PANDAS and Anorexia Nervosa-A Spotters' Guide: Suggestions for Medical Assessment
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
RESEARCH ARTICLE
PANDAS and Anorexia Nervosa—A Spotters’ Guide:
Suggestions for Medical Assessment
Brenda Vincenzi1, Julie O’Toole2,3 & Bryan Lask4,5,6*
1
Department of Mother–Child and Biology–Genetics, Verona University, Verona, Italy
2
Kartini Clinic, Portland, OR, USA
3
Oregon Health Sciences University Portland, OR, USA
4
Ulleval University Hospital, Oslo, Norway
5
Department of Child and Adolescent Mental Health, Gt. Ormond Street Hospital, London, UK
6
Ellern Mede Centre, London, UK
Abstract
Objective: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS)
should be considered in sudden onset, prepubertal Anorexia Nervosa (AN), arising shortly after an apparent
streptococcal infection. However, the absence of a specific biological marker of PANDAS renders the diagnosis
difficult. This paper critically reviews available tests for PANDAS and recommends a standardized approach to its
investigation.
Method: Medline database review between 1990 and 2008.
Results: Existing tests may be categorized as: (i) Non-specific markers of inflammation or immune response
(Erythrocyte sedimentation rate, ESR; C-reactive protein, CRP; Neopterin), (ii) specific markers of streptococcal
infection (throat swab and anti-streptococcal antibodies, Anti-streptolysin, ASO; Antideoxyribonuclease B,
antiDNaseB), (iii) non-specific markers of auto-immune reaction (Antineuronal antibodies, AnAb; D8/17). No
one test reliably identifies PANDAS. The lack of specificity and methodological problems may lead to errors of
diagnosis.
Discussion: When PANDAS–Anorexia Nervosa (PANDAS–AN) is suspected clinically we recommend conducting
all the above investigations. The more positive results there are the more likely is the diagnosis, but particular
weighting should be given to AnAb and D8/17. Copyright # 2010 John Wiley & Sons, Ltd and Eating Disorders
Association.
Keywords
PANDAS; anorexia nervosa; streptococcal infection; autoimmunity
*Correspondence
Bryan Lask, F.R.C.Psych, Regional Eating Disorder, Service (RASP), Building 31a, Ulleval University Hospital, Kirkeveien 166, NO 0407 Oslo,
Norway. Tel: (0047) 23 01 62 30. Fax: (0047) 23 01 62 31.
Email: bryanlask@mac.com
Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/erv.977
process is similar to that deemed to be central to Rheumatic
Introduction Fever, a well-recognized auto-immune response within
The acronym PANDAS stands for Pediatric Auto- cardiac muscle to streptococcal infection. Sydenham’s
immune Neuropsychiatric Disorders Associated with Chorea, the neurological manifestation of Rheumatic
Streptococcal infection (Swedo et al., 1998). This Fever, represents a similar process in the brain (Ayoub
116 Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.B. Vincenzi et al. PANDAS and Anorexia Nervosa—A Spotters’ Guide
& Wannamaker, 1966). The current hypothesis to explain the illness. There are adventitious (purposeless and
the pathogenesis of post-streptococcal neuropsychiatric involuntary) movements, such as motor restlessness,
disorders is the ‘molecular mimicry model’ in which fidgetiness or hyperactivity, such as remorseless pacing
people with a genetic susceptibility develop a cross or exercising.
reactive or auto-immune response to self-antigens after Unfortunately these diagnostic criteria for PANDAS–
an appropriate immune response to inciting bacterial AN are insufficiently precise and there are many
antigens, homologous with human antigens (Martino, methodological problems in identifying an auto-
Church, & Giovannoni, 2007). immune response to streptococcal infection. Thus
A number of conditions have been postulated to there is considerable debate as to whether or not
represent a neuropsychiatric manifestation of this auto- PANDAS–AN is a valid entity (Puxley, Midtsund, Iosif,
immune reaction. These include obsessive-compulsive & Lask, 2008). Nonetheless it is important to reach
disorder (OCD), movement disorders such as tics and resolution of this controversy, as there are a number of
Tourette’s Syndrome (TS) (Hoekstra, Kallenberg, Korf, potentially useful treatments available for PANDAS.
& Minderaa, 2002) and some dystonias (Snider & These include antibiotics (e.g. penicillin) and immu-
Swedo, 2003), trichotillomania (Niehaus et al., 1999) nomodulatory therapies such as immunoglobulin
and autistic spectrum disorder (Hollander et al., 1999; injections and plasmapharesis (Perlmutter et al.,
Swedo & Grant, 2005). In the last decade or so some 1999; Puxley et al., 2008; Sokol & Gray, 1997; Sokol,
cases of anorexia nervosa (AN) have been attributed to 2000; Swedo & Grant, 2005).
the same process (Sokol et al., 2002; Sokol, 2000; Sokol What is required are investigations that can reliably
& Gray, 1997). In the light of the diagnostic criteria distinguish AN from PANDAS–AN by providing
for PANDAS–tics/OCD (National Institute of Mental evidence of an auto-immune reaction to streptococcal
Health, 2005), Sokol suggested five criteria for infection. The aims of this paper are to: (i) Offer a
identifying patients with PANDAS–Anorexia Nervosa critical review of the tests that have been used to identify
(henceforth described as PANDAS–AN), summarized PANDAS (ii) recommend a standardized approach to
in Table 1. the investigation of PANDAS–AN (iii) consider the
Patients with possible PANDAS–AN should meet methodological issues for future research into PAN-
DSM-IV diagnosis of AN (American Psychiatric Associa- DAS–AN.
tion, 2000). The onset is abrupt and generally occurs
prepubertally, although there have been some reports of Method
post-pubertal onset (Sokol, 2000). Exacerbations also
Review of the scientific literature for each potential
tend to be abrupt but may not be confined to
biological marker, using MEDLINE database, searched
prepuberty. Episodes are deemed to be associated with
between 1990 and 2008, in both children/adolescents
an antecedent or concomitant streptococcal infection,
and adults suffering from disorders that have been
as evidenced by a clinical history, positive throat culture
associated with an auto-immune reaction to strepto-
and positive serological findings. However, it is far from
coccal infection (rheumatic fever, Sydenham’s chorea,
common to have serological investigations during or
tics, TS and other movement disorders, OCD,
after suspected streptococcal infections. There would
trichotillomania, autistic spectrum disorder and AN).
generally be increased psychiatric symptoms, such as
depression and anxiety, not necessarily associated with
Findings
Table 1 Hypothesized criteria of PANDAS–Anorexia Nervosa
The investigations of PANDAS that have been used may
1. Prepubertal onset of AN
be categorized as: (1) Non-specific markers of
2. Acute onset and/or symptom exacerbation of AN
3. Evidence of antecedent or concomitant streptococcal infection:
inflammation or immune response (2) specific markers
Positive throat culture of streptococcal infection (3) non-specific markers of
Positive serological findings (elevated antibody titre) an auto-immune reaction.
4. Increased psychiatric symptoms that do not occur exclusively
during stress or physical illness (1) Non-specific markers of inflammation or immune
5. Concomitant neurological abnormalities, with motor hyperac- response
tivity and/or adventitious movements
Three non-specific markers have been identified.
Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association. 117PANDAS and Anorexia Nervosa—A Spotters’ Guide B. Vincenzi et al.
(a) Erythrocyte sedimentation rate (ESR) (b) (GABHS) antibodies (see below).
ESR is the oldest and probably still the most widely There are two GABHS antibodies of relevance: (i)
used indicator of inflammation. It is a laboratory Anti-streptolysin O (ASO) titres and (ii) Antideoxyr-
measurement of the rate of sedimentation of erythro- ibonuclease B (antiDNaseB) titres, identified through
cytes that is dependent on their degree of aggregation blood tests.
and the packed cell volume (PCV) (Thompson D & (a) ASO levels reach their peak three to six weeks after
Bird HA, 2004). An ESR of above 20 mm/hour is a streptococcal infection.
indicative of inflammation. Other causes of an elevated (b) AntiDNaseB levels reach their peak six to eight
ESR include anaemia, rheumatic disease, liver and weeks after a streptococcal infection.
kidney disease, neoplasm and dysproteinemias (Weber
R & Fontana A, 2007). The laboratory at NIMH considers ASO and Anti-
DNaseB streptococcus titers between 0-400 IU/ml to be
(b) C-reactive protein (CRP)
normal (National Institute of Mental Healh, 2005).
CRP is an acute-phase circulating protein secreted Other labs set the upper limit at 150 or 200 IU/ml.
predominantly by hepatocytes, that play a role in the Since each lab measures titers in different ways, it is
human innate immune response and provides a stable important to know the range used by the laboratory
plasma biomarker for low-grade systemic inflammation where the test was done.
(Sen & Belli, 2007). A CRP level is regarded as elevated
when above 5 g/ml. Serum levels of CRP are often Problems with the specific markers
elevated among patient with acute rheumatic fever
There are a number of problems associated with the
(ARF) (Du Clos, 2000, 2003; Bisno AL, 2000).
specific markers for streptococcal infection. Firstly
(c) Neopterin there is a high prevalence of GABHS infections in
childhood with up to 20% of school-age children being
Neopterin is a protein produced by human mono-
‘streptococcus carriers’ (positive throat culture, but no
cytes/macrophages which serves as a biomarker of cell-
serological evidence of infection nor any clinical
mediated immunity. Serum levels of Neopterin are
manifestations nor any immune response) (Leonard
considered as elevated when exceeding 10 nmol/L. Such
& Swedo, 2001).
levels of neopterin have been observed in association
Secondly ASO and antiDNase B may remain elevated
with several auto-immune diseases and suggest a chal-
for months after the infection, thus, to make a diagnosis
lenge to the immune mechanisms. However, this does
of current streptococcal infection, be that the first time
not specifically indicate either a streptococcal infection
or an exacerbation, longitudinal measures are required
or an auto-immune reaction (Altindag, Sahin, Inanici,
to check whether antibodies are rising or falling. The
& Hascelik, 1998; Berdowska & Zwirska-Korczala,
‘sine qua non’ of the diagnosis of PANDAS is that either
2001; Giovannoni et al., 1997; Horak et al., 2001).
onset or exacerbations of neuropsychiatric symptoms
The main problem with each of these markers is that
have to be temporally related to GABHS infection.
they reflect only a generalized inflammatory response to
Elevated titres of streptococcus antibodies at any one
an unknown agent and cannot be used as evidence of
time are insufficient to diagnose current infection;
either a streptococcal infection or an auto-immune
antibodies titres should be measured repeatedly to
reaction.
assess whether they are rising or falling (de Oliveira,
(2) Specific markers of streptococcal infection 2007). Furthermore some control subjects have elevated
titres (Loiselle, Wendlandt, Rohde, & Singer, 2003). It is
(a) Throat swab remains the gold standard for doc- not known whether these are false positives or subjects
umenting the presence of the relevant infective who have had an earlier streptococcus infection, but
agent, Group A b-haemolytic streptococcus without obvious symptoms.
(GABHS) (Leung, Newman, Kumar, & Davies, Finally, between 90 and 95% of sore throats have a
2006). While it is a useful marker in the acute viral aetiology (Murphy et al., 2007), so a history of sore
phase of infection, it is of very limited value once throat alone does not necessarily indicate a strepto-
this phase has passed. coccal infection.
118 Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.B. Vincenzi et al. PANDAS and Anorexia Nervosa—A Spotters’ Guide
(3) Non-specific markers of an auto-immune response Finally negative AnAb results in some patients could
reflect the point in the natural history of the disease at
Two such markers have been identified.
which AnAb levels are analyzed. This does not always
(a) Antineuronal antibodies (AnAb) correspond to the most symptomatic period. It is
possible that AnAb reactivity is a phenomenon that
AnAb (sometimes referred to as anti basal ganglia
waxes and wanes with the clinical course (Church, Dale,
antibodies or ABGA) are autoantibodies that cross-
Lees, Giovannoni, & Robertson, 2003; Morer et al.,
react with human brain tissue, specifically with the
2008). Longitudinal studies are necessary to investigate
basal ganglia nuclei, caudate and putamen. They may
the temporal association between AnAb positive results,
be ascertained by using both qualitative (Western blot-
streptococcus infection and neuropsychiatric symptoms.
ting) and quantitative techniques (ELISA) (Martino
& Giovannoni, 2004; Martino et al., 2007). Their pre- (b) D8/17 Monoclonal Antibody
sence indicates an ongoing auto-immune process
D8/17-specific monoclonal antibody is a mouse
(Martino et al., 2007).
immunoglobulin M (IgM) monoclonal antibody that
AnAb are associated with a wide spectrum of post-
can detect specific proteins on the surface of cells.
streptococcal neuropsychiatric disorders such as
Individuals are classified as ‘D8/17 positive’ if they have
Sydenham’s chorea, the prototype of post-streptococcal
12% or more D8/17 positive cells (Gibofsky, Khanna,
disease of the CNS, acute disseminated encephalomye-
Suh, & Zabriskie, 1991; Herdy, Zabriskie, Chapman,
litis, encephalitis lethargica, TS, OCD, infantile bilateral
Khanna, & Swedo, 1992; Khanna et al., 1989).
striatal necrosis, paroxysmal dystonia syndrome,
D8/17 levels have been found to be elevated, when
anxiety disorders, depressive disorders, enuresis, con-
compared with controls, in the Rheumatic Fever (Khanna
duct disorder and ADHD (Martino et al., 2007).
et al., 1989), and in some cases of tics/TS and OCD
Common to all these disorders is basal ganglia
(Murphy et al., 1997; Murphy et al., 2001), trichotillo-
dysfunction (Martino & Giovannoni, 2004).
mania (Niehaus et al., 1999), autism (Hollander et al.,
1999) and AN (Sokol, 2000). Elevated levels have not
been found in adults with OCD (Eisen et al., 2001).
Problems with AnAb
The presence of the blood-brain barrier (BBB) renders
Problems with D8/17
the basal ganglia, like most CNS structures, relatively
inaccessible to circulating antibodies. It is unclear how Studies of D8/17 have used different techniques and as
autoantibodies could have access to the CNS but a yet there is no uniform standardized laboratory
variety of possible mechanisms have been suggested procedure (Chapman, Visvanathan, Carreno-Manjar-
(Martino et al., 2007; Moretti, Pasquini, Mandarelli, rez, & Zabriskie, 1998; Hoekstra et al., 2002; Murphy
Tarsitani, & Biondi, 2008). et al., 1997). Furthermore there is some evidence
There is a lack of any uniform standardized labo- suggesting that ethnicity may confound results and
ratory procedure in this area of interest (i.e. differences reduce their discriminatory ability (Kumar, Kaur,
in tissue conditions and serum dilutions). Different Grover, Singal, & Ganguly, 1998). For example,
basal ganglia nuclei (putamen, caudate or globus 90–100% of patients with Acute Rheumatic Fever
pallidus) have been studied with different results (ARF) patients in USA (of unspecified ethnic origin)
(Morer, Lazaro, Sabater, Massana, Castro, & Graus, were found to have elevated D8/17 B cell expression,
2008), suggesting varying degrees of sensitivity to auto- but only 66% of such patients in India (Ganguly,
immune reactivity. Furthermore, since it is possible that Anand, Koicha, Jindal, & Wahi, 1992). In contrast some
other brain areas might be involved, further studies of earlier studies found similar results across different
multiple brain areas, including those not thought to be ethnic population and geographic regions (Gibofsky
involved in these disorders, are needed (Kiessling, et al., 1991).
Marcotte, & Culpepper, 1994). There is some uncertainty regarding gender differ-
In addition AnAb are not specific for post- ences in D8/17 reactivity. Hollander et al. (1999) raised
streptococcal disease, but for an auto-immune process a possible association between gender and D8/17
that could be triggered also by different pathogens. positivity and Eisen et al. (2001) found a significantly
Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association. 119PANDAS and Anorexia Nervosa—A Spotters’ Guide B. Vincenzi et al.
higher incidence of D8/17-positive B cells in males than precision renders them of little value in investigating
females with OCD. However, previous studies do not PANDAS. Although normal values would suggest that
support this difference (Khanna et al., 1989; Swedo, an active PANDAS process is very unlikely they would
1994). not exclude a previous history of such a process.
Finally although D8/17 positivity has been viewed as Specific markers of streptococcal infection are throat
a heritable trait (much like blood group substances A, B, swab culture and the GABHS antibodies, i.e. ASO, whose
O etc.) and therefore should not vary with age, there has titre peaks 3 to 6 weeks after streptococcal infection, and
been some suggestion that it might decline with age antiDNaseB, peaking after 6 to 8 weeks. When positive
(Eisen et al., 2001). they provide evidence of recent or current streptococcal
These problems may explain some of the incon- infection. Normal levels exclude recent or current
sistencies in the findings and contribute to the infection, but not previous infection.
uncertainty as to their significance. Nonetheless there The non-specific markers of an auto-immune
is sufficient indication to conclude that D8/17 positivity reaction are AnAb and D8/17. When positive they
could represent a marker of PANDAS. A further issue provide evidence of current or recent auto-immune
for consideration relates to whether D8/17 levels reactivity, but make no statement about the infective
fluctuate during the disease or with PANDAS exacer- agent itself.
bations. If so then D8/17 should not be treated as a There are numerous other problems associated with
dichotomous variable (positive or negative) but attempting to identify possible PANDAS through serum
possibly as an indicator of stage or severity. It is as markers: (i) Lack of standardized analytical methods; (ii)
yet uncertain whether or not D8/17 is an indicator of an possible variation in levels with age, ethnicity, gender and
auto-immune reaction specifically to streptococcus. stage of illness; (iii) lack of definite cut-off points for D8/
17 which would deem clinical significance.
Detection of PANDAS–AN is a complex and
Discussion hazardous endeavour due to our inadequate current
The term PANDAS implies an auto-immune response state of knowledge, the lack of specific markers and the
to streptococcal infection. Although PANDAS-mediated methodological problems associated with existing
OCD and tics/TS have been generally accepted as valid markers. Nonetheless every effort should be made to
entities, the concept of PANDAS–AN remains con- identify the species and as much information as possible
troversial. The clinical criteria for such a diagnosis have should be gathered to enhance our knowledge base.
been only loosely defined and there are no conclusive Accordingly we offer here suggestions for medical
diagnostic investigations. If PANDAS–AN can be assessment of those cases that raise clinical suspicion.
accurately diagnosed then antibiotic and immuno- We recommend the following screening procedures be
modulatory treatments might possibly be implemented. considered in children and young adolescents with
The aim of this paper has been to review the possible abrupt and early onset AN, particularly if they have had
markers for PANDAS–AN in the hope that future an upper respiratory infection within the preceding
investigations may yield a pattern of reactivity we can month.
use to define and eventually treat this subset of children
(1) A throat swab with a specific request for examin-
with acute onset AN. This review has identified three
ation for GABHS infection
categories of marker: (i) Non-specific markers of
(2) ESR, CRP and routine blood tests e.g. white cell
inflammation or immune response (ii) specific markers
counts
of streptococcal infection and (iii) non-specific markers
(3) GABHS antibodies, either ASO or antiDNAseB,
of an auto-immune response. There are no markers that
but preferably both
specifically identify an auto-immune response to
(4) AnAb and, if at all possible, D8/17. Although this
streptococcal infection.
latter is probably the least available of all the
The non-specific markers of inflammation or
relevant investigation it is likely to be the most
immune response, (ESR, CRP and neopterin) when
useful
positive, provide evidence of current inflammation, but
do not identify specific pathogenic agents nor are they What then would be sufficient to make a diagnosis of
evidence of an auto-immune reaction. This lack of PANDAS–AN? Clearly the more positive features there
120 Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.B. Vincenzi et al. PANDAS and Anorexia Nervosa—A Spotters’ Guide
are the more likely is the diagnosis. To take an extreme Markers should be measured in a standardized way
example, in the presence of the clinical features outlined and all test results should be reported non-dichot-
above and with all the markers being positive, the omously if possible, to avoid arbitrary and therefore
diagnosis of PANDAS–AN would seem very likely. At misleading reports of normality or abnormality.
the opposite extreme, when none of the clinical features ‘Normal’ control groups should be included as much
are present and all the investigations are normal, PAN- as possible given that the rates of streptococcal infection
DAS–AN is extremely unlikely. There are an enormous may be influenced by age, geographical, annual and
number of possible permutations between these two seasonal variations, socioeconomic status, site of infec-
extremes. However, some of the markers are more tion and time since the onset of infection. Laboratory
relevant than others. Should either AnAb or D8/17 variation may affect the reported incidence (Murphy
be positive, even if other markers are normal, suspicion et al., 2007). We should also take into account that
should be aroused, especially in the presence of an GABHS could be just one possible agent responsible
abrupt and early onset, with evidence of preceding sore for a neuropsychiatric manifestation of AN. Allen,
throat, episodic course and neurological abnormalities. Leonard, and Swedo (1995) have coined the acronym
As for future research there is much to be done. First PITANDs (Paediatric Infection-Triggered, Auto-
and foremost we are dependent upon our colleagues in immune, Neuropsychiatric Disorders) to allow for
the specialty of auto-immune disease to discover more the possibility of other aetiological agents for neurop-
specific markers for auto-immune reactions to strep- sychiatric phenomena.
tococcal infection. In the meantime the eating disorders
can still make a significant contribution. We need to
design studies that overcome the many methodological
weaknesses in earlier reports. Index samples should be
Conclusions
as large and as homogenous as possible, and should be Given the current state of knowledge, diagnosing
based upon the reported criteria for PANDAS–AN: (i) PANDAS is extraordinarily difficult. However, extra-
Prepubertal onset (ii) acute onset and/or symptom polating from knowledge about Sydenham’s chorea and
exacerbation of AN (iii) evidence of antecedent or PANDAS–OCD and PANDAS–tics/TS, a heightened
concomitant streptococcal infection: Positive throat index of suspicion for the existence of an auto-immune
culture and positive serological findings (elevated reaction in the brain response to environmental
antibodies titre) (iv) increased psychiatric symptoms infectious agents culminating in ‘anorexia nervosa’
that do not occur exclusively during stress or physical should be maintained.
illness (v) concomitant neurological abnormalities, The ultimate goals in the identification of the
with motor hyperactivity and/or adventitious move- existence of PANDAS–AN are two-fold. The first is
ments. The index sample should be compared with a to help elucidate the biological basis for changes within
matched group of patients with AN who have no the brain, which culminate as AN. The second is to
evidence of PANDAS. Ethical considerations may enhance the possibility of new treatments for AN such
exclude the possibility of a healthy control group, as antibiotics for acute onset or exacerbations and
but normative data should be obtained if possible immunomodulatory therapies for some of those who
because of the high prevalence of GABHS infections in appear to be treatment-resistant. In the light of this
childhood and the fact that up to 20% of school-age review we recommend to clinicians and researchers the
children are ‘streptococcus carriers’ i.e. they have a following method of identification. PANDAS–AN
positive throat culture in the absence of any clinical should be considered in the following circumstances
manifestations or serological evidence of infection (i) prepubertal onset (ii) acute onset and/or symptom
(Leonard & Swedo, 2001). Screening, using all the exacerbation of AN (iii) evidence of antecedent or
PANDAS markers, should be conducted as early in the concomitant streptococcal infection: Positive throat
disease process as possible. Longitudinal evaluations are culture and positive serological findings (elevated
necessary because, in OCD and tics/TS associated with antibodies titre) (iii) increased psychiatric symptoms
PANDAS, symptom exacerbations are associated with that do not occur exclusively during stress or physical
seropositivity and symptom remission is associated illness (iv) concomitant neurological abnormalities,
with falling titres or seronegativity (Swedo et al., 1998). with motor hyperactivity and/or adventitious move-
Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association. 121PANDAS and Anorexia Nervosa—A Spotters’ Guide B. Vincenzi et al.
ments. In such circumstances the following tests should de Oliveira, S. K. (2007). PANDAS: A new disease? Journal of
be conducted: Pediatric, 83, 201–208.
(i) Full blood counts, ESR, CRP and Neopterin, (ii) Du Clos, T. W. (2000). Function of C-reactive protein.
Annal of Medicine, 32, 274–278.
Throat swab (monthly surveillance), (iii) ASO and
Du Clos, T. W. (2003). C-reactive protein as a regulator of
antiDNaseB (monthly surveillance), (iv) AnAb and
autoimmunity and inflammation. Arthritis Rheum., 48,
D8/17.
1475–1477.
We are unlikely to spot PANDAS unless we seek it Eisen, J. L., Leonard, H. L., Swedo, S. E., Price, L. H.,
and without so doing we may miss new therapeutic Zabriskie, J. B., Chiang, S. Y., et al. (2001). The use of
opportunities. antibody D8/17 to identify B cells in adults with obsessive-
compulsive disorder. Psychiatry Research, 104, 221–225.
Ganguly, N. K., Anand, I. S., Koicha, M., Jindal, S., & Wahi,
P. L. (1992). Frequency of D8/17 B lymphocyte alloanti-
Acknowledgements
gen in north Indian patients with rheumatic heart disease.
The authors acknowledge the pioneering work con- Immunology and Cell Biology, 70, 9–14.
ducted by the late Dr. Mae Sokol who was the first to Gibofsky, A., Khanna, A., Suh, E., & Zabriskie, J. B. (1991).
describe PANDAS–AN and whose untimely death The genetics of rheumatic fever: Relationship to strepto-
spurred us to continue on her behalf. coccal infection and autoimmune disease. Journal of
Rheumatology, 1–5.
Giovannoni, G., Lai, M., Kidd, D., Thorpe, J. W., Miller,
References
D. H., Thompson, A. J., et al. (1997). Daily urinary
Altindag, Z. Z., Sahin, G., Inanici, F., & Hascelik, Z. (1998). neopterin excretion as an immunological marker of dis-
Urinary neopterin excretion and dihydropteridine ease activity in multiple sclerosis. Brain, 120, 1–13.
reductase activity in rheumatoid arthritis. Rheumatology Herdy, G. V., Zabriskie, J. B., Chapman, F., Khanna, A., &
International, 18, 107–111. Swedo, S. (1992). A rapid test for the detection of a B-cell
Allen, A. J., Leonard, H. L., & Swedo, S. E. (1995). Case marker (D8/17) in rheumatic fever patients. Brazilian
study: A new infection-triggered, autoimmune subtype of Journal of Medical and Biological Research, 25, 789–794.
pediatric OCD and Tourette’s syndrome. J. Am. Acad. Hoekstra, P. J., Kallenberg, C. G., Korf, J., & Minderaa, R. B.
Child Adolesc. Psychiatry, 34, 307–311. (2002). Is Tourette’s syndrome an autoimmune disease?
American Psychiatric Association. (2000). Diagnostic and Molecular Psychiatry, 7, 437–445.
statistical manual of mental disorders (text revision) (4th Hollander, E., DelGiudice-Asch, G., Simon, L., Schmeidler,
ed.). Washington, DC: A.P.A. J., Cartwright, C., DeCaria, C. M., et al. (1999).
Ayoub, E. M., & Wannamaker, L. W. (1966). Streptococcal B lymphocyte antigen D8/17 and repetitive behaviors
antibody titers in Sydenham’s chorea. Pediatrics, 38, 946– in autism. American Journal of Psychiatry, 156, 317–
956. 320.
Berdowska, A., & Zwirska-Korczala, K. (2001). Neopterin Horak, P., Scudla, V., Hermanovo, Z., Pospisil, Z., Faltynek,
measurement in clinical diagnosis. Journal of Clinical L., Budikova, M., et al. (2001). Clinical utility of selected
Pharmacology Therapy, 26, 319–329. disease activity markers in patients with systemic lupus
Bisno, A. L. (2000). Nonsuppurative poststreptococcal erythematosus. Clinical Rheumatology, 20, 337–344.
sequelae: Rheumatic fever and glomerulonephritis. In Khanna, A. K., Buskirk, D. R., Williams, R. C., Jr., Gibofsky,
G. L. Mandell, & L. Dolin (Eds.), Principles and practice A., Crow, M. K., Menon, A., et al. (1989). Presence of a
og infectious disease (15th ed. pp. 2117–2118). Philadel- non-HLA B cell antigen in rheumatic fever patients and
phia: Churchill Livingstone. their families as defined by a monoclonal antibody.
Chapman, F., Visvanathan, K., Carreno-Manjarrez, R., & Journal of Clinical Investment, 83, 1710–1716.
Zabriskie, J. B. (1998). A flow cytometric assay for D8/17 Kiessling, L. S., Marcotte, A. C., & Culpepper, L. (1994).
B cell marker in patients with Tourette’s syndrome and Antineuronal antibodies: tics and obsessive-compulsive
obsessive compulsive disorder. Journal of Immunological symptoms. Journal of Developmental and Behavioral
Methods, 219, 181–186. Pediatrics, 15, 421–425.
Church, A. J., Dale, R. C., Lees, A. J., Giovannoni, G., & Kumar, D., Kaur, S., Grover, A., Singal, P. K., & Ganguly,
Robertson, M. M. (2003). Tourette’s syndrome: A cross N. K. (1998). An easy method for detection of rheumatic
sectional study to examine the PANDAS hypothesis. antigen(s) in rheumatic fever/rheumatic heart disease
Journal of Neurogical Neurosurgery Psychiatry, 74, 602– patients by dot-ELISA. Canadian Journal of Cardiology,
607. 14, 807–810.
122 Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association.B. Vincenzi et al. PANDAS and Anorexia Nervosa—A Spotters’ Guide Leonard, H. L., & Swedo, S. E. (2001). Paediatric auto- Perlmutter, S. J., Leitman, S. F., Garvey, M. A., Hamburger, immune neuropsychiatric disorders associated with strep- S., Feldman, E., Leonard, H. L., et al. (1999). Therapeutic tococcal infection (PANDAS). International Journal of plasma exchange and intravenous immunoglobulin for Neuropsychopharmacology, 4, 191–198. obsessive-compulsive disorder and tic disorders in child- Leung, A. K., Newman, R., Kumar, A., & Davies, H. D. hood. Lancet, 354, 1153–1158. (2006). Rapid antigen detection testing in diagnosing Puxley, F., Midtsund, M., Iosif, A., & Lask, B. (2008). group A beta-hemolytic streptococcal pharyngitis. Expert PANDAS anorexia nervosa–endangered, extinct or non- Reviews in Molecular Medicine, 6, 761–766. existent? International Journal of Eating Disorders, 41, 15– Loiselle, C. R., Wendlandt, J. T., Rohde, C. A., & Singer, H. S. 21. (2003). Antistreptococcal, neuronal, and nuclear anti- Sen, J., & Belli, A. (2007). S100B in neuropathologic states: bodies in Tourette syndrome. Journal of Pediatric Neurol- The CRP of the brain? Journal of Neuroscience Research, ogy, 28, 119–125. 85, 1373–1380. Martino, D., & Giovannoni, G. (2004). Antibasal ganglia Snider, L. A., & Swedo, S. E. (2003). Post-streptococcal antibodies and their relevance to movement disorders. autoimmune disorders of the central nervous system. Curr. Opin. Neurol, 17, 425–432. Current Opinion in Neurology, 16, 359–365. Martino, D., Church, A., & Giovannoni, G. (2007). Are Sokol, M. S. (2000). Infection-triggered anorexia nervosa antibasal ganglia antibodies important, and clinically in children: Clinical description of four cases. Journal useful? Practice in Neurology, 7, 32–41. of Child and Adolescent Psychopharmacology, 10, 133– Morer, A., Lazaro, L., Sabater, L., Massana, J., Castro, J., & 145. Graus, F. (2008). Antineuronal antibodies in a group of Sokol, M. S., & Gray, N. S. (1997). Case study: An infection- children with obsessive-compulsive disorder and Tourette triggered, autoimmune subtype of anorexia nervosa. Jour- syndrome. Journal of Psychiatric Research, 42, 64–68. nal of the American Academy of Child and Adolescent Moretti, G., Pasquini, M., Mandarelli, G., Tarsitani, L., & Psychiatry, 36, 1128–1133. Biondi, M. (2008). What every psychiatrist should know Sokol, M. S., Ward, P. E., Tamiya, H., Kondo, D. G., about PANDAS: A review. Clinical Practice and Epide- Houston, D., & Zabriskie, J. B. (2002). D8/17 expression miology in Mental Health, 4, 13. on B lymphocytes in anorexia nervosa. American Journal Murphy, T. K., Benson, N., Zaytoun, A., Yang, M., Braylan, of Psychiatry, 159, 1430–1432. R., Ayoub, E., et al. (2001). Progress toward analysis of Swedo, S. E. (1994). Sydenham’s chorea. A model for child- D8/17 binding to B cells in children with obsessive hood autoimmune neuropsychiatric disorders. JAMA, compulsive disorder and/or chronic tic disorder. Journal 272, 1788–1791. of Neuroimmunology, 120, 146–151. Swedo, S. E., & Grant, P. J. (2005). Annotation: PANDAS: A Murphy, T. K., Goodman, W. K., Fudge, M. W., Williams, model for human autoimmune disease. Journal of Child R. C., ,Jr., Ayoub, E. M., Dalal, M., et al. (1997). Psychology and Psychiatry, 46, 227–234. B lymphocyte antigen D8/17: A peripheral marker for Swedo, S. E., Leonard, H. L., Garvey, M., Mittleman, B., childhood-onset obsessive-compulsive disorder and Allen, A. J., Perlmutter, S., et al. (1998). Pediatric Tourette’s syndrome? American Journal of Psychiatry, autoimmune neuropsychiatric disorders associated with 154, 402–407. streptococcal infections: Clinical description of the first Murphy, T. K., Snider, L. A., Mutch, P. J., Harden, E., 50 cases. American Journal of Psychiatry, 155, 264– Zaytoun, A., Edge, P. J., et al. (2007). Relationship of 271. movements and behaviors to Group A Streptococcus Thompson, D., & Bird, H. A. (2004). Investigation of the infections in elementary school children. Biological rheumatic diseases. In D. A. Isenberg, P. Maddison, P. Psychiatry, 61, 279–284. Woo, D. Glass, & F. Breedveld (Eds.), Oxford textbook of National Institute of Mental Health [Online]. (2005). Avail- rheumatology (3rd ed., pp. 473–479). UK: Oxford Uni- able at: http://intramural.nimh.nih.gov/pdn/faqs/htm versity Press. Niehaus, D. J., Knowles, J. A., van, K. J., du, T. W., Kaminer, Weber, R., & Fontana, A. (2007). Fever. In W. Siegenthaler, D., Seedat, S., et al. (1999). D8/17 in obsessive-compulsive & A. Aeschlimann (Eds.), Differential diagnosis in disorder and trichotillomania. South African Medical internal medicine: From symptom to diagnosis Journal, 89, 755–756. (pp. 196–197). New York: Thieme Medical Publishers. Eur. Eat. Disorders Rev. 18 (2010) 116–123 ß 2010 John Wiley & Sons, Ltd and Eating Disorders Association. 123
You can also read
