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PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci

PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci
Literature review current through: Jan 2024.
This topic last updated: Apr 25, 2022.

INTRODUCTION — An overview of pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) will be presented below. The diagnosis, complications, and treatment of group A streptococcal (GAS) infection, obsessive-compulsive disorder, and tic disorders in children are discussed separately:

(See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis".)

(See "Complications of streptococcal tonsillopharyngitis".)

(See "Treatment and prevention of streptococcal pharyngitis in adults and children".)

(See "Obsessive-compulsive disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

(See "Tourette syndrome: Pathogenesis, clinical features, and diagnosis".)

TERMINOLOGY

PANDAS – Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) is a term used to describe a subset of children whose symptoms of obsessive-compulsive disorder, tic disorders, or other neuropsychiatric symptoms (eg, anxiety) are exacerbated by GAS infection [1,2]. The hypothesized association between PANDAS and GAS is controversial, as is the limitation of the diagnosis exclusively to the pediatric age group. (See 'Areas of controversy' below.)

PANS/CANS – Pediatric acute-onset neuropsychiatric syndrome (PANS), sometimes referred to as childhood acute neuropsychiatric symptoms (CANS), is a diagnostic entity introduced to broaden the scope of these disorders and allow for inciting events other than GAS [3].

This topic focuses on PANDAS. Detailed discussion of PANS/CANS is beyond the scope of this review, but available in review articles published in 2021 [4,5].

BACKGROUND

Historical perspective — Most of the knowledge about PANDAS has been obtained by studying patients with a known tic disorder or long-standing obsessive-compulsive disorder (OCD) in research facilities and referral centers [1,6-8]. Investigators at these centers noted an association between Sydenham chorea and OCD [9-11]. Sydenham chorea is a movement disorder characterized by chorea, emotional lability, and hypotonia. It is one of the major clinical manifestations of acute rheumatic fever. The investigators also identified a subset of children with OCD or tic disorders following GAS infection who did not meet criteria for Sydenham chorea [8,12,13]. This subset is described by the acronym PANDAS [1]. (See "Sydenham chorea" and "Acute rheumatic fever: Clinical manifestations and diagnosis".)

The diagnostic criteria for PANDAS include [1,14]:

OCD and/or tic disorder (Tourette syndrome, chronic motor or vocal tic disorder)

Pediatric onset (between three years and onset of puberty)

Abrupt onset and episodic course of symptoms

Temporal relation between GAS infection and onset and/or exacerbation

Neurologic abnormalities, such as motoric hyperactivity, choreiform movements, or tics during exacerbations

In the original description of 50 patients with PANDAS in 1998, approximately 40 percent of all presentations and exacerbations were related to preceding or concurrent GAS infections and each patient had at least one episode in which the relationship to GAS was established [1]. In 2012, PANDAS investigators proposed modifying the PANDAS criteria to describe pediatric acute-onset neuropsychiatric syndrome (PANS), also called also called childhood acute neuropsychiatric symptoms [3].

The proposed diagnostic criteria for PANS include all three of the following [3]:

Abrupt, dramatic overnight onset of OCD or severely restricted food intake

Concurrent abrupt onset of additional severe neuropsychiatric symptoms from at least two of the following seven categories:

Anxiety

Emotional lability and/or depression

Irritability, aggression, and/or severe oppositional behaviors

Developmental regression

Deterioration in school performance

Sensory or motor abnormalities, including heightened sensitivity to sensory stimuli, hallucinations, dysgraphia, complex motor and/or vocal tics

Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency

Symptoms are not better explained by a known neurologic or medical disorder

Whether PANDAS is a distinct form of more typical cases of OCD or tic disorder and the proposed pathogenesis are controversial [15-20]. (See 'Areas of controversy' below.)

However, the author of this topic agrees with the commentary by Wald: "For those of us familiar with the sequelae of streptococcal disease and the concerns of community physicians faced with the care of children with these neuropsychiatric symptoms, the controversy has proven to be a disservice to both pediatricians and families. It has fostered a dismissive attitude toward important clinical observations" [18,21]. Continued study is essential to better address the concerns of families of children with neuropsychiatric symptoms and their health care providers. Whether PANS is a distinct entity is also controversial. The reported pathogens include Mycoplasma pneumoniae, enteroviruses, Chlamydia pneumoniae, Borrelia burgdorferi, Toxoplasma gondii, and human immunodeficiency virus (HIV) [4,22]. However, evidence regarding the association among infectious pathogens other than GAS and OCD, tic, and other neuropsychiatric disorders are largely based on small numbers of cases or case reports.

Areas of agreement — There is general agreement on the following points:

GAS is one of several factors that can exacerbate OCD or tic disorder in a subset of patients [1,13,23-27].

Children with signs and symptoms compatible with GAS infections should be evaluated for GAS infection [14,16]. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Diagnosis'.)

Children with GAS infection and OCD/tic disorder require standard treatments for these problems (regardless of whether GAS and OCD/tic disorder are causally associated) [14,16]. (See 'Management' below.)

Sydenham chorea is a manifestation of GAS infection and up to 70 percent of patients with Sydenham chorea have psychiatric symptoms; in patients with recurrent chorea, 100 percent have psychiatric symptoms [6,28]. (See "Sydenham chorea", section on 'Neuropsychiatric symptoms'.)

There can be a one- to eight-month latency period between GAS infection and onset of nonsuppurative poststreptococcal sequelae such as Sydenham chorea and acute rheumatic fever. Therefore, when sequelae become clinically apparent, detection of GAS by culture or serology may not occur.

Pharyngeal GAS infections that precede development of nonsuppurative sequelae may be subclinical or mild [29,30].

Not all strains of GAS cause nonsuppurative sequelae, and infection with a rheumatogenic strain is followed by nonsuppurative sequelae in only 0.1 to 5 percent of infected, untreated patients, suggesting a genetic component to susceptibility [31]. (See "Acute rheumatic fever: Epidemiology and pathogenesis", section on 'Pathogenesis'.)

Interpretation of antistreptococcal serology is complicated by multiple factors, including an inconsistent response to acute GAS infections and GAS asymptomatic carriage [32].

Areas of controversy — Controversies surrounding PANDAS include:

Is PANDAS sufficiently different from OCD/tic disorder and other neuropsychiatric disorders to be considered a separate entity [23,26,33,34]? (See 'Clinical features' below.)

Is the association between GAS and PANDAS authentic [17,20,23,26,34-39]? (See 'Epidemiology and association with GAS' below.)

Is PANDAS an autoimmune disorder [33,34,36,40]? (See 'Pathogenesis' below.)

Should evidence of GAS infection be sought in patients with OCD/tic disorders or other neuropsychiatric symptoms [15,16,41]? (See 'Diagnostic process' below.)

Is administration of immunomodulatory therapy (eg, glucocorticoids, plasma exchange, intravenous immune globulin) warranted for children who meet PANDAS or PANS criteria [14,16,42]?

Is administration of prophylactic antibiotics warranted for children who meet PANDAS criteria [14,16]?

PATHOGENESIS

Pathogenetic models

The major model for PANDAS pathogenesis is based upon the clinical similarities between Sydenham chorea and PANDAS [1]. The pathogenesis of Sydenham chorea and acute rheumatic fever involve a preceding GAS pharyngitis infection and an abnormal immune response (in which antibodies directed against GAS antigens cross-react with host antigens in brain and heart valves) are widely accepted as important components. (See "Acute rheumatic fever: Epidemiology and pathogenesis", section on 'Molecular mimicry'.)

The autoimmune complications of GAS infections are caused by an atypical immune response to antigens of GAS bacteria that cross-react with self-tissues. Children between the ages of 5 and 12 years are more susceptible to autoimmune complications because they have more frequent exposure and typically respond to GAS (and other infections) with higher quantities of antibodies than older adolescents and adults. The more controlled response in older adolescents and adults may be related to immune mechanisms that dampen proinflammatory processes.

Another proposed model is based on studies in animals and humans, including children with pediatric acute-onset neuropsychiatric syndrome/PANDAS, that suggest that alterations of gut microbiota are associated with neuroinflammation [43-45]. In a case-control study, 30 children with PANDAS had higher circulating levels of markers of oxidative stress (eg, soluble NOX2, isoprostanes) than 30 age- and sex-matched controls [46].

Epidemiology and association with GAS

Epidemiology – The incidence and prevalence of PANDAS are not known, although it is rare. In a prospective study, only 10 cases were identified among 30,000 throat cultures positive for GAS [38].

In the original description of PANDAS in 50 patients, the mean age of onset was 6.3 years for children with tics and 7.4 years for children with obsessive-compulsive disorder (OCD) [1]. The overall ratio of males to females with PANDAS was 2.6 to 1, and among children under eight years of age the ratio was 4.7 to 1. PANDAS was more common among children with a family history of rheumatic fever.

Epidemiologic studies of PANDAS association with GAS – An association between neuropsychiatric symptoms or PANDAS and GAS infection has been assessed in multiple studies with varying conclusions.

GAS and neuropsychiatric symptoms – In a case-control study from a large health maintenance organization with a population of approximately 75,000 children, 144 patients with OCD, Tourette syndrome, or a tic disorder were matched with one to five controls [13]. Cases were more likely than controls to have had a GAS infection in the three months before the onset of neurologic disease (odds ratio [OR] 2.2, 95% CI 1.1-4.7) and to have had multiple GAS infections during the 12 months before the onset of neurologic disease (OR 3.1, 95% CI 1.8-9.0).

Similarly, prospective studies suggest that GAS is associated with the onset or exacerbation of OCD or tic disorder or other neuropsychiatric symptoms in a subset of patients [23,24]. In a population-based cohort study including more than one million children in Denmark, children with a streptococcal throat infection had increased risks of OCD and tic disorders [27]. Other investigators analyzing data from the same cohort affirmed an association between infections and neuropsychiatric disorders but did not specifically evaluate GAS infections [47].

In another longitudinal study, in which 693 children were evaluated monthly (October through May) with throat cultures and for behaviors (eg, fidgeting, balance/swaying, non-tic facial movements), tics, and choreiform movements, there was an association between GAS infection in the previous three months and behaviors and between repeated GAS infection and behaviors and choreiform movements [48].

GAS and PANDAS – In contrast, several epidemiologic studies have failed to identify an association of GAS infections with PANDAS [38]. In a prospective study, although children diagnosed with PANDAS had a higher rate of exacerbations than control children with OCD or Tourette syndrome without a history of PANDAS, most of the exacerbations in children with PANDAS had no observable association with GAS infection [23]. In another prospective study, the number of clinical exacerbations and newly diagnosed GAS infections were similar in children diagnosed with PANDAS and children with OCD or Tourette syndrome without a history of PANDAS [26].

Taken together, these studies do not provide definitive answers. Although some studies detected an association between GAS and OCD/tic disorder exacerbations, the high background rates of GAS infection, GAS carriage, and OCD/tic disorders in prepubertal children make it difficult to establish causality [14,16,17,20]. The studies that did not detect a clear association between GAS and OCD/tic disorder exacerbations may have been limited by small sample size, antibiotic treatment of GAS preventing nonsuppurative sequelae, or, possibly, differences in genetic susceptibility and PANDAS-specific GAS strains.

Autoimmunity — Similar to Sydenham chorea and acute rheumatic fever, molecular mimicry (ie, production of autoantibodies following GAS infections that target cells of the basal ganglia) is the proposed pathogenesis of PANDAS.

Multiple studies have demonstrated increased antineuronal antibodies in patients with PANDAS compared with patients with OCD/tic disorders without evidence of GAS infection and patients with GAS infection without OCD/tic disorder [22,34,49-66]. However, other studies have been unable to distinguish patients with PANDAS or Tourette syndrome from control patients on the basis of autoantibody profiles [67-70]. The inconsistent findings may be related to methodologic differences [71,72]. As an example, the control sera used in different studies may have different antineuronal antibody concentrations [64].

Support for a role of autoimmunity is provided by reports of response to treatment with immune-modifying therapies, such as glucocorticoids, intravenous immune globulin, and plasma exchange [8,49,50,73]. The response to plasma exchange appears to be specific to children with OCD/tic disorders and preceding GAS infection; in an open trial, plasma provided no benefit for children with OCD whose symptom exacerbation did not follow GAS infection [74].

An autoimmune mechanism for PANDAS also is supported by animal studies. Rodents hyperimmunized with GAS have been reported to demonstrate behaviors consistent with PANDAS [62]. When transferred to naïve animals, serum from hyperimmunized rodents displaying PANDAS behaviors produced PANDAS behaviors [63,75]. Although human sera from PANDAS patients failed to induce PANDAS behaviors in a rodent model [76], human sera from PANDAS patients has been shown to bind to cholinergic interneurons in rodents [77].

CLINICAL FEATURES

Working diagnostic criteria — PANDAS is characterized by five working criteria [1,8,14]:

Obsessive-compulsive disorder (OCD) and/or tic disorder (Tourette syndrome, chronic motor or vocal tic disorder that meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria). (See "Obsessive-compulsive disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Tourette syndrome: Pathogenesis, clinical features, and diagnosis" and "Hyperkinetic movement disorders in children", section on 'Tic disorders'.)

Pediatric onset (between three years and onset of puberty). (See 'Pathogenesis' above.)

Abrupt onset and episodic course of symptoms. (See 'Clinical course' below.)

Temporal relation between GAS infection and onset and/or exacerbation. The time frame for the temporal relation was not specified in the original description [1]. Antibody levels to streptolysin O and DNase B remain elevated for several months after an acute infection, complicating the applicability and interpretation of elevated titers [78]. (See 'Diagnostic process' below.)

Neurologic abnormalities, such as motoric hyperactivity (eg, fidgeting, difficulty remaining seated), choreiform movements (elicited through stressed postures [eg, standing upright with the feet together and the eyes closed, holding the arms outstretched with the hands extended] but not present at rest), or tics during exacerbations. Frank chorea (rapid, irregular, and nonstereotypic jerks that are continuous while the patient is awake but improve with sleep) suggests Sydenham chorea. (See "Sydenham chorea".)

Observational studies suggest that clinical and laboratory features can distinguish PANDAS from OCD or tic disorder without PANDAS:

In a prospective study, 12 children with PANDAS were identified in a primary care practice over a three-year period [24]. All had positive throat cultures at the time of onset of neuropsychiatric symptoms and improvement of neuropsychiatric symptoms with antibiotic therapy. Symptoms resolved completely in four patients within 5 to 21 days after onset, and none of these patients had a recurrence. Recurrent symptoms developed in the remaining children, and each recurrence was associated with a new episode of culture-proven GAS tonsillopharyngitis and amelioration of symptoms with antibiotic therapy.

In another study of 109 prepubertal children with tics, OCD, or both, clinical features that were more frequent among the 48 children who met criteria for PANDAS included dramatic onset of symptoms, remissions in neuropsychiatric symptoms, a clinical course marked by definite remissions, and remission of neuropsychiatric symptoms during antibiotic therapy [2].

However, some experts have questioned whether these studies are useful, challenging whether they distinguished patients with PANDAS from patients with more typical cases of OCD, tic disorder, or other neuropsychiatric disorders [15,16,33].

Clinical course — The most striking feature of PANDAS is the abrupt onset [1,24]. However, abrupt onset of OCD/tic disorder symptoms also has been noted in patients without PANDAS [17,79]. Subsequently, the clinical course of PANDAS may be characterized by a "sawtooth" pattern with periods of symptom quiescence, followed by exacerbations with abrupt onset and gradual resolution (over weeks to months) [1,8,14,24]. Neuropsychiatric exacerbations in children with PANDAS may begin at the time of GAS infection or within weeks after GAS infection; however, symptom onset may be delayed by one to eight months, similar to Sydenham chorea and acute rheumatic fever, when culture evidence of GAS will be absent [1,14,24].

Children with PANDAS and tics occasionally have simultaneous onset of frequent, severe, and varied motor and vocal tics, prompting caregivers to seek emergency treatment [14]. This is in contrast to the typical onset of isolated, intermittent, simple motor or vocal tic that has a much more gradual onset and is milder [14,80].

Children with PANDAS have been described as having an "explosion" of OCD symptoms, reaching clinically significant impairment in 24 to 48 hours [1]. This is in contrast to the typical undulating waxing and waning pattern of OCD symptoms in patients without PANDAS [81,82]. (See "Obsessive-compulsive disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Course'.)

DIAGNOSTIC PROCESS

When to consider the diagnosis – The author of this topic suggests that children who present with abrupt onset of obsessive-compulsive disorder (OCD)/tic disorder, separation anxiety, or urinary frequency (which can be a form of anxiety) be evaluated for PANDAS by testing for GAS infection [24].

Evaluation for GAS infection – Evidence of GAS is provided by one of the following [1,14,83]:

A positive throat culture, rapid antigen detection test (RADT), or molecular assay for GAS pharyngitis or positive skin culture from infected skin. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Microbiologic tests'.)

RADT results may be inaccurate, particularly if they are negative. In a meta-analysis of studies comparing RADT and throat culture for GAS, RADT had a sensitivity of 86 percent (95% CI 83-88 percent) and a specificity of 95 percent (95% CI 94-96 percent) [84]. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'RADT for GAS'.)

A clinically significant rise in antistreptococcal antibody (antistreptolysin O [ASO] and/or anti-DNase B [ADB]) titers between the onset of symptoms and four to six weeks later [78]. It is important to obtain ADB as well as ASO titers since ADB titers are elevated in approximately 80 percent of PANDAS cases, whereas ASO titers are elevated in only 20 to 50 percent of cases [24].

The diagnosis of PANDAS (but not pediatric acute-onset neuropsychiatric syndrome [PANS]) is unlikely if antistreptococcal antibodies are undetectable or low. Such negative test results can be helpful in removing PANDAS from a differential diagnosis. The autoantibodies thought to be responsible for the neuropsychiatric symptoms should rise in parallel with the antistreptococcal antibodies. It would be improbable to have sufficient autoantibodies to cause neuropsychiatric symptoms without concomitant elevation of other measurable antistreptococcal antibodies. (See 'Pathogenesis' above.)

Although it is likely that the antibody response in PANDAS is similar to that of other types of GAS infections, this has not been systematically studied. The antibody response of ASO peaks three to five weeks after GAS pharyngitis and the antibody response of ADB peaks six to eight weeks after GAS pharyngitis [85,86]. Antibody titers fall off rapidly in the next several months and, after six months, have a slower decline. A key concept is that a measurable antibody titer could be from a fairly recent infection or an infection months or even a year earlier, although very high levels suggest more recent infections and a titer that increases compared with a prior titer should be construed to indicate that a GAS infection occurred in the interim between the titers.

The antibody response to GAS pharyngitis is discussed in greater detail separately. (See "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Evidence of preceding GAS infection'.)

Preliminary interpretation – A diagnosis of probable PANDAS may be suspected in children with:

Abrupt onset of neuropsychiatric symptoms

Evidence of recent GAS infection

Remission of neuropsychiatric symptoms with antistreptococcal antibiotic therapy

Monitoring for neuropsychiatric symptoms – Monitoring for occurrence of neuropsychiatric symptoms temporally associated with evidence of GAS infection is warranted for patients in whom a diagnosis of probable PANDAS is being considered. In a prospective study, approximately 50 percent of patients with a diagnosis of probable PANDAS had recurrence of neuropsychiatric symptoms associated with GAS infections [24].

Some authorities suggest repeat cultures and/or serology when children with suspected recurrent episodes of PANDAS are well to exclude streptococcal carriers [1,14,78,83]. Demonstration of negative throat culture or declining antistreptococcal antibody titers during remission of neuropsychiatric symptoms decreases the likelihood of GAS carriage [1].

Trial of prophylactic antibiotics – The role of prophylactic antibiotics in the management of PANDAS is uncertain. If the pathogenesis of PANDAS is similar to that of acute rheumatic fever and Sydenham chorea, then prophylactic antibiotics may be expected to prevent recurrences of PANDAS as it does in these conditions [87]. However, the pathogenesis of PANDAS has not been established. (See "Acute rheumatic fever: Treatment and prevention" and "Sydenham chorea".)

Although some experts recommend against the use of prophylactic antibiotics for children with PANDAS [14,15], in the experience of the author of this topic, a brief trial of prophylactic antibiotics is an option to aid in the diagnosis and prevent symptom recurrences.

The author uses one of the following regimens:

Amoxicillin 250 mg orally twice per day (available in chewable tablets)

Azithromycin 5 mg/kg orally once per day (for children with penicillin allergy)

Oral prophylaxis is preferred to monthly injections of intramuscular penicillin.

The trial of prophylaxis should be long enough that a relapse of PANDAS symptoms would be expected to occur in the individual patient – generally a few months. It should be continued through one winter season, coinciding with the peak seasonal occurrence of GAS. Prophylaxis is discontinued if neuropsychiatric symptoms do not improve or the child has a recurrence of neuropsychiatric symptoms. Prolonged antibiotic therapy is challenging and associated with substantial adverse consequences (eg, diarrhea, pseudomembranous colitis, candida infections, and increased rates of antibiotic resistance [88]).

The clinical course during prophylaxis may provide insight into the disease for the patient/caregiver and clinician:

Remission of neuropsychiatric symptoms supports the potential diagnosis of PANDAS

Recurrence of neuropsychiatric symptoms during prophylaxis excludes the diagnosis

Observational studies suggest an association between prophylactic antibiotics and decreased frequency of GAS infections, decreased frequency of neuropsychiatric exacerbations, and improvement in neuropsychiatric symptoms [7,89]. In the only placebo-controlled trial, an equal number of GAS infections occurred in the penicillin and placebo groups; failure to achieve adequate prophylaxis against GAS prohibited drawing conclusions regarding efficacy of PANDAS prevention [90]. A subsequent study compared rates of streptococcal infections and neuropsychiatric symptom exacerbation before and during 12 months of prophylaxis with penicillin or azithromycin [7]. Prophylaxis was associated with fewer episodes of GAS infection and fewer neuropsychiatric exacerbations compared with baseline. However, the lack of a placebo group and other design problems (eg, small numbers, inadequate blinding, nonstandardized definition of exacerbation, failure to exclude GAS carriage) make these results inconclusive [91]. In a cohort of children with PANDAS, prophylactic intramuscular penicillin was associated with improvement in neurologic symptoms, primarily in the first three to five months of treatment; however, infection-related relapses occurred in 45 percent of patients over the long-term (five to seven years) [89].

Recommendations of others – The diagnostic process described above is that of the author of this topic.

Investigators at the National Institutes of Mental Health (NIMH) have also outlined a diagnostic process [1,14]. They maintain that the risk of acute rheumatic fever mandates the detection and appropriate treatment of GAS infections, including mildly symptomatic infections and infections in which neuropsychiatric manifestations are the only symptoms. (See "Acute rheumatic fever: Treatment and prevention".)

The PANS Consensus Conference provides recommendations for the clinical evaluation and management of children with suspected PANS [22,92-94].

The author's, NIMH, and PANS Consensus approaches to diagnostic evaluation of PANDAS/PANS are not endorsed by all experts. Although the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee and the American Academy of Pediatrics Committee on Infectious Diseases recommend evaluation for GAS in children with clinical symptoms and signs of acute GAS pharyngitis, they do not recommend routine laboratory testing for GAS to diagnose PANDAS in children with OCD/tic disorders or other neuropsychiatric symptoms [15,39].

The evaluation of children with pharyngitis in the absence of neuropsychiatric manifestations is discussed separately. (See "Evaluation of sore throat in children" and "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The major considerations in the differential diagnosis of PANDAS are obsessive-compulsive disorder (OCD)/tic disorder in a child with coincident intercurrent episodes of GAS infection or a child with GAS carriage and Sydenham chorea [1,14,16,87].

Tic disorder or OCD — Both neuropsychiatric symptoms and GAS are common in prepubertal children. OCD occurs in 1 to 2 percent of school-age children and transient motor tics in as many as 25 percent [95-97]. GAS accounts for 15 to 30 percent of all cases of pharyngitis in children between the ages of 5 and 15 years. Prospective surveillance identified GAS carriage in 2.5 percent of well children and 4.4 percent of children with upper respiratory infection (including a sore throat) [98]. (See "Obsessive-compulsive disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Epidemiology'.)

Strict adherence to the diagnostic process described above should help to distinguish between PANDAS and coincidental simultaneous occurrence of these problems [14]. Documenting negative throat culture and/or declining antistreptococcal antibody titers during remission helps to exclude GAS carriage. (See 'Diagnostic process' above.)

Sydenham chorea — Sydenham chorea is a movement disorder characterized by chorea, emotional lability, and hypotonia. Neuropsychiatric manifestations that may be present in Sydenham chorea also may occur in PANDAS patients (eg, OCD, separation anxiety, hyperactivity, adventitious movements) [10,87,99]. (See "Sydenham chorea".)

NATURAL HISTORY — The natural history of PANDAS was described in a prospective case-control study of 40 children with PANDAS and 40 children with obsessive-compulsive disorder (OCD)/tic disorders but no evidence of GAS infection [23]. Throat cultures were obtained once per month, and streptococcal antibody titers were measured at least once every three months, for two years; testing for GAS also was performed during exacerbations. Case subjects were treated with standard therapies for their neuropsychiatric symptoms and received prompt antibiotic therapy for GAS infections. Prophylactic antibiotics and immune modulating therapy were not administered. Laboratory personnel were blinded to the status of the patient (case versus control and exacerbation versus routine monitoring), and clinical raters were blinded to the laboratory results.

The following observations were made [23]:

Forty neuropsychiatric exacerbations (clinically significant worsening for ≥5 days unrelated to a change in medication) occurred in 21 case patients (0.56 exacerbations per person year), and 25 neuropsychiatric exacerbations occurred in 14 control subjects (0.28 exacerbations per person year). These rates were lower than expected.

Only five neuropsychiatric exacerbations occurred within four weeks of GAS infection; all of these occurred in PANDAS patients. This was greater than the number expected by chance (1.6).

Definite or probable GAS infection was more frequent among cases than controls (0.43 versus 0.13 infections per person-year; relative risk 2.76, 95% CI 1.4-5.3).

These observations and those from other studies suggest that a subgroup of patients with tics/OCD may be vulnerable to GAS as a precipitant of neuropsychiatric symptoms, but the majority of exacerbations have other triggers [23,26,38].

MANAGEMENT — The management of children with PANDAS is multidisciplinary and centers on providing standard therapies for GAS infection, obsessive-compulsive disorder (OCD)/tic disorder, and other neuropsychiatric disorders [14,16,92].

Antibiotic therapy — Antibiotic therapy is indicated for the treatment of acute streptococcal infection as diagnosed by a positive throat culture or rapid antigen detection test (RADT) or positive skin culture from infected skin [14].

GAS infection — Children with signs and symptoms of acute GAS infection and positive culture or RADT for GAS require antistreptococcal therapy (whether they have neuropsychiatric symptoms). Antimicrobial therapy is administered to reduce the severity and duration of signs and symptoms, including suppurative complications, reduce the incidence of nonsuppurative complications, and reduce the risk of transmission. Treatment of GAS pharyngitis is discussed separately. (See "Treatment and prevention of streptococcal pharyngitis in adults and children".)

PANDAS subgroup — For children with suspected PANDAS (ie, abrupt onset of neuropsychiatric symptoms and evidence of recent GAS infection), the author of this topic suggests treatment with azithromycin or a cephalosporin rather than other antistreptococcal antibiotics or no antibiotics. Azithromycin is preferred for patients with suspected PANDAS previously treated with a penicillin or cephalosporin antibiotic without clear clinical benefit. Antistreptococcal therapy has been associated with prompt resolution of symptoms and prompt resolution is consistent with the diagnosis of probable PANDAS [24].

Azithromycin or cephalosporin therapy is provided even if the episode of GAS was already treated with a penicillin antibiotic (given the failure rates for penicillin and amoxicillin therapy). (See "Treatment and prevention of streptococcal pharyngitis in adults and children", section on 'Alternatives to penicillin'.)

Suggested doses are as follows:

Azithromycin 12 mg/kg orally in one dose for 5 days (maximum dose 500 mg/day)

Cefadroxil 30 mg/kg per day orally in one dose for 10 days

Cephalexin 30 mg/kg per day orally in two divided doses for 10 days

Cefuroxime 30 mg/kg per day orally in two divided doses for 10 days

Cefpodoxime 10 mg/kg per day orally in two divided doses for 5 days

Cefdinir 14 mg/kg per day orally in two divided doses for 5 days

Although treatment with azithromycin or clindamycin is advocated by some experts because of the possibility that GAS is intracellular [100-104], the author of this topic prefers azithromycin because it has fewer adverse effects than clindamycin (eg, gastrointestinal symptoms, potential to cause Clostridioides difficile) and the suspension is more palatable. The author of this topic avoids amoxicillin-clavulanate for the treatment of PANDAS. It does not provide improved intracellular penetration and is only active when bacteria are dividing.

There are no randomized controlled trials of antibiotic treatment of children suspected of having PANDAS syndrome. In a prospective study that identified 12 children with abrupt onset of neuropsychiatric symptoms and evidence of recent GAS infection, antistreptococcal (cephalosporin) therapy was associated with prompt symptom resolution in all cases [24]. Antistreptococcal therapy also was associated with prompt resolution of symptoms in the six patients who developed recurrent symptoms associated with GAS infection. The mean time to resolution of symptoms was shorter among children treated with cephalosporin than with penicillin (5 to 6 versus 14 days, respectively).

Neuropsychiatric therapy — Children with OCD, tic disorders, and/or other neuropsychiatric disorders should receive individualized standard neuropsychiatric treatment for these disorders (whether the children have evidence of recent GAS infection) [14,16,92]. Treatment of neuropsychiatric symptoms should not be delayed pending confirmation of PANDAS (eg, documenting rise in antistreptococcal antibodies or while monitoring for a second episode).

The neuropsychiatric manifestations of children in the PANDAS subgroup respond to treatment with standard pharmacologic and behavior therapies [14]. OCD symptoms generally respond to a combination of pharmacotherapy (typically a selective serotonin reuptake inhibitor) and cognitive-behavioral therapy. Motor and vocal tics can be treated with a variety of medications. (See "Obsessive-compulsive disorder in children and adolescents: Treatment overview" and "Tourette syndrome: Management", section on 'Approach to management'.)

Other therapies

Immune modulating therapy — Immune modulating therapies include plasma exchange, intravenous immune globulin (IVIG), glucocorticoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) [105]. If PANDAS is an autoimmune disorder (and this remains controversial), immunomodulatory treatments might be beneficial, but they are as yet unproven and they carry risks [106,107]. Although the pediatric acute-onset neuropsychiatric syndrome (PANS) Collaborative Consensus group has proposed indications for use of immunomodulatory therapies in children with PANS/PANDAS [93], the author of this topic and other experts caution against their routine use [34].

Plasma exchange or IVIG – The potential benefits of treatment with plasma exchange or IVIG compared with placebo were evaluated in a randomized controlled trial in 29 children who met PANDAS criteria and were severely affected [73]. Symptom severity was rated at baseline and at 1 and 12 months after treatment. Substantial improvement in symptoms from baseline was noted in the treatment groups at one month; improvements were maintained at one year, although psychotropic medications were decreased or discontinued in only 7 of 13 patients who required them at baseline. Adverse effects occurred in approximately two-thirds of patients in the treatment groups and included nausea, vomiting, headache, and dizziness.

Limitations of the trial included the lack of a control for plasma exchange, open treatment of controls after the one-month follow-up (making it impossible to exclude the possibility of spontaneous improvement in the control group at the 12-month follow-up), lack of correlation between therapeutic response and rate of antibody removal, and poorly understood mechanism of therapeutic benefit [33,73].

A subsequent randomized trial of IVIG in 35 children who met criteria for PANDAS and moderate to severe OCD failed to demonstrate a benefit of IVIG over placebo [108].

A subsequent open trial of plasma exchange in children with OCD who did not meet PANDAS criteria failed to demonstrate a benefit [74]. This finding suggests that the effects of plasma exchange in children with OCD may be limited to those with preceding GAS infection, lending support to the autoimmune hypothesis. (See 'Autoimmunity' above.)

Oral glucocorticoids – The effects of oral glucocorticoid treatment of PANS/PANDAS flares were evaluated in a retrospective study of 98 patients who met research criteria for PANS/PANDAS and had a total of 403 flares, 85 of which were treated with oral glucocorticoid [106]. Administration of oral glucocorticoids was associated with shorter duration of flares (6.4±5 weeks versus 11.4±8 weeks), particularly when administered early. Additional evaluation in a randomized controlled trial is necessary.

NSAIDs – The effects of NSAID treatment of PANS/PANDAS flares were evaluated in a retrospective study of 95 patients who met research criteria for PANS/PANDAS and had a total of 390 flares for which duration could be assessed [107]. Among the 390 flares, 270 were not treated with NSAIDs, 43 were treated early with NSAIDs (within 30 days of flare onset), and 76 were treated prophylactically (use of NSAIDs before the flare and continued for the duration of the flare). The mean duration of untreated flare was 12.2 weeks; it was 2.6 weeks shorter with early NSAID treatment and 4 weeks shorter with prophylactic treatment. Additional evaluation in a randomized controlled trial is necessary.

Tonsillectomy — The author of this topic suggests against tonsillectomy for children with PANDAS unless they have other indications for tonsillectomy. (See "Tonsillectomy and/or adenoidectomy in children: Indications and contraindications", section on 'Indications'.)

A systematic review of five studies evaluating tonsillectomy for children with PANDAS found no clear evidence of benefit [109]. The risks of tonsillectomy are discussed separately. (See "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications", section on 'Complications'.)

Referral indications — Referral to a specialist (neurologist, psychiatrist, mental health provider) for treatment of OCD, tic disorder, or other neuropsychiatric symptoms may be indicated for children who meet criteria for PANDAS. (See 'Neuropsychiatric therapy' above.)

Referral to a rheumatologist/immunologist for consideration of other diagnoses also may be warranted for patients with severe symptoms that are unresponsive to standard therapies.

PROGNOSIS — The long-term outcome of children who meet criteria for PANDAS is not known. Cases of carditis (as occurs in patients with Sydenham chorea) have not been reported [16]. Unrecognized PANDAS and untreated PANDAS may result in an increased risk of progression to lifelong obsessive-compulsive disorder and tic disorders that show the more typical waxing and waning pattern and are not associated with GAS infections [23].

PREVENTION — If the proposed model for PANDAS pathogenesis described above is correct, it might be possible to prevent PANDAS by preventing GAS infection. Recognition of the sentinel PANDAS episode and its prompt treatment may impact the likelihood of a recurrence and prevent kindling (eg, repeated stimulation of autoantibodies that target brain tissue, which eventually results in permanent destruction of the brain cells and permanent disability in the form of obsessive-compulsive or tic disorder). (See 'PANDAS subgroup' above.)

Measures to prevent GAS infection include early recognition and prompt initiation of antistreptococcal therapy and taking steps to decrease transmission. School-age children with sore throat or unexplained fever should be evaluated for GAS infection and treated with antibiotics if throat culture or rapid antigen detection test is positive. (See "Treatment and prevention of streptococcal pharyngitis in adults and children".)

SUMMARY AND RECOMMENDATIONS

Background – Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) is a term used to describe a subset of children whose symptoms of obsessive-compulsive disorder (OCD), tic disorders, or other neuropsychiatric symptoms are exacerbated by group A streptococcal (GAS) infection. The association between PANDAS and GAS is controversial. PANDAS is a subgroup of pediatric acute-onset neuropsychiatric syndrome (PANS), a diagnostic entity introduced to broaden the scope and allow for inciting events other than GAS. The pathogenesis of PANDAS and PANS is uncertain and there is controversy regarding their evaluation and management. (See 'Background' above.)

Working criteria – PANDAS is characterized by five working criteria (see 'Clinical features' above):

OCD and/or tic disorder

Pediatric onset (between three years and onset of puberty)

Abrupt onset and episodic course of symptoms

Temporal relation between GAS infection and onset and/or exacerbation

Neurologic abnormalities or tics during exacerbations

The abrupt onset is most striking feature.

Diagnostic evaluation

The author of this topic evaluates children who present with abrupt onset of OCD/tic disorder, separation anxiety, or urinary frequency (which can be a form of anxiety) for PANDAS by testing for GAS infection. (See 'Diagnostic process' above.)

A diagnosis of probable PANDAS may be suspected in children with:

-Abrupt onset of neuropsychiatric symptoms

-Evidence of recent GAS infection (positive throat culture or rapid antigen detection test [RADT] for GAS, positive skin culture from infected skin or rising antistreptococcal antibody titers)

-Remission of neuropsychiatric symptoms with antistreptococcal therapy

Children in whom a diagnosis of probable PANDAS is suspected should be monitored for occurrence of neuropsychiatric symptoms temporally associated with evidence of GAS infection.

A brief trial of prophylactic antibiotics can aid in the diagnosis:

-Remission of symptoms during prophylaxis supports the diagnosis of PANDAS

-Recurrence of neuropsychiatric symptoms during prophylaxis excludes the diagnosis of PANDAS

Differential diagnosis – The major considerations in the differential diagnosis of PANDAS are OCD/tic disorder in a child with coincident intercurrent episodes of GAS infection or a child with GAS carriage and Sydenham chorea. (See 'Differential diagnosis' above.)

Management – Children with positive culture or RADT for GAS require antistreptococcal therapy (whether they have associated neuropsychiatric symptoms). (See 'GAS infection' above and "Treatment and prevention of streptococcal pharyngitis in adults and children".)

For children with evidence of GAS infection temporally associated with abrupt onset of OCD, tic disorders, and other neuropsychiatric symptoms (ie, those in whom probable PANDAS is suspected), the author of this topic suggests antistreptococcal therapy with azithromycin or cephalosporins rather than other antistreptococcal agents (Grade 2C). (See 'PANDAS subgroup' above.)

Children with OCD, tic disorders, and other neuropsychiatric disorders require standard neuropsychiatric treatment if the symptoms do not remit after antibiotic therapy. (See 'Neuropsychiatric therapy' above.)

Referral indications – Referral to a specialist (neurologist, psychiatrist, mental health provider) for treatment of OCD/tic disorder and other neuropsychiatric symptoms may be indicated for children who meet criteria for PANDAS.

Referral to a rheumatologist/immunologist for consideration of other diagnoses also may be warranted for patients with severe symptoms that are unresponsive to standard therapies. (See 'Referral indications' above.)

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Topic 6031 Version 33.0

References

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