within certain chromosomal regions have been

reported recently.13

Our lack of understanding of the pathophysiology of TS

and associated phenomena is reflected in the paucity of existing treatment

options. They are all purely symptomatic and consist largely of the use of

various forms of psychotropic medications, mostly antipsychotic agents.14 In

some individual cases, however, medication does not show any effect on tic

severity, whereas in many other cases, the decrease of tic severity achieved by

medication is only marginal and far from sufficient. Besides, many patients

suffer from troublesome medication side effects, such as sedation and weight

gain. This unfavorable situation can be illustrated by the fact that many

patients, on long term, choose to live without medication, despite the existence

of debilitating tics.

What model of auto-immunity may be involved in the

pathogenesis of tic disorders?

Over the past decade a significant amount of research

has been conducted on the role of autoimmunity in tic disorders. The proposed

model of pathogenesis of tic disorders in this research is analogous to

Sydenham's Chorea.15 In genetically predisposed individuals, tics and associated

phenomena are thought to arise as a consequence of the immunological response to

infections with Group A beta hemolytic Streptococci (GABHS). Antibodies directed

against the streptococci are hypothesized to cross-react with structures of the

central nervous system, subsequently leading to damage to these structures,

which eventually results in the emergence of tics and associated features. This

mechanism of autoimmunity is supposed to be based on molecular mimicry between

host and micro-organism.

What data point towards involvement of autoimmunity?

Several clinical observations led to the hypothesis that

Sydenham's Chorea might be a model for some types of childhood-onset OCD and tic

disorders. First, it had been noted that patients with Sydenham's Chorea shared

certain behavioral characteristics with patients with OCD and/or tic disorders,

such as emotional lability, marked irritability, but also frank

obsessive-compulsive symptoms.16 Second, a substantial number of children with

OCD were reported to show choreiform movements or tics.17 In addition, in some

children with OCD and/or tic disorders, an episodic course and/or abrupt onset

of their symptoms seemed to be temporally related to signs of GABHS

infections.15 Following these observations, case studies began to appear in the

literature, in which children with OCD and/or tic disorders were described in

whom a temporal relationship between symptom onset or exacerbations and GABHS or

viral infections seemed apparent.18,19,20

Researchers of the National Institute of Mental Health

(NIMH) subsequently proposed criteria to identify a putatively unique subgroup

of patients from the spectrum of illness encompassing Tourette's syndrome and

obsessive-compulsive disorder (OCD), whose tics and obsessive-compulsive

symptoms are shown to arise in response to beta-hemolytic streptococcal

infections. They designated it by the term pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections (PANDAS),19 implicitly

suggesting that in non-PANDAS cases auto-immunity would not be involved. This

concept is not without controversy, however, as will be addressed later in this

review. What percentage of children with TS and/or OCD would meet criteria for

PANDAS is unknown.

Thus, clinical observations might point to a role for

infections preceding the onset or exacerbations of tic or obsessive-compulsive

disorders. Other clues for such a relationship stem from laboratory work. Most

importantly, autoantibodies reacting with basal ganglia,21,22,23,24,25,26

increased serum levels of streptococcal antibodies27,28,29 as well as the

presence of increased binding of an IgM monoclonal antibody to

B-lymphocytes,22,30,31 a suggested susceptibility marker for the development of

rheumatic fever, have been reported in a majority of patients with OCD and/or

tic disorders. Other laboratory hints may come from limited findings on

tryptophan metabolism32,33,34 and cytokine profiles.35 Finally, rather

fascinating is the reported success of immunomodulatory interventions

(plasmapheresis or intravenous immunoglobulins).36 All these items will be

discussed in the next sections.

Studies demonstrating antineuronal antibodies

A possible indicator of autoimmunity is the presence of

autoantibodies directed against components of the central nervous system. So

far, several research groups reported the increased presence of these

antineuronal antibodies in sera from patients with tic and/or obsessive

compulsive disorders, compared to healthy controls.21,22,23,24,25,26 Results,

however, have been partially conflicting, and relatively high levels of

antineuronal staining have been found in sera from healthy control subjects.

Kiessling and coworkers21 were the first to assess antineuronal antibody status

in children with recent onset of movement disorders (Tourette syndrome, motor

and/or vocal tics, chorea or choreiform movements), compared with a group of

children referred for evaluation of ADHD, behavior disorders, and learning

disabilities who did not show signs of a movement disorder. They applied an

indirect immunofluorescence technique, with unfixed frozen human caudate nucleus

sections as antigenic substrate, using undiluted sera and fluorescein

isothiocyanate-labeled secondary antibody directed against human IgG, and found

44% of children with a movement disorder to be strongly positive for

antineuronal antibodies. However, also 21% of the control group were strongly

positive for antineuronal antibodies. It is unlikely, that the behavioral

symptoms of the control group explain the positive antineuronal status in the

controls, since two more studies applying the same technique,16,22 also found

relatively high levels of antineuronal staining in healthy controls, as will be

addressed later. Unfortunately, no subsequent two-fold titrations of positive

sera were performed in this study, which could have been used to compare titers

between patients and controls.

Previously, in 46% of children with Sydenham's chorea,

the presence of antibodies reacting with caudate nuclei neurons had been

reported.37 In that study, however, which applied an indirect immunofluorescence

technique similar to that in Kiessling's study, contrary to the latter study,

none of the healthy control children showed evidence of the presence of

antineuronal antibodies. In contrast, two additional studies, which, like

Kiessling's work, adopted the method of indirect immunofluorescence on human

caudate nucleus sections as described by Husby,37 found relatively high

percentages of positive staining using undiluted sera of healthy controls: Swedo

and colleagues16 reported positive antineuronal antibody titers in 50% and

22 in 24% of healthy control children. Unfortunately, in these studies, no

explicit data are available about the presence of intercurrent infectious

illness or autoimmune disorders in the control subjects. In both studies, the

percentages of positive antineuronal staining were consistently higher for the

patient groups, being 91% for children with Sydenham's chorea in Swedo's

study,16 and 39% for children with tic and/or obsessive compulsive disorder in

the report of .22 However, again, a comparison of titers between diseased

children and controls could not be made, as serum dilutions were not performed.

To summarize, a major problem with previous studies

reporting high levels of antineuronal antibodies in patients with tic disorders

is the relatively high level of, possibly, non-specific antineuronal staining in

normal controls. Therefore, it would have been important, if in both patients

and comparison subjects, staining of antibodies to other brain regions than the

caudate nucleus would also have been assessed, in order to control for

non-specific antineuronal staining. A recent study, also applying indirect

immunofluorescence with unfixed frozen caudate sections, using undiluted sera

and fluorescein isothiocyanate-labeled anti-human IgG as secondary antibody,

was, however, able to detect antineuronal antibody staining in all patients with

acute chorea, whereas healthy control subjects showed a complete absence of

antineuronal antibodies.38 Contrary to the previous studies,16,21,22 which used

fresh human brains from adult victims of sudden or accidental death, this study

used a fresh human brain obtained from an autopsied stillborn cadaver, aged 34

weeks. It would be of interest to apply the same methodology in TS patients.

Measuring levels of antineuronal antibodies more

quantitatively, by applying an enzyme-linked immunosorbent assay (ELISA) with

human neural tissue from basal ganglia as substrate, TS subjects were shown to

have a significant increase in the mean and median ELISA optical density (OD)

levels of serum antibodies against putamen, but not against caudate or globus

pallidus, when compared with healthy controls. Differences in magnitude of

binding were, however, relatively low.23 These results suggest that the putamen

may be a major target site for antineuronal antibodies. Two other studies did

not use human neural tissue but an immortal cell line of neural origin as

substrate, and also applied ELISA assays. Though using the same methodology,

results were conflicting. When described originally, the assay was shown to have

the capability to differentiate between normal and Tourette syndrome

populations, with a sensitivity and specificity for TS of 79.1 and 61.2%,

respectively.24 A later study, however, did not find differences between

children with TS and control children, due to high optical density (OD) values

in controls in this study.25 Finally, a recent study assessed the presence of

antineuronal antibodies in subjects with TS and healthy controls with an

indirect immunofluorescent assay on unfixed frozen sections from rat brain

striatum, and performed serum titrations to an end point by two-fold serial

dilutions in order to quantify the levels of immunoreactivity.26 Again, there

was much overlap in levels of immunoreactivity between patients and controls. It

is unclear how to interpret this overlap between patients and controls. It

raises suspicions of methodological flaws, suggesting rather high levels of

non-specific binding, albeit not necessarily, since autoantibodies in healthy

subjects have repeatedly been reported.39 Clearly, according to what criteria an

individual's antineuronal antibody assay should be regarded positive has

insufficiently been operationalized as yet.

Many questions remain regarding the significance,

magnitude and pathophysiological meaning of serum reactivity with neuronal

tissue in tic disorders. In paraneoplastic syndromes (PNS) involving the central

nervous system, the role of antineuronal antibodies is much more established.

First, in this area, the nature of several neuronal antigens has been

characterized. Furthermore, end-point titers for positive identification of

antibody in general are much higher than is the case in movement disorders.

Mostly, titers of >1:500 will be regarded as positive in the field of PNS,40

whereas most titers do not exceed 1:8 when movement disorders are concerned.

Given these apparently low titers in tic disorders, discriminating differences

from controls are fairly small. Correspondingly, confounds of non-specific

binding form a great risk when studying antineuronal antibody status in patients

with tic disorders, paralleled by relatively high levels of positive reactivity

in normal controls reported so far.

To conclude, though several studies suggest the presence

of autoantibodies reacting with brain tissue in patients with OCD and/or tic

disorders, some of these raise concerns regarding methodology. Moreover, the

presence of autoantibodies in the serum of patients with tic disorders does not

necessarily point to an autoimmune basis of tic disorders. Autoantibodies are

also found when tissue damage is caused by trauma or infection. In other words,

autoantibodies can result from, rather than be the cause of tissue damage, as

has been reviewed elsewhere.41 One recent study, however, elegantly suggested a

pathogenic role for antineuronal antibodies for tic disorders. Through the

transfer of antineuronal antibodies of children with TS to the striatum of rats,

stereotypic movements and utterances could be induced in these animals.42

Much remains to be investigated in this area, eg, how

autoantibodies present in sera are able to cross the blood-brain barrier, or

whether IgG production takes place inside the central nervous system. Simply

measuring albumin and total IgG in serum as well as in cerebrospinal fluid would

give valuable information about IgG production in the central nervous system and

about the functional integrity of the blood-brain barrier. Recently, basic

principles of these measurements have been adequately reviewed.43 Theoretically,

in this respect, it would be also of interest, to compare antineuronal

antibodies instead of total IgG in both serum and cerobrospinal fluid. Contrary

to total IgG, however, we lack accurate quantitative methods of measuring levels

of antineuronal antibodies, as has been outlined in the previous sections.

Also, the way in which antibodies against neuronal

antigens might induce tics and associated features is unknown. No evidence of

antibody-associated inflammation or indications of autoantibody binding to

functional cell-surface receptors in central nervous tissue have been collected

in the field of tic and related disorders. An animal model as described above,42

or careful postmortem neuropathological examinations may be fruitful future

approaches in this respect.

Association with anti-streptococcal antibody titers

Conflicting results have also been reported on the issue

whether increased levels of anti-streptococcal antibodies (antistreptolysin O

and antideoxyribunuclease are associated with TS. Two recent studies27,28

reported large differences between TS cases and normal controls. Muller et al27

found that 85% of the subjects with TS vs 8% of normal controls had elevated

antideoxyribunuclease B levels. The same researchers subsequently showed the

presence in TS patients of increased titers against the streptococcal M12 and

M19 proteins in TS patients as compared with controls, while antibody titers

against M1, M4 and M6 did not differ between the TS and control groups.29 Also,

Cardona et al28 reported significantly higher mean antistreptolysin titers in

children with tics compared to control children, and found a positive

correlation between antistreptolysin titers and severity of tic disorder as

measured by the Yale Global Tic Severity Scale. Others, however, reported less

striking differences in this respect.23

Despite some inconsistency in these data, overall, a

clear association is noticeable between anti-streptococcal antibody titers and

tic disorders, further strengthening the relationship between tic disorders and

preceding streptococcal infections. Longitudinal data, however, intending to

link symptom fluctuations over time to fluctuations of anti-streptococcal

antibody titers are highly needed. In addition, though Muller et al27 did not

find increased anti-streptococcal antibody titers in a comparison group of

patients with schizophrenia, it remains to be systematically investigated

whether elevated anti-streptococcal antibody titers would also be associated

with other related neuropsychiatric disorders such as OCD, autism spectrum

disorders and anorexia nervosa, or other mental disorders in which mechanisms of

autoimmunity sometimes have been suggested, such as affective disorders.

Studies demonstrating elevated D8/17 expression on B

lymphocytes, a marker of rheumatic fever

One finding which somehow links tic disorders to

rheumatic fever is the greater than usual binding of a D8/17-specific monoclonal

antibody to B lymphocytes, reported in patient groups of both disorders.22

D8/17-specific monoclonal antibody is a mouse monoclonal IgM antibody originally

prepared from fusions of spleen cells from mice that had been repeatedly

immunized with isolated human B cells obtained from patients with rheumatic

fever or rheumatic heart disease. Elevated D8/17 B cell expression was

originally investigated as a putative susceptibility marker of rheumatic

fever.44 Two independent research centers reported elevated D8/17 expression on

B cells in patients with tic disorders. In these studies, B cells were incubated

with the D8/17-specific monoclonal antibody and an anti-mouse IgM specific

conjugate, after which D8/17-positive cells were counted by means of fluorescent

microscopy.22,30 Using the same, somewhat subjective method, elevated D8/17 B

cell binding in autism has also been reported.45 We recently demonstrated higher

than usual D8/17 overexpression compared to a control monoclonal antibody in

patients with a tic disorder, by means of flow cytometry, an objective rating

method in which no operator variability is involved.31 A significant minority of

our patients (39.4%), however, had levels of D8/17 expression within the range

of that of our healthy comparison subjects.

The exact meaning and pathogenetic significance of these

findings is unknown. The D8/17-specific monoclonal antibody has not only been

found to bind to B cell surface structures, but also to the cytoskeletal helical

coil/coiled structures myosin and tropomyosin as well as to streptococcal M

proteins, possibly suggesting a substrate for structural homologies between host

and streptococci.46 Given the specificity of elevated D8/17 B cell expression

for poststreptococcal disorders as reported after extensive studies with this

antibody across different autoimmune disease categories,47 elevated D8/17 B cell

expression might point to the involvement of poststreptococcal (auto)immunity in

tic disorders. Whether, however, the finding of elevated B cell expression in

autistic subjects45 also implies the involvement of poststreptococcal

(auto)immunity in the pathophysiology of autistic disorder, remains to be

specifically investigated. In other words, the precise meaning of elevated D8/17

expression remains obscure.

Altered tryptophan metabolism and data on cytokines

One well known and sensitive marker of cellular immune

activation is the increased degradation of tryptophan via the kynurenine

pathway, leading to elevated plasma levels of kynurenine and subsequent

metabolites.48 Up-regulation of the kynurenine pathway can be induced through

increased activity of Indoleamine 2,3-Dioxygenase (IDO), an enzyme active in

extra-hepatic tissue including brain, which is sensitive to Interferon-gamma, a

major cytokine of cellular immunity.49

Indeed, in one study, involving only seven patients with

a tic disorder, the serum kynurenine level was found to be clearly increased in

all seven patients whereas serum tryptophan was normal,32 thus, possibly

reflecting immune activation. In a subsequent larger scale study, involving 72

TS patients and 46 matched controls, again, plasma kynurenine levels were found

to be significantly elevated.33 Interestingly, both studies32,33 reported a

significant positive correlation in TS patients between levels of kynurenine and

neopterin. This finding further supports involvement of (auto)immunity, given

the fact that neopterin is a well known marker of cellular immunity, which is,

like IDO activity, induced by cytokines. We know of one other independent report

of increased plasma kynurenine,34 further strengthening the significance of this

finding.

Also, significantly decreased serum tryptophan levels of

TS patients have been reported in two large-scale studies,50,51 which would be

compatible with increased turnover of tryptophan along the kynurenine pathway.

However, cerebrospinal fluid tryptophan levels were found to be normal in a

different study.52 Interestingly, conversion of tryptophan to kynurenine can be

triggered by GABHS, as has been recently shown in vitro.53 In that study,

streptococcal erythrogenic toxins, exposed to a peripheral blood mononuclear

cell culture were demonstrated to stimulate tryptophan degradation to

kynurenine.

An alternative explanation for increased plasma

kynurenine, other than through immune based IDO activation, would be activation

of cortisol-inducible tryptophan dioxygenase (TDO), possibly reflecting

heightened stress response.54 However, contrary to neopterin, cortisol was not

found to show a correlation with kynurenine.33 Surprisingly, the studies

reporting on elevated plasma kynurenine32,33,34 did not yield elevated levels of

quinolinic acid and kynurenic acid, two further metabolites along the kynurenine

pathway.55 Increased levels of quinolinic acid are known to be correlated with

different immune-based neurologic conditions, among others the AIDS dementia

complex.56,57 When present in higher than usual levels in brain tissue,

quinolinic acid is toxic to neurons, leading to a loss of neuronal cell density.

Cerebrospinal fluid levels of quinolinic acid are closely associated with

severity of neurologic damage in inflammatory brain disease.56,58 Therefore, it

would be of interest, to study kynurenine pathway metabolites in cerebrospinal

fluid of TS patients.

Precisely how an altered metabolism of tryptophan might

contribute to the pathogenesis of tics is not clear. It can be an epiphenomenon,

merely reflecting a state of immune activation. Another possibility is a direct

toxic effect of kynurenine or one of its metabolites in the basal ganglia. Some

authors found that kynurenine increases tic-like behaviour in an animal model of

TS: in mice, head-shakes which had been induced by the 5-hydroxytryptamine

receptor agonist dimethoxy-iodophenyl-aminopropane were potentiated by

administration of kynurenine.59 A third possibility would be that reduced levels

of tryptophan could lead to reduced synthesis of serotonin causing perturbations

in serotonergic transmission. The last two possibilities are not mutually

exclusive.

Clearly, however, more data are needed concerning

altered tryptophan metabolism in patients with tic and related disorders to

allow for more definite conclusions. Unfortunately, studies which investigated

cytokines in pediatric neuropsychiatric disease are scarce. Patients with OCD

were reported in one study to show a relative preponderance in cerebrospinal

fluid of type 1 cytokines, notably interleukine-2, suggesting the involvement of

cell-mediated immunity.35 This could be consistent with a role for streptococcal

infection, through the involvement of streptococcal erythrogenic toxins, which

can act as superantigens and are known to induce type 1 cytokines.53,60

Cytokines are proteins made by cells that affect the

behavior of other cells. One function of cytokines is to shape the type of

adaptive immunity in response to a pathogen, by determining the fate of naive

CD4 T cells. Proliferating CD4 T cells can differentiate into type 1 CD4 T cells

(Th1 cells) or type 2 CD4 T cells (Th2 cells), which mainly depends on the type

of cytokines produced in response to pathogens by cells of the innate

non-adaptive immune system. Th1 cells are involved in activating macrophages,

resulting in cell-mediated immunity whereas type Th2 cells have their main

function in stimulating B cells to become antibody producing plasma cells.

Given the known IDO induction capacities of interferon

gamma, it would be of interest to study cytokine profiles in patients with tic

disorders. At present, no such studies are available.

Application of immunomodulatory interventions in tic

disorders

One attractive consequence of the accumulating evidence

supporting the involvement of autoimmunity in the pathophysiology of tic

disorders is the development of new treatment options, targeting on the supposed

pathophysiology instead of being purely symptomatic. The existing literature

concerning immunomodulatory therapy for Tourette's and related disorders is

still surprisingly scarce, and is confined to a handful of case studies and one

placebo controlled study.

A small number of case studies reported improvement in

tic severity after immunosuppression with corticosteroids.61,62,63 Other case

studies in the literature report dramatic symptom improvement in children

fulfilling criteria of PANDAS with either plasmapheresis,18,19,20 or intravenous

immunoglobulin (IVIG).20,64,65 In some of these case studies, after successful

plasmapheresis, attempts have been made to prevent new GABHS infections with

penicillin prophylaxis.20

We know of only one placebo controlled study on the

efficacy of immunomodulatory therapy in patients with TS/OCD.36 In that study, a

total number of 30 children meeting PANDAS criteria, were randomly assigned to

either plasmapheresis, IVIG or a placebo condition (saline solution given in the

same manner as IVIG), and subsequently each patient was given a regimen of

penicillin prophylaxis. Symptom severity was rated at baseline and at 1 month

and 12 months after treatment by use of standard assessment scales for OCD,

tics, anxiety, depression and global functioning. At 1 month after treatment the

IVIG/placebo masking was broken. At 1 month, the IVIG and plasma-exchange groups

showed striking improvements in severity of OCD symptoms, anxiety and overall

functioning. Tic symptoms were significantly improved by plasma exchange only.

The children in the placebo condition did not show any amelioration.

Interestingly, these improvements were maintained at 1 year after treatment for

both plasmapheresis and IVIG. Though these results are intriguing, the study of

Perlmutter and colleagues has some serious drawbacks. At baseline, tic severity

in the plasma-exchange group was significantly higher than in the IVIG and sham

IVIG groups, which makes it hard to evaluate the effect of IVIG on tic severity.

Blinding of the treatment groups was already broken at 1 month after treatment.

In fact the study lacks an acceptable sustained placebo condition. Another

serious drawback is the limited number of symptom rating moments, both before

and after treatment. As a consequence, we lack knowledge of the way of natural

symptom fluctuation in the groups vs the possible effect of intervention.

Perlmutter and colleagues did not use laboratory

measures in their assessment after treatment, so from Perlmutter's data, we

cannot gain insight in possible treatment mechanisms. More specifically,

baseline and post treatment levels of antineuronal antibodies and percentages of

D8/17 positive B-lymphocytes would have been of interest. Two more problems are

the small number of patients in each treatment arm and the confounding role of

the use of penicillin.

Certainly, further, larger scale studies on the

effectiveness of immune-based therapies in well characterized patients with tic

disorders would be of great interest.

How valuable is the PANDAS concept?

Many problems are associated with the concept of PANDAS,

both methodologically and fundamentally. The diagnostic criteria for PANDAS are

not easy to apply. Especially, it is hard to demonstrate a temporal association

between GABHS infection and symptom onset and exacerbations. In fact, as far as

such an association in tic or obsessive compulsive disorder exists, no knowledge

is available of the nature of this association. Interestingly, in Sydenham's

chorea, a latent period between onset of symptoms and the preceding GABHS

infection as long as 6 months is not uncommon.66 Streptococcal infections are

fairly common in children in general,67 as are remissions and exacerbations in

children with tic disorders.68 Another criterion for PANDAS, the presence of an

episodic course of symptom severity with explosive exacerbations and remissions

has insufficiently been operationalized. An episodic course of symptoms is

characteristic of pediatric tic and OCD symptoms in general, but it is hard to

say when exacerbations can exactly be called explosive.

The significance and validity of PANDAS remains to be

established, since we lack direct comparisons between TS subjects who do and TS

subjects who do not meet criteria for PANDAS. Comparative studies in this

respect should include comprehensive clinical and serological features in

relation to response to treatment. Besides, much of the evidence supporting a

role for autoimmunity in tic disorders in general has been based on unselected

subjects. Findings in unselected cases have been similar in magnitude as in

cases fulfilling criteria for PANDAS. All of the findings supporting

autoimmunity as outlined in the previous sections are equally valid for

unselected TS patients. These include the D8/17 B cell overexpression22,31 and

levels of increased antineuronal autoantibodies,24 both of which are the most

robust indicators of a role for autoimmunity. There is, however, one major

exception: researchers at the NIMH recently conducted an open trial of plasma

exchange in five patients with non-PANDAS OCD, after which none showed

significant improvement.69 To fully investigate the usefulness of the proposed

PANDAS concept, more studies comparing TS subjects fulfilling the PANDAS

criteria with non-PANDAS subjects will have to be performed. At present it

suffices to state that PANDAS probably simply represents those patients who

feature the most obvious relationship with GABHS infections.

Apart from the point whether or not PANDAS is a useful

concept, one may question, what type of symptoms should be included in the

spectrum of tic and related disorders. The PANDAS criteria simply require the

presence of OCD and/or a tic disorder as the first criterion,70 thus lumping

together two types of disorders, which are generally regarded distinct in

phenomenology and presumed etiology.71 Only a subgroup of pediatric OCD may be

etiologically related to tic disorders, characterized by a family history of

tics, a more familial subtype in general, male preponderance, association with

disruptive behavior and developmental disorders, and a less striking association

with mood disorders.72 The predominant phenomenology of obsessions/compulsions

also differs between tic-related and non-tic-related OCD. Presence of

hoarding/symmetry and sexual and aggressive symptoms predominates in the former,

whereas in non-tic-related OCD symptoms of contamination/checking prevail.73 In

tic-related OCD, compulsions do not generally appear to be anxiety-driven, but

rather could be phenomenologically regarded as complex tic behaviors. It is well

known that so-called mental tics form a part of tic symptomatology, and it is

our clinical impression that in many cases certain obsessions and compulsions

could be better conceptualized as mental and complex tics, respectively. Thus,

it may well be that the presence of tics, or, more general, a movement disorder,

in contrast to anxiety-driven obsessions and compulsions, forms the distinctive

feature of those neuropsychiatric disorders which may be related to

autoimmunity. Our preliminary, unpublished data on D8/17 B cell overexpression

in OCD suggest, that only tic-related OCD shows increased expression of this

marker of rheumatic fever.

In conclusion, the concept of PANDAS is ill defined, is

not supported by unique immunologic findings which have not been reported in

unselected patients, and is phenomenologically unsound. It would be better to

define homogeneous subgroups by means of both clinical and laboratory

characteristics. Presence of antineuronal antibodies, or levels of D8/17 B cell

overexpression might be two candidate approaches.

Conclusions and future directions

A growing body of research data indicates the

involvement of autoimmunity in the pathogenesis of at least a subgroup of

patients with tic and related disorders. The most fascinating data include the

work on antineuronal autoantibodies,21,22,23,24,25,26 especially regarding their

potential in generating disease in an animal model,42 the association with B

lymphocyte D8/17 expression,22,30,31 and the promising data concerning

immunomodulatory approaches36 in a disorder which is otherwise hard to manage.

Given the economic costs, and the invasiveness of these interventions, future

research should focus on the identification of patients in whom autoimmunity may

be involved, and who may subsequently profit from immunomodulatory treatments.

Much more work remains to be done in this field,

however. The characterization of the antigen recognized by the D8/17-specific

monoclonal antibody as well as the characterization of the brain antigenic

structures recognized by the antineuronal antibodies awaits further study.

Western blot analyses which can identify antibodies against specific antigenic

structures have been inconclusive so far.23 Post-mortem studies in search of

inflammatory alterations warrant further attention.

Furthermore, large-scale longitudinal data are needed to

investigate the role of infections with regard to symptom fluctuation. Many

areas remain neglected. Just a few studies examined the Human Leukocyte Antigen

(HLA) system.74,75,76 Since many human autoimmune diseases show HLA-linked

disease associations, studying HLA-associations would be of great interest in

homogeneous, immune-based subgroups of tic disorders. Also, we lack imaging

studies aimed at visualizing possible blood-brain barrier ruptures. Of special

interest in this regard is the report by Kienzle and coworkers77 demonstrating

focal blood-brain barrier disruption confined to the head of the caudate nucleus

in two patients with Sydenham's chorea during the active phase of the disease by

magnetic resonance imaging after intravenous administration of gadopentetate

dimeglumine. Interestingly, when repeating the procedure in these patients after

symptoms had greatly diminished, leakage of contrast was absent.

Ultimately, unraveling the genetic background of tic and

related disorders will hopefully lead to a better understanding of environmental

factors and more targeted treatment.

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Received 19 April 2001; revised 10 June 2001; accepted

20 June 2001

2002, Volume 7, Number 5, Pages 437-445

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