Definition

Formal definitions of tics include the terms involuntary, sudden, rapid, abrupt, repetitive, recurrent, nonrhythmic, motor movements or vocalizations (phonic productions). The use of the term “stereotyped” is not favored, since it implies a fixed condition and may lead to diagnostic confusion with another movement condition called stereotypic movement disorder. Tics are manifested in an extensive variety of forms, locations, and types; they are often considered to be fragments of a normal movement or vocal production that is misplaced and easily mimicked. Tics have differing degrees of intensity and frequency, and have unpredictable durations. Observation, either directly in the office or via homemade video, is essential for the correct diagnosis. Since some vocal (phonic) tics are the result of muscle contractions of the diaphragm or oropharynx forcing air across the vocal cords or through the nose and mouth, the formal separation of tics into motor and vocal components has been questioned. Several factors, however, support continuing the separation of motor and vocal tics; these include tradition and factor analysis data showing the groups to be distinct entities [Storch et al., 2005] with differing comorbidities [Khalifa and von Knorring, 2006].

Concept of Simple and Complex

Both motor and phonic tics are subdivided into simple and complex categories: constructs that may be valuable for classification and determining impact. For example, several recent studies using principal component factor analyses have identified differences in patients based on the presence of simple or complex motor and vocal tics [Alsobrook and Pauls, 2002; Mathews et al., 2007; Robertson, 2008a, b].

In general, simple tics typically precede the onset of more complex tics. Simple motor tics are brief, rapid movements that involve only a single muscle or localized group, e.g., eye blinking, head jerking, nose wrinkling, shoulder shrugging, abdominal tensing. In contrast, complex motor tics involve either a cluster of simple actions or a more coordinated sequence of movements. Complex motor tics can be nonpurposeful (facial or body contortions), have a more prolonged maintenance of a position (dystonic character), or appear purposeful but actually serve no purpose (touching, hitting, smelling, jumping, repeating observed movements [i.e., echopraxia], or making obscene gestures [i.e., copropraxia]). Unique tics have included vomiting and retching [Rickards and Robertson, 1997], anterior-posterior displacement of the external ear [Cardoso and Faleiro, 1999], sign language tics [Morris et al., 2000], air swallowing [Weil et al., 2008], palatal myoclonic movements [Schwingenschuh et al., 2007], and symptoms such as immobility, staring, and posturing (“blocking” tics) [Cavanna et al., 2008a]. Some investigators have subdivided tic movements into additional categories, such as clonic (eye blinking, head jerking), tonic (muscle tensing), dystonic (sustained posture), and blocking (prolonged tonic or dystonic tics that interrupt on-going motor activity).

Simple phonations include various sounds and noises (grunts, barks, yelps, sniffs, screeches, and throat clearing). Complex vocalizations involve the repetition of words (i.e., syllables, phrases, echolalia [repeating other people’s words], palilalia [repeating one’s own words], or coprolalia [obscene words]). Vocal tics can interfere with the flow of speech, causing difficulties at the initiation of speech resembling a stammer/stutter or at phrase transitions. In some individuals, there may be an alteration of volume, slurring of phrases, or accenting a particular word. An array of nonspeech motor behaviors (eye blinking or deviation, head jerks, limb and trunk movements) have been described in individuals who stutter [Abwender et al., 1998].

Characteristics

Several common characteristics of tics include their presence in typical locations, a waxing and waning course, the presence of particular factors that exacerbate or reduce tics, a suggestible nature, the report of a premonitory sensation, and suppressibility. Although tics may involve almost any external body part, nearly all TS patients at some time have tics involving the face and head regions. The precise underlying environmental or biological factor that causes tic variability and waxing and waning, over days or years, remains undetermined. Psychosocial stress and adversities have been implicated in exacerbations [Sukhodolsky et al., 2003], but the onset of tics has not been shown to be related to stressful life events [Wood et al., 2003; Horesh et al., 2008]. In most patients, changes in tics are not accounted for by small stressful life events [Hoekstra et al., 2004a] or by infections [Luo et al., 2004]. A nonrandom, “burstlike” pattern has led to suggestions of a “fractal, deterministic, and possibly chaotic process” underlying tic activity [Peterson and Leckman, 1998]. Tics can be exacerbated by periods of anticipation, emotional upset (e.g., stress, anxiety, excitement, anger), or fatigue [O’Connor et al., 2003; Wood et al., 2003]. In some individuals, a particular environment or condition is required, e.g., an inappropriate vocalization triggered by the presence of a person from a particular racial, religious, or ethnic group. Tics are also suggestible (i.e., appear during inquiries about specific movements or following observation of a movement or sound [echo phenomena]). Tic reduction often occurs when the affected individual is concentrating, focused, engaged in an activity, or emotionally pleased, or during sleep. Observation of reduced involuntary movements while asking the patient to perform a complex motor task can often assist in separating tics from other extrapyramidal disorders. Although a reduction or complete absence of tics is frequently noted during sleep, polysomnograms of TS subjects have demonstrated an increased rate of tics during all sleep stages [Cohrs et al., 2001].

Premonitory sensations are sensory phenomena, often a feeling, urge, impulse, tension, pressure, itch, burning, or tingle that occurs before a motor or phonic tic. These sensations are often localized to discrete anatomical regions (shoulders, girdle, hands, throat, and abdomen) [Leckman et al., 1993], but can be more generalized and ill defined. These sensations occur in more than 90 percent of adults [Kwak et al., 2003], but less frequently in young children (37 percent) [Banaschewski et al., 2003]. The “urge” often immediately disappears following performance of the tic, but recurs. Premonitory urges do not correlate with tic severity, and in older children seem to be related to obsessions, compulsions, and depression [Steinberg et al., 2009]. The ability to suppress tics briefly is relatively common. This active suppression of tics, however, is often associated with an exacerbation of premonitory sensations or a sense of increased “internal tension” that resolves when the tic is permitted to occur. Lastly, similar to what is observed in Sydenham’s chorea, patients with tics may occasionally attempt to disguise a tic as a seemingly purposeful behavior.

Misdiagnoses

Misdiagnoses are common. For example, eye-blinking tics may be thought to stem from ophthalmologic problems, ocular tics are confused with opsoclonus, throat-clearing tics are thought to be due to sinusitis or allergic conditions, involuntary sniffing frequently results in referral to an allergist, and a chronic persistent coughlike bark is called asthma. Non-tic movements that need to be distinguished include motor stereotypies, drug-induced akathisia, dystonia, or parkinsonism, and those associated with common comorbidities such as OCD, ADHD, and impulsive and antisocial behaviors [Kompoliti and Goetz, 1998; Mahone et al., 2004].

Tic Assessment Scales

The Yale Global Tic Severity Scale (YGTSS), a semistructured clinical interview, is the most widely used tic-severity ranking instrument [Leckman et al., 1989]. This scale consists of two components:

The latter subjective component is scored based on the impact of the tic disorder on self-esteem, family life, and social acceptance. A TS health-related quality of life scale (GTS-QOL) has been developed and validated [Cavanna et al., 2008b]. This is a 27-item, patient-reported, TS-specific scale with four subscales (psychological, physical, obsessional, and cognitive).

Provisional Tic Disorder

Provisional tic disorder is a new recommended term established to designate an individual with on-going fluctuating motor and/or vocal tics that began before age 18 years and have been present for less than 1 year. This category has been formally suggested, since it is impossible to predict whether an individual’s tics will persist for the requisite 1-year time interval required for a “chronic” designation or will fall into the previously used “transient tic disorder” category. The latter, a strictly retrospective diagnosis, required that tics be present for at least 4 weeks and resolve before 1 year, typically after several months’ duration.

Chronic (Motor or Vocal) Tic Disorder

Chronic (motor or vocal) tic disorder (CMVTD) requires that fluctuating tics start before age 18, that they be present for more than 1 year, and that individuals have either entirely motor or, less commonly, solely vocal tics. The 12-month minimum duration from time of first onset of symptoms admittedly represents an arbitrary, historical cutoff point. Several studies have documented the fact that chronic motor tic disorder represents a mild form of Tourette’s syndrome and that both are transmitted as inherited traits in the same family [Saccomani et al., 2005; Diniz et al., 2006].

Tourette’s Syndrome/Tourette’s Disorder

Formal criteria for Tourette’s syndrome, based on the definition provided by the Tourette Syndrome Classification Study Group [Tourette Syndrome Classification Study Group, 1993] are now very similar to those for Tourette’s disorder (TD) in the proposed DSM-V. Diagnoses require multiple motor and at least one vocal tic to have been present at some time during the illness, although not necessarily concurrently. TS and TD are chronic disorders with no specific limitation on the duration of a tic-free interval. Formal criteria for TS still retain an age of onset before 21 years, rather than the DSM’s age of onset limitation to less than 18 years. Most individuals, however, manifest their symptoms before the age of 11 years. Tics should occur many times a day, nearly every day, or intermittently throughout a period of 1 year. The disturbance should not be the result of the use of a substance or general medical condition. Coprolalia, one of the most socially distressing symptoms, is not a diagnostic criterion and studies have suggested that only 10–19 percent of patients exhibit this symptom [Goldenberg et al., 1994; Freeman et al., 2009]. TS is not a unitary condition, with factor analyses suggesting several different forms based on the presence of associated problems (i.e., solely tics, predominantly ADHD and aggressive behaviors, or primarily affective-anxiety-obsessional symptoms and self-injurious behaviors) [Robertson and Cavanna, 2007; Grados and Mathews, 2009; Rothenberger et al., 2007].

Substance-Induced Tic Disorder and Tic Disorder due to a General Medical Condition

These are suggested formal categories to replace previously used terminology such as tic disorder not otherwise specified, Tourettism, Tourette-like or secondary tic disorders. Substance-induced tic disorder requires evidence that the symptoms developed during or within 1 month of substance intoxication or withdrawal, and that there is existing evidence to support the role of the substance in causing tics [Klawans et al., 1978; Moshe et al., 1994; Lombroso, 1999]. Stimulants are not considered a good example, since there is existing evidence that they are no more commonly associated with tics as an adverse event than placebo or other medications [Gadow et al., 1995; Group, 2002]. Tic disorder due to a general medical condition requires evidence that the disturbance is the direct physiological consequence of a general medical condition [Mejia and Jankovic, 2005], such as infection [Devinsky, 1983; Northam and Singer, 1991; Riedel et al., 1998; Luo et al., 2004], toxins [Ko et al., 2004], stroke [Kwak and Jankovic, 2002; Gomis et al., 2008], head trauma [Krauss and Jankovic, 1997; Majumdar and Appleton, 2002; O’Suilleabhain and Dewey, 2004], peripheral trauma [Erer and Jankovic, 2008], and surgery [Singer et al., 1997; Chemali and Bromfield, 2003], or is found in association with a variety of sporadic, genetic, and neurodegenerative disorders, such as neuroacanthocytosis, Huntington’s disease, and Creutzfeldt–Jakob disease [Sacks, 1982; Jankovic and Ashizawa, 1995; Scarano et al., 2002].

Tic Disorder Not Otherwise Specified

This designation has been retained to include disorders that do not meet criteria for a specific tic disorder because the movements or vocalizations are atypical in age of onset (i.e., adult onset) or clinical presentation. Tic disorders in adults usually have their onset in childhood, although some have had their onset beyond the age of 21 years. Symptoms with origination in adulthood are often associated with potential environmental triggers, are typically more severe, and have a greater social morbidity and a poorer response to medications [Eapen et al., 2002].

Attention-Deficit Hyperactivity Disorder

ADHD is characterized by impulsivity, hyperactivity, and a decreased ability to maintain attention. Symptoms begin in early childhood and typically precede the onset of tics. ADHD is reported to affect about 50 percent (range 21–90 percent) of referred cases with TS [Comings and Comings, 1987; Khalifa and von Knorring, 2005]. The appearance of ADHD is not associated with the concurrent severity of tics, although it is common in those with more severe tics [Robertson et al., 1988]. ADHD symptoms in patients with TS correlate with increased psychosocial difficulties, disruptive behavior, peer rejection, emotional problems, functional impairment, family conflict, learning disabilities, and school problems [Hoekstra et al., 2004b; Freeman, 2007; Huckeba et al., 2008; Mol Debes et al., 2008]. TS and ADHD are not alternate phenotypes of a single underlying genetic cause but there is likely an overlap in their underlying neurobiology [Stewart et al., 2006]. It has been suggested that there may be two distinct populations of TS patients with comorbid ADHD: those with onset of ADHD before the onset of tics, and those with onset after, or in concert with, the onset of tics [Pauls et al., 1993].

Obsessive-Compulsive Disorder

OCD is characterized by persistent obsessions (persistent, recurrent, intrusive thoughts, images, or impulsions that are unwelcome and intrude upon conscious thought) or compulsions (repetitive, seemingly purposeful behaviors, usually performed in response to an obsession, in accord with certain rules, or in a stereotyped fashion). Obsessive-compulsive behaviors (OCB) become a disorder (OCD) when activities are sufficiently severe to cause marked distress, take up more than 1 hour of the day, or have a significant impact on normal routine, function, social activities, or relationships. Several differences have been reported between behaviors in TS patients with OCD and those with only OCD [George et al., 1993; Miguel et al., 1997, 2000; Mula et al., 2008]. For example, in patients with TS, behaviors usually include a need for order or routine, and a requirement for things to be symmetrical or “just right” (e.g., arranging, ordering, hoarding, touching, tapping, rubbing, counting, checking for errors, and performing activities until things are symmetrical or feel/look just right [“evening-up” rituals]). In contrast, OCD subjects without tics typically have fear of contamination and have cleaning compulsions. Similar to tics, OCB are exacerbated by stress and anxiety, and have a preceding sense or desire. Differentiating OCB from tics may be difficult. Clues favoring OCB include a cognitive-based drive and need to perform the action in a particular fashion – a certain number of times, for example – until it feels “just right,” or equally on both sides of the body. OCB occur in 20–89 percent of patients with TS, generally emerge several years after the onset of tics, typically become more severe at a later age, and are more likely to persist than tic symptoms [Bloch et al., 2005, 2006a; Gaze et al., 2006; Lombroso and Scahill, 2008; Mula et al., 2008]. The presence of OCD, in addition to ADHD, has an additional impact on school, social, and family activities [Sukhodolsky et al., 2005]. A genetic association has been identified between OCD and TS [Pauls et al., 1995; Nestadt et al., 2000; Grados et al., 2001].

Anxiety and Depression

Several studies have found an increased incidence of depression and anxiety in patients with TS [Coffey and Park, 1997; Rickards and Robertson, 2003; Sukhodolsky et al., 2003]. Common non-OCD anxiety disorders include separation anxiety, agoraphobia, and panic disorder [Coffey et al., 2000]. Depression in TS might be explained, in part, by the presence of a chronic stigmatizing or socially disabling disorder, based on studies showing that depression correlates positively with earlier onset and longer duration of tics [Coffey and Park, 1997; Rickards and Robertson, 2003]. Whether depressive symptoms are related to the severity of tics remains controversial. It is likely, however, that the etiology of depression in TS is multifactorial, since symptoms are also seen in patients with OCD or ADHD alone, and in patients receiving antipsychotic medications. Genetic studies have demonstrated that major depressive disorder (MDD) is genetic, but that TS and MDD are unrelated [Pauls et al., 1994].

Episodic Outbursts (Rage) and Self-Injurious Behavior

Some individuals with TS have significant problems with labile emotion, anger control, and aggression. Episodic outbursts of anger may include screaming, threatening behaviors, stomping, kicking, destroying objects, punching holes in walls, and so on. Rage attacks, difficulty with aggression, and self-injurious behaviors are common in patients with TS [Budman et al., 2003; Mathews et al., 2004]. Again, whether these behaviors are due to the presence of other disruptive psychopathology, such as obsessions, compulsions, ADHD-related impulsivity, risk-taking, or affective disorders, is unclear. Self-inflicted, nonaccidental behaviors (head banging, body punching or slapping, banging oneself against a hard object, poking sharp objects into the body, scratching body parts) also occur in TS [Robertson and Yakeley, 1993]. It has been suggested that the mild/moderate form of self-injurious behavior correlates with OCD, whereas more severe forms of self-injurious behavior occur in conjunction with episodic rages and risk-taking behaviors [Mathews et al., 2004].

Other Psychopathologies

Personality disorders, antisocial and oppositional behaviors, and schizotypal traits are more common in TS, but the cause may be attributed to other comorbid problems or economic issues [Robertson et al., 1997; Cavanna et al., 2007]. Studies in TS using the Child Behavior Checklist have shown that up to two-thirds of TS subjects had abnormal scores, with clinical problems including OCB, aggressiveness, hyperactivity, immaturity, withdrawal, and somatic complaints [Singer and Rosenberg, 1989; Rosenberg et al., 1994; Ghanizadeh and Mosallaei, 2009]. There is no evidence that TS patients are more likely to engage in criminal behavior than those without TS [Jankovic et al., 2006].

Academic Difficulties

Despite typically having normal intellectual functioning, poor school performance is common in children with tics. Depending on the academic skill tested, 16–68 percent of children with TS function below educational expectancy [Hagin and Kugler, 1988], and about one-quarter of children receiving special education have tic disorders [Comings et al., 1990; Kurlan et al., 1994]. Potential etiologies are multiple and include severe tics, psychosocial problems, ADHD, OCD, learning disabilities, executive dysfunction, or medications [Singer et al., 1995]. The importance of comorbid ADHD has been emphasized. For example, poor arithmetic performance was found only in children with TS who had attentional deficits [Huckeba et al., 2008]. Discrepancies are reported between performance and verbal IQ scores, and impairments are noted in visual perceptual achievement and visual-motor skills [Harris et al., 1995; Schuerholz et al., 1996, 1998; Brand et al., 2002; Channon et al., 2003].

Sleep Disorders

Problems associated with sleep have been reported in about 20–50 percent of children and young adults with TS – primarily difficulties with insomnia, bedtime rituals, dreams, and parasomnias [Allen et al., 1992; Cohrs et al., 2001; Kostanecka-Endress et al., 2003; Kirov et al., 2007]. TS patients, without comorbid ADHD, had longer sleep period time, longer sleep latency, reduced sleep efficiency, and prolonged wakefulness after sleep onset, with more time awake and less stage II sleep [Kostanecka-Endress et al., 2003]. Associated comorbidities, including ADHD, anxiety, separation anxiety, mood disorders, and OCD, can also be contributors to the sleep deficits [Allen et al., 1992]. Restless leg syndrome (RLS) has been reported in up to 10 percent of patients with TS [Lesperance et al., 2004].

Genetic Basis

Georges Gilles la Tourette, in the 1880s, suggested that TS was inherited. Nevertheless, despite extensive subsequent investigations, the precise pattern of transmission and the identification of the gene remain elusive. Family studies clearly show a 10- to 100-fold increase of TS in first-degree relatives. However, since family members also share common environmental influences, this does not confirm a genetic disorder. A variety of approaches have been used to confirm the role of genetics, including twin studies, genetic linkage analysis, cytogenetics, candidate gene, and molecular genetic studies [Leary et al., 2007; O’Rourke et al., 2009]. The strongest support for a genetic disorder is based on studies of monozygotic and dizygotic twins; TS is 77–94 percent concordant for tic disorders in monozygotic twins versus 23 percent in dizygotic twins [Price et al., 1985; Hyde et al., 1992]. Linkage analyses have suggested a number of chromosomal locations, but without a clear reproducible locus or convergence of findings. One analysis performed in 238 affected sibling-pair families and 18 large multigenerational families (2040 individuals) identified strong evidence for linkage to markers on chromosome 2p23.2, with suggestive evidence for linkage on chromosomes 5p and 6p [Pauls, 2006]. In several families, three chromosomal regions (7q22–q31, 8q13–q22, and 18q22) have been observed to co-segregate with chronic tic disorders or OCD [O’Rourke et al., 2009]. Candidate gene studies, focused primarily on genes involved in dopamine, serotonin, norepinephrine, and GABA pathways, have not identified a reproducible causative susceptibility gene. A significant association has been reported between TS and a dopamine transporter polymorphism (DAT1 Ddel) [Yoon et al., 2007a] and a serotonin receptor polymorphism (HTR2C) [Dehning et al., 2010]. Linkage analysis in a ten-member, two-generation pedigree has identified a heterozygous loss-of-function mutation in l-histidine decarboxylase, which encodes the rate-limiting enzyme in histamine biosynthesis [Ercan-Sencicek et al., 2010]. Suggestions of an association with SLITRK1 have not been confirmed [Scharf et al., 2008]. A complex genetic etiology is supported by a study of at-risk children free of tics at baseline who subsequently developed a tic disorder [McMahon et al., 2003]. A genome-wide association study, with its ability to detect common alleles with low penetrance and small associated DNA loci, is currently under way in large samples of TS subjects. These investigations include the examination of both single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). CNV studies, detecting short genomic duplications or deletions ranging from 1 kilobase to several megabases, have been used successfully in other neuropsychiatric disorders [Cook and Scherer, 2008].

Some investigators have suggested that no causative gene has been identified because of phenotypic heterogeneity [Grados and Mathews, 2008]. The possible effects of genomic imprinting (sex of the transmitting parent affects the clinical phenotype), bilineal transmission (genetic contribution from both sides of the family) [Eapen et al., 1997; Hanna et al., 1999; Lichter et al., 1999], genetic heterogeneity, epigenetic factors, and gene–environment interactions further complicate the understanding of TS genetics. Potential epigenetic risk factors that have been suggested include timing of perinatal care, severity of mother’s nausea and vomiting during the pregnancy, low proband birth weight, the Apgar score at 5 minutes, thimerosal [Thompson et al., 2007], nonspecific maternal emotional stress [Burd et al., 1999], and prenatal maternal smoking [Mathews et al., 2006]. Further replication of these latter studies is necessary before any significance can be truly claimed.

Based on an assessment of available information, suggested risk guidelines have been published [Tourette Syndrome Association, 2008]. If a mother or father has TS, the likelihood that a son will develop something in the TS spectrum is estimated to be about 40–45 percent; the approximate risk for TS is 10–15 percent; for chronic tics, 15–20 percent; and for OCB without tics, approximately 5–10 percent. The overall risks for a daughter are about 25–35 percent; 3–5 percent for TS; 10–15 percent for chronic tics; and 10–20 percent for OCB without tics. If both parents have TS and/or OCD, based on studies of only small numbers of bilineal families, the offspring risk for a TS spectrum problem may be as high as 70–90 percent, TS 25–50 percent, and for chronic tics an additional 15 percent. It is emphasized, however, that although susceptibility risks may be high, most affected individuals have very mild conditions.

Autoimmune Disorder

Several investigators have proposed that, in a subset of children, tic symptoms are caused by a preceding β-hemolytic streptococcal infection (GABHS) [Swedo et al., 1998; Snider and Swedo, 2003]. Labeled as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), proposed criteria include the presence of OCD and/or tic disorder; prepubertal age at onset; sudden, “explosive” onset of symptoms and/or a course of sudden exacerbations and remissions; a temporal relationship between symptom exacerbations and GABHS; and the presence of neurological abnormalities, including hyperactivity and choreiform movements. On the basis of a model proposed for Sydenham’s chorea, it has been hypothesized that the underlying pathology in PANDAS involves an immune-mediated mechanism with molecular mimicry [Swedo et al., 1998]. Inconsistent with Sydenham’s chorea, however, PANDAS is more common in boys and does not include cardiac, joint, or skin abnormalities or the presence of chorea.

The existence of PANDAS as an etiological entity remains controversial, based on both epidemiological and autoimmune studies [Kurlan, 1998; Singer and Loiselle, 2003; Kurlan, 2004; Kurlan and Kaplan, 2004; Singer et al., 2008; Morris et al., 2009]. On clinical grounds, in many individuals the diagnosis was based on incomplete criteria [Shet and Kaplan, 2002; Gabbay et al., 2008; Shulman, 2009]. Concerns about individual criteria proposed for the diagnosis include an age of onset that does little to separate tic disorders from the PANDAS subgroup; neuropsychological and family-genetic studies of PANDAS cases that show few differences from what is typically seen in early-onset OCD or TS [Lougee et al., 2000; Hirschtritt et al., 2008]; the sudden explosive onset or worsening of tic symptoms that occurs frequently in unselected children with tic disorders [Singer et al., 2000]; studies that do not consistently support an epidemiological link to GABHS [Perrin et al., 2004; Schrag et al., 2009]; the fact that clinical exacerbations in PANDAS cases are usually not temporally related to a streptococcal infection [Kurlan et al., 2008; Leckman et al., 2011]; studies suggesting that antibiotic prophylaxis prevents recurrences [Snider et al., 2005], which are incomplete; and the fact that neurologic abnormalities were not identified during exacerbations [Leckman et al., 2011].

If PANDAS is an autoimmune disorder, it would be expected that serum antineuronal antibodies or other immune factors would be abnormal in affected individuals. Results to date, however, have been inconclusive, despite the use of various detection methodologies, i.e., immunofluorescent histochemistry (IF), enzyme-linked immunosorbent assay (ELISA), and Western immunoblotting. In one IF study, about two-thirds of children with PANDAS had positive staining [Pavone et al., 2004], but another, using lower serum dilutions and confocal microscopy, showed no association between IF positivity and the diagnosis of PANDAS or TS [Morris et al., 2009]. Several investigators have claimed that, in PANDAS, there is an increased serum antibody reactivity against postmortem basal ganglia samples at 60, 45, and 40 kDa (epitopes defined as pyruvate kinase M1, neuronal-specific and non-neuronal enolase, and aldolase C) [Church et al., 2003; Dale et al., 2005]. Questions, however, have been raised about the functional aspects of these antibodies, given a lack of association with a distinct, clinically meaningful, phenotypic finding [Martino et al., 2007] or structural abnormality in gray or white matter [Martino et al., 2008]. In contrast, other researchers, using ELISA and immunoblotting against a variety of brain epitopes, were unable to distinguish PANDAS subjects from children with TS or controls [Singer et al., 2005, 2008]. Further, a longitudinal study in children with PANDAS showed little association between GABHS and symptom exacerbation [Kurlan et al., 2008], and no correlation between exacerbation of symptoms and changes in antineuronal or anti-lysoganglioside GM₁ antibodies [Singer et al., 2008].

Recognizing that other immune mechanisms could be induced by streptococcal infection, investigators have also pursued abnormalities of cytokines, changes in lymphocyte subpopulations, protein array profiling of sera [Bombaci et al., 2009], and activity of cell-mediated mechanisms [Martino et al., 2009]. Suggestions that cytokines may be an important contributor to PANDAS [Leckman et al., 2005] have not been supported by results of longitudinal studies [Singer et al., 2008]. Lastly, putative biomarkers for Sydenham’s chorea, including lysoganglioside GM₁, tubulin, and D₂ receptor [Kirvan et al., 2003, 2006a, b, 2007] do not consistently distinguish subjects with TS or PANDAS from controls [Singer et al., 2008; Pollard et al., 2009