the Most Recent Data to 'Bear' In Carving Nature at its Joints
an outbreak of streptococcal infections on Rhode Island in 1991, Dr.
Louise Kiessling observed that strep infections seemed to precipitate
the onset of tic disorders (TSA, 1993; in Kushner & Kiessling, 1993;
Kurlan, 1998). The subsequent link made between alpha beta hemolytic
streptococcal infections and neurological sequelae, evidence for which
had already appeared sporadically within the literature (Kondo & Kabasawa,
1978; Matarazzo, 1992) was a valuable display of reciprocal transaction
in the medical literature. Rather than engaging in fruitless and tired
debates over whether a particular disorder's etiology lies in "nature"
or "nurture", neurology or psychology, both environmental trigger and
neurological diathesis could readily be seen to interact and influence
one another in the development of pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infections (PANDAS).
that PANDAS has been established and verified as a diagnosis, however,
discussions now turn to the question of where PANDAS fits in the context
of other syndromes and disorders with similar collections of symptoms.
Is PANDAS similar enough to other manifestations of rheumatic fever
(such as Sydenham's Chorea; SC) to be subsumed under this? Are all instances
of disorders such as Tourette Syndrome (TS) and Obsessive-Compulsive
Disorder (OCD) subsumed under the label PANDAS - is PANDAS simply our
first clear etiological delineation of these conditions? Or are all
three (SC, PANDAS, TS) unique diagnoses unto themselves? While definitive
answers to these issues are yet to be found, the elucidation of how
at least a subset of the population experiencing tics, obsessions, and
compulsions have come to develop these symptoms brings whole new perspectives
on prevention and treatment to attention.
have known since the early 1960's of the connection between opportunistic
childhood streptococcal infections and SC (Kushner & Kiessling, 1993).
Although at the time considerable opposition to this idea was raised,
the suggestion that Group Alpha beta hemolytic streptococcus infection
(GABHS) elicits antibodies that cross-react with the basal ganglia to
produce involuntary movements and abnormal behaviours in SC is widely
recognized today (Garvey, Giedd, & Swedo, 1998). It is believed that
the GABHS infection leads to rheumatic fever in about 2-3% (Murphy,
Goodman, Ayoub & Voeller, 2000), usually within 20 days. The fever manifests
with inflammation of the heart (carditis), joints (arthritis), and brain.
Two to six months following the infection, SC then manifests in ballismus,
facial grimacing, fasciculations of the tongue, fine motor control loss,
hypotonia, motor impersistence, gait disturbance, and speech abnormalities
(Kurlan, 1999; Murphy, Goodman, Ayoub & Voeller, 2000). How exactly
the antibodies are able to permeate the blood-brain barrier (BBB) to
cross-react with the basal ganglia is not precisely known; it has been
suggested that immunologic stress may cause increased permeability of
the BBB, thus allowing antineuronal antibodies to pass (Kurlan, 1998).
the last decade, evidence has begun to accumulate to suggest that this
same basal ganglia autoimmunization may also be a trigger for many movement
disorders in genetically predisposed individuals causing tics and/or
obsessive-compulsive symptoms. Rather striking is the finding by Singer,
Giuliano, Hansen et al. (1998) that the mean levels of serum antibodies
found to be increased in a TS sample were those against putamen, and
that antibodies specific to the caudate and putamen occurred more frequently
in TS individuals: the various cortico-striato-thalamo-cortical (CSTC)
circuits implicated in TS all involve the caudate or putamen (Rauch,
1999; Sawle, Lees, Hymas, et-al 1993). As well, while the precise neurological
abnormalities associated with TS remain debatable, an overwhelming number
of the studies implicate either the putamen or caudate (Wolf, 1996;
Malison et al., 1995; Riddle et al., 1992; Moriarty, 1995).
and other discoveries have prompted a parallel conflict in the scientific
community (Garvey, Giedd, & Swedo, 1998). One of the biggest matters
to address is how do we alter our current diagnostic practices to accommodate
this new knowledge. What if any new categories do we create, and what
if any categories are now rendered obsolete?
PANDAS a Subtype of Sydenham's Chorea?
In at least one study, those in the PANDAS sample were screened carefully
for signs of rheumatic fever using the Jones criteria; no typical manifestations
were found (Swedo, Leonard, Mittleman, et al., 1997). For example, there
is no evidence of brain inflammation and the resulting delirium in PANDAS
cases. There is also no evidence to suggest that individuals with TS
suffer an increased incidence of cardiac disease (Murphy, Goodman, Ayoub
& Voeller, 2000). It is even debated whether true chorea (brief, arrhythmic,
"dancing" movements) is seen in the PANDAS population (Kurlan, 1999;
Swedo, Leonard, Mittleman et al., 1997); currently PANDAS will not be
considered as a diagnosis if chorea is present (Murphy, Goodman, Ayoub
& Voeller, 2000).
seems more likely that PANDAS and SC are both distinct manifestations
of a similar underlying streptococcal autoimmunity. Swedo, Leonard,
Mittleman, et al. (1997) conducted a study to determine whether children
diagnosed with PANDAS could be identified by the same marker as for
rheumatic fever susceptibility (D8/17, found on DR+ cells in the peripheral
circulation). Compared to controls (who were D8/17 positive only 17%
of the time), those diagnosed with PANDAS were significantly more likely
to carry this marker (85% were D8/17 positive). Moreover, the percentage
of positive carriers in the PANDAS population was quite similar to that
of a population of children diagnosed with SC (89%; Swedo, Leonard,
Mittleman, et al., 1997). This latter finding should be viewed cautiously
however, as the n for the SC sample was only a third of the PANDAS sample.
The authors go on to postulate that different genetic vulnerability,
neurodevelopmental maturation, and host-microbe interaction specificity
may account for the different responses to GABHS in the two populations.
TS a Subtype of Sydenham's Chorea?
enough, the original observers of TS (such as Itard) actually resisted
the formation of a category for these cases separate from general choreas
(Kushner & Kiessling, 1993). While in general terms tics are distinct
from chorea, it is not uncommon for individuals with SC to exhibit some
motor and phonic tics, and individuals with TS may show chorea-like
movements (Murphy, Goodman, Ayoub & Voeller, 2000). Streptococcal M
proteins (particularly M12) evoke an autoimmune response in neurons
of the basal ganglia in SC: antibodies against M12 proteins were also
found to be significantly increased in a sample of TS individuals (Muller,
Kroll, Schwarz, et al, poster A). In addition, increased titers of antistreptococcal
antibodies were found in children and adolescents with TS as compared
to controls (Muller, Riedel, Straube, et al, poster). Kiessling, Marcotte,
and Culpepper (1993) further note that the percentage of children in
their sample with a high quantity of antineuronal antibodies was very
similar to the percentage found in children with SC (44% vs. 46%).
the similarities between TS and SC, there are some important differences.
While it was widely believed that the involuntary movements observed
in both chorea and what was to be eventually called TS in all likelihood
shared a common pathology, the latter, like PANDAS, did not exhibit
any delirium or signs of rheumatic fever (Kushner & Kiessling, 1993).
Another problem is that symptoms SC has in common with TS usually resolve
themselves within one or two years (Kiessling, 1997). TS tends to be
considerably longer in duration, first diagnosed before the age of 11
in 96% of cases (Robertson, 1989) and lasting until at least late adolescence
(Goetz, Tanner, Stebbins et al. 1992). New research has even questioned
whether in the majority of cases tics DO resolve in early adulthood
- it now seems more likely that the majority of people with TS can expect
to have some level of tic activity throughout life (Goetz, Tanner, Stebbins,
et al. 1992). Based on the available evidence, it seems safe to assert
that Charcot and Tourette acted appropriately in discriminating the
diagnoses of TS and SC.
TS a Subtype of PANDAS?
PANDAS nor TS seem to fit the Sydenham's Chorea label well; while the
evidence of high levels of antineuronal antibodies in both groups has
been well replicated (for example, Kiessling, Marcotte, & Culpepper,
1993), the symptoms that individuals with TS and PANDAS experience are
of considerably longer duration than those seen in Sydenham's Chorea,
and do not include any symptoms of rheumatic fever. Perhaps, though,
TS and PANDAS are one and the same.
first blush, the TS cases subsumed within the PANDAS diagnosis do not
appear to differ from TS cases in general. Judging from PANDAS samples
taken from Swedo, Leonard, Mittleman et al. (1997) and Garvey, Perlmutter,
Allen, et al. (1999), similar sex ratios (more boys to girls), incidences
of "pure" TS (tics without comorbid diagnoses), and incidences of comorbid
OCD and ADHD appear in both PANDAS and TS populations (Fast & Freeman,
1997; Robertson, 1989). Average age of onset for both PANDAS and TS
are similar (Murphy, Goodman, Ayoub & Voeller, 2000). Furthermore, both
TS and PANDAS follows a waxing and waning course (it was thought at
one time that PANDAS was distinctively episodic; more recent descriptions
have turned from this notion), and it is put forward that while greater
awareness of TS may be creating the illusion of increased incidence,
a very real incident increase may be occurring due to the development
of more virulent strains of GABHS (Kurlan, 1998). Children with tics
were 4 to 6 more likely to have evidence of streptococcal infection,
and to have serological (blood) antibodies to central nervous system
cells (tested on caudate sections; Kiessling, Marcotte, & Culpepper,
1993). This finding was replicated by the same authors. Individuals
with TS symptoms have been found to carry the same marker as that found
in rheumatic fever on their b-lymphocytes, known to be caused by infection
by alpha-beta hemolytic streptococcus (Swedo, Leonard, Mittleman, et
al. 1997). Finally, a recent study by Kleinsasser, Misra, Bhatara, and
Sanchez (1999) documented the effective treatment of a PANDAS case with
risperidone, a neuroleptic well documented to be effective in the treatment
of TS (for example, Zhang 1999 poster).
are problems with considering all cases of TS to be included beneath
the PANDAS construct. The diagnostic criteria for PANDAS, while somewhat
of a "moving target" (Murphy, Goodman, Ayoub & Voeller, 2000), are currently
a virtual mirror of TS. They are as follows: the presence of a tic disorder
with pediatric onset, an episodic course, neurological, psychological
(such as impulsivity) and cognitive (such as distractibility) abnormalities,
and finally the presence of comorbid psychiatric difficulties including
but not limited to Attention-Deficit Hyperactivity Disorder (ADHD),
Conduct Disorder, mood disorders, and anxiety disorders (Kurlan, 1999;
Swedo, 1999). The only unique criterion is that of temporal association
of tics subsequent to a strep infection (Kurlan, 1998). When one defines
PANDAS using all TS criteria it is hard for them NOT to appear similar.
This seems somewhat self-fulfilling. Despite this similar criteria,
evidence is mounting that TS is not restricted to childhood and adolescence
(Robertson, 1989; Goetz, Tanner, Stebbins, et al. 1992), although PANDAS
by definition is.
is more than one explanation for why one might expect to see an increase
of tic symptoms following a strep infection other than a causal one.
For instance, it could be a simple non-specific stress response: TS
literature has documented the exacerbating effect stress has on tics
(Robertson, 1989). This brings up the important caveat that correlation
does not equal causation.
an even more fatal blow comes in the discovery that the relationship
between the presence of antineuronal antibodies and tic symptoms is
not a clean one. Elevated neuronal antibodies cited so frequently in
the literature are missing in some individuals with TS; likewise they
are present in some controls without a tic disorder being present (Kurlan,
1998). Exacerbations in tic severity have been seen without concomitant
GABHS infection (Murphy, Goodman, Ayoub & Voeller, 2000). Moreover,
there appears to be no relationship between level of antineuronal antibodies
and tic severity.
seems then while we can tentatively conclude that perhaps a subset of
individuals currently diagnosed with TS may be best considered PANDAS
patients there are some with TS that remain distinct from this category.
In a recent review of the data, 10-20% was an agreed on figure for several
groups (Trifiletti & Packard, 1999; Murphy, Goodman, Ayoub & Voeller,
2000). Potential red flags for identifying the PANDAS subset of TS cases
could be acute and dramatic onset, a relapsing-remitting symptom pattern,
and a preceding GABHS infection or exposure, or pharyngitis or upper
respiratory infection (Swedo, Leonard, Garvey et al. 1998).
study of PANDAS provides a real opportunity to move further "upstream"
in the understanding and remediation of certain cases of TS: armed with
the knowledge of how and through what process this pathology appears,
clinicians are equipped to act much more proactively.
best, if a subgroup of TS patients is found to have their pathology
triggered by GABHS, the opportunity arises to screen vulnerable individuals
and prevent the onset of symptoms. Weiss and Garland (1997) warn that
positive antistreptolysin O (ASO) titers were rarely associated with
positive throat culture results in their client (Weiss & Garland, 1997),
suggesting that individuals being assessed for tic disorders should
be routinely checked for abnormally high antineuronal antibodies whether
or not their history includes sore throats.
worst, if an increase in tics following a strep infection only represents
a non-specific stress response, preventing and/or treating that stressor
will have beneficial effects in that exacerbations of the existing disorder
will be minimized. In a case study report, Weiss and Garland (1997)
note that treatment with amoxicillin was followed by a return to baseline
symptoms, although trials of thioridazine, alprazolam, paroxetine, risperidone,
clonidine, haloperidol, and sertraline each produced questionable improvements
those TS cases not responsive to traditional (dopamine-antagonist neuroleptics)
treatment, this new research could provide a possible new avenue for
treatment (Kurlan, 1999 symposium), although further work in this area
still needs to be done. Intravenous immune globulin (IVIG), plasmapherisis,
and penicillin have all been claimed beneficial in treating acute, severe
PANDAS (Swedo, 1999 symposium), although Kurlan (1998) points out that
many of these studies have not been controlled. Garvey, Perlmutter,
Allen et al., the following year, published a well-controlled, double-blind,
balanced cross-over study on the use of penicillin prophylaxis in the
treatment of PANDAS. Startlingly, the investigators found no change
in tic severity between placebo and drug trial phases (Garvey, Perlmutter,
Allen et al., 1999).
this research may also have similar repercussions for OCD and ADHD,
as these two disorders often co-occur with TS, and both may share similar
genetic heritages - namely an exaggerated reaction to GABHS infections,
leading to altered neuroanatomical circuitry. The degree to which the
PANDAS construct should be widened to accommodate these other disorders
is yet to be determined (Murphy, Goodman, Ayoub & Voeller, 2000).
evidence leads to the conclusion that PANDAS accounts for a subset of
individuals diagnosed with TS, and possibly other disorders such as
OCD and ADHD. PANDAS itself seems to share a similar etiology with SC,
but is best considered as a separate condition. Future work in the area
of PANDAS will no doubt be fruitful and exciting, for within the pursuit
of increased understanding of this causal pathology arises the potential
to minimize, alternatively treat, or prevent tic symptoms in some individuals
with TS altogether.
S. (1999). Is Tourette's syndrome one of the PANDAS? Molecular Medicine
Today, 5(1), 6.
DK; Freeman, RD (1997, October). Differences among TS clinics: preliminary
results from the CATS database. Tourette Syndrome: The Complexities
of Treatment. Symposium conducted at the Tourette Syndrome Foundation
of Canada International Symposium, Quebec City, QC.
MA; Giedd, J; Swedo, SE (1998). PANDAS: the search for environmental
triggers of pediatric neuropsychiatric disorders. Lessons from rheumatic
fever. Journal of Child Neurology, 13(9), 413-23.
MA; Perlmutter, SJ; Allen, AJ; Hamburger, S; Lougee, L; Leonard, HL;
Witowski, ME; Dubbert, B; Swedo, SE. (1999). A pilot study of penicillin
prophylaxis for neuropsychiatric exacerbations triggered by streptococcal
infections. Biological Psychiatry, 45(12), 1564-1571.
CG; Tanner, CM; Stebbins, GT; et al. (1992). Adult tics in Gilles de
la Tourette's syndrome: Description and risk factors. Neurology, 42,
LS; Marcotte, AC; Culpepper, L (1993). Antineuronal antibodies in movement
disorders. Pediatrics, 92(1), 39-43.
BJ; Misra, LK; Bhatara, VS; Sanchez, JD (1999). Risperidone in the treatment
of choreiform movements and aggressiveness in a child with "PANDAS".
South Dakota Journal of Medicine, 52(9), 345-7.
K; Kabasawa, T (1978). Improvement in Gilles de la Tourette syndrome
after cortcosteroid therapy. Annals of Neurology, 4, 387.
R. (1999, June). Symposium conducted at the Tourette Syndrome Association
3rd International Symposium on Tourette Syndrome, New York, NY.
R. (1998). Tourette's syndrome and 'PANDAS': will the relation bear
out? Neurology, 50(6), 1530-4.
HI, Kiessling, LS (1993). Rethinking the diagnostic boundaries of TS:
The possible role of streptococcal antibodies in TS. Tourette Syndrome
Association, 4, 6.
RT; McDougle, CJ; van Dyck, CH; Scahill, L; Baldwin, RM; Seibyl, JP;
Price, LH; Leckman, JF; Innis, RB (SPECT imaging of striatal dopamine
transporter binding in Tourette's disorder. American Journal of Psychiatry,
EB (1992). Tourette's syndrome treated with ACTH and prednisone: report
of two cases. Journal of Child and Adolescent Psychopharmacology, 2,
J; Costa, DC; Schmitz, B; Trimble, MR; Ell, PJ; Robertson, MM (1995).
Brain perfusion in Gilles de la Tourette's syndrome. British Journal
of Psychiatry, 167, 249-254.
N; Kroll, B; Schwarz, MJ; Riedel, M; Straube, A; Lutticken, R; Reinert,
RR; Kuhnemund, O (1999, June). Antibodies against streptococcal M 12
proteins are increased with Tourette's syndrome. Poster presented at
the Tourette Syndrome Association 3rd International Symposium on Tourette
Syndrome, New York, NY.
N; Riedel, M; Straube, A; Gunther, W; Wilske, B (1999). Anti-streptococcal
Antibodies and Tourette's Syndrome. 3rd International Scientific Symposium
on Tourette Syndrome. Poster presented at the Tourette Syndrome Association
3rd International Symposium on Tourette Syndrome, New York, NY.
TK; Goodman, WK; Ayoub, EM; Voeller, KK. (2000). On defining Sydenham's
chorea: where do we draw the line? Biological Psychiatry, 47(10), 851-7.
(1999). Symposium conducted at the Tourette Syndrome Association 3rd
International Symposium on Tourette Syndrome, New York, NY.
MA; Rasmusson, AM; Woods, SW; Hoffer, PB (1992). SPECT imaging of cerebral
blood flow in Tourette syndrome. British Journal of Psychiatry, 167,
MM (1989). The Gilles de la Tourette syndrome: the current status. British
Journal of Psychiatry, 154, 147-169.
KP. (1998). Tourette's syndrome and 'PANDAS'. Neurology, 51(5), 1516.
GV; Lees, AJ; Hymas, NF; Brooks, DJ; et-al (1993). The metabolic effects
of limbic leucotomy in Gilles de la Tourette syndrome. Journal of Neurology,
Neurosurgery and Psychiatry, 56(9), 1016-1019.
SE. (1999). Symposium conducted at the Tourette Syndrome Association
3rd International Symposium on Tourette Syndrome, New York, NY.
SE; Leonard, HL; Garvey, M; Mittelman, B; Allen, AJ; Perlmutter, S;
Lougee, L; Dow, S; Zamkoff, J; ad Dubbert, BK. (1998). Pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections:
clinical description of the first 50 cases. American Journal of Psychiatry,
SE; Leonard, HL; Mittleman, BB; Allen, AJ; Rapoport, JL; Dow, SP; Kanter,
ME; Chapman, F; Zabriskie, J. (1997). Identification of children with
pediatric autoimmune neuropsychiatric disorders associated with streptococcal
infections by a marker associated with rheumatic fever. American Journal
of Psychiatry, 154(1), 110-2.
RR; Packard, AM (1999). Immune mechanisms in pediatric neuropsychiatric
disorders. Tourette's syndrome, OCD, and PANDAS. Child and Adolescent
Psychiatric Clinics of North America, 8(4), 767-75.
M; Garland, J. (1997). More on PANDAS. Journal of the American Academy
of Child and Adolescent Psychiatry, 36(9), 1163-65.
SS; Jones, DW; Knable, MB; Gorey, JG; Lee, KS; Hyde, TM; Coppola, R;
Weinberber, DR (1996). Tourette syndrome: prediction of phenotypic variation
in monozygotic twins by caudate nucleus D2 receptor binding. Science,
273, 1225- 1227.
SJ (1999). An open trial of risperidone in the treatment of Tourette
syndrome. Poster presented at the Tourette Syndrome Association 3rd
International Symposium on Tourette Syndrome, New York, NY.