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Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Clinical Report

Pediatrics ·Volume 155·Number 3

March 1, 2025

The sudden onset of severe behavioral and neuropsychiatric symptoms in children is a frightening and potentially life-changing situation. The pediatric health care providers and clinicians to whom families turn need guidance on how to accurately diagnose and treat new-onset neuropsychiatric symptoms in children. They need expert guidance about whether these symptoms indicate a diagnosis compatible with pediatric acute-onset neuropsychiatric syndrome (PANS). The cause of PANS is unknown, but it is theorized to be triggered, in some cases, by a recent infection and/or autoimmunity issues (similar to Sydenham chorea, autoimmune encephalitis [AE], and Guillain-Barré syndrome). The condition is challenging from a clinical perspective, because it lacks disease-specific biomarkers, strong evidence for pathogenic causes, and consensus on treatment of clinical symptoms. Further, the evidence base for PANS encompasses multiple subspecialties, including child and adolescent psychiatry, pediatric rheumatology, pediatric neurology, pediatric infectious diseases, pediatric immunology, and developmental-behavioral pediatrics.Given this complexity, there is a clear need for guidance and advice for pediatric clinicians and the families they serve and support. To that end, with the encouragement of the Board of Directors, the American Academy of Pediatrics (AAP) has developed this clinical report. It focuses primarily on PANS, an umbrella condition that encompasses pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although PANDAS is, by definition, associated with streptococcal infection,1 it is now considered by many to represent a subset of the larger spectrum of infection-induced acute-onset neuropsychiatric symptoms.2,3 This clinical report was developed after a comprehensive literature review and analysis of the findings. Because they are limited by the present level of evidence on the topic, the findings are presented as a report rather than a clinical practice guideline. The contents are intended to aid the pediatric health care provider in evaluating, diagnosing, and treating sudden-onset and severe behavioral changes in children that could indicate potential PANS and in supporting these children and their families.The AAP leadership formed an expert panel of experienced clinicians to provide their perspectives and guide the development of this clinical report. The expert panel members were recruited from relevant subspecialty areas (eg, rheumatology, neurology, child and adolescent psychiatry, infectious diseases, developmental-behavioral pediatrics, and primary care) and focused on the existing evidence basis associated with PANS. The panel met 3 times to discuss relevant questions and reach consensus on diagnosis, treatment, research needs, and other key issues. These discussions were facilitated by senior leaders of the AAP. To support the expert panel's deliberations, the AAP commissioned an external evidence review of pertinent literature on PANS/PANDAS to gather the comprehensive base of published research. The comprehensive review of the literature was performed in March-April 2020 and included literature in PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsychInfo databases. The expert panel members also provided additional references for consideration throughout the process. A subsequent review of more recent literature was conducted in June 2023, and new information integrated into the document. The final document was reviewed by expert panel members along with other members with expertise in immunology, mental health, and emergency medicine. It was reviewed and approved by the AAP Board of Directors.The AAP recognizes that PANS is likely a valid diagnosis, although the diagnostic process is challenged by a lack of well-accepted evidence to guide the clinician. Much remains unknown about the condition, however. This clinical report explicitly acknowledges the pressing need for research and enrollment of patients in multicenter studies to explore the potential etiology, epidemiology, evaluation, and treatment for PANS. The AAP is committed to working collegially with other physicians and scientists to learn more about this condition and develop a dependable and clear evidence base that supports evaluation, diagnosis, and treatment to address a specific child's symptoms. Until that goal has been reached, the AAP recommends a deliberate and cautious approach, grounded in evidence, and focused on helping children who have the symptoms of possible PANS. The AAP further recommends that the best care for children with potential or diagnosed PANS is provided in a medical home, is family centered, and is delivered by a multidisciplinary team.PANS is a condition that involves a constellation of psychiatric and neurologic symptoms that present simultaneously and in rapid onset, the cause or causes of which are unknown. Although the cause is still under investigation, the manifestations may follow a recent infection. The acute onset of symptoms can appear similar to both infectious and noninfectious conditions that may have classic features of sudden onset neuropsychiatric symptoms. Although other neuropsychiatric conditions have been associated with infection (Sydenham chorea is a classic example of this paradigm), there are additional noninfectious autoimmune etiologies for acute neuropsychiatric symptoms, such as anti-NMDAR (N-methyl-D-aspartate receptor) autoimmune encephalitis (AE).PANS was first described as a diagnostic entity in 2012, more than a decade after the description of PANDAS, in order to expand the characterization and broaden the scope of pediatric neuropsychiatric disorders. Although group A beta-hemolytic streptococcal (GAS) infection is a hallmark of PANDAS' description, PANS encompasses other potential instigator events.4 PANS has the following criteria5: Unusually abrupt and dramatic onset of obsessive compulsive disorder (OCD) or severely restricted food intake;Concurrent, abrupt onset of additional severe neuropsychiatric symptoms from at least 2 of the following 7 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, and complex motor and/or vocal tics; andSomatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency that are not better explained by a known neurologic or medical disorder.2,3Again, it is important to note that the most distinctive characteristic of both PANS and PANDAS is the dramatic acuity of onset and short time to peak severity of the cardinal symptom(s) of OCD, tics, or food restriction.The factors that trigger PANS symptoms are postulated to be multimodal and include psychological trauma, genetic predisposition, and postinfectious autoimmune causes.6,7 The OCD, tics, and other neuropsychiatric symptoms seen in these patients are theorized to sometimes result from postinfection autoimmunity, similar to Sydenham chorea.2,8 Infections that have been suggested as triggers of PANS-like symptoms include group A Streptococcus, Mycoplasma pneumoniae, influenza, and sinusitis.6 Not all cases of PANS are reported to be triggered by an infection, however, and no single microbe has been associated with the onset of PANS.9As noted, PANS is an umbrella term that subsumes PANDAS. PANDAS' 5 diagnostic criteria include presence of OCD and/or tic disorder; prepubertal onset of symptoms; episodic course characterized by acute, severe onset and dramatic symptom exacerbations; temporal relationship between GAS infection, symptom onset, and exacerbations; and association with neurologic abnormalities (eg, choreiform movements, motor hyperactivity, tics).1,9 The hypothesis for PANDAS' pathophysiology is that GAS infection in a susceptible host incites the production of antibodies to group A Streptococcus, which cross-react with antigens in the basal ganglia, particularly in the caudate nucleus and putamen, through molecular mimicry. This relationship remains unproven based on current evidence.Historically, research has described this condition as 'PANDAS,' without differentiating between PANDAS and the more recently defined PANS. Although much of the evidence specifies PANDAS, the findings have relevance to understanding the possible etiology in both that condition and PANS. A 2020 review of articles from 1977 onward noted that children in whom PANDAS was diagnosed had some evidence of alterations within the structures of the central nervous system (CNS), including caudate, putamen, globus pallidus, and striatum. Additionally, autoantibodies that interact with basal ganglia were observed in some patients with PANDAS.10Researchers have used animal models to test for the plausibility of GAS infection causing immunologic abnormalities in the brain, as summarized by Wald.4 Brimberg and colleagues demonstrated that autoimmune-prone strains of rats immunized with GAS antigen exhibited motor symptoms and compulsive behaviors (grooming, marble-burying) that are similar to those seen in Sydenham chorea and PANDAS and were alleviated by haloperidol and selective serotonin reuptake inhibitors (SSRIs).11 Examination of the brains of those rats showed autoantibodies deposited in the striatum, thalamus, and frontal cortex. When immunoglobulin G (IgG) was infused from these GAS-exposed rats into naïve rats, the latter demonstrated similar behavioral and motor problems and had IgG deposits in the striatum of their brains.12 Further evidence comes from a 2018 experiment of Frick and colleagues in which sera from patients with well-characterized PANDAS were infused into the striatum of mice; antibodies from these children were found to be bound to 80% of cholinergic interneurons (which have been implicated in the pathogenesis of tic disorders).13 After the patients were treated with immune globulin intravenous (IGIV) and their symptoms improved, their sera no longer contained antibodies that had elevated binding to cholinergic interneurons in the mice. Conflicting evidence also exists. Loiselle and colleagues found that sera from patients with PANDAS and Tourette syndrome infused into striata in rats did not induce behavioral changes.14 Further, Gilbert and colleagues point out that attempts to identify definite autoantibodies in PANDAS have yielded inconsistent results and that there is no association between symptom exacerbations and changes in levels of antineuronal antibodies in patients with PANDAS.15,16The risk factors, diagnostic biomarkers, and biological mechanisms are not clearly established, creating challenges in making a definite diagnosis. The lack of longitudinal high-quality research, consistent diagnostic criteria, and a national database hamper a precise estimation of the prevalence and incidence of PANS.PANS and AE are not the same. The 2 conditions have different diagnostic criteria, treatment recommendations, and testing and diagnostic workups. Children with AE present with acute or subacute (usually less than 3 months) onset of neuropsychiatric symptoms attributable to an underlying abnormal immune response of the CNS.17 These patients also present with seizures, complex movement disorders, and/or focal neurologic signs on examination. The diagnostic criteria for pediatric seronegative AE require evidence of inflammation within the CNS (ie, by examination of the cerebrospinal fluid or magnetic resonance imaging [MRI]). When a pathogenic antibody (such as NMDAR antibody) is identified in the serum and/or cerebrospinal fluid, patients are described to have seropositive AE, whereas the absence of such an antibody is described as seronegative AE. AE symptoms also persist over time, which differs from the relapsing-remitting course observed with PANS.17 The vast majority of children with AE demonstrate some degree of cognitive impairment, whereas most children with PANS demonstrate normal cognition on formal testing.17The diagnosis and workup of PANS/PANDAS is complicated by several issues: There is a lack of clarity about the potential causes of PANS and a broad array of possible causes to be considered.There is no listing of PANS in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), which provides diagnostic criteria for recognized mental health conditions, or the International Classification of Diseases, 11th Revision (ICD-11) coding system, which is the global standard for recording health information.PANS is characterized as being a 'diagnosis of exclusion,' which requires the clinician to rule out many other diseases that may explain the acute onset of symptoms before a diagnosis of PANS can be assigned to the patient.7,9The average child experiences multiple infections a year, including a high prevalence of streptococcal infections.Pediatric anxiety and tic disorders occur frequently.Thus, the patient may face an extensive workup before a diagnosis is made, often based on uncertain causes and without any guidance from widely recognized systems like the DSM-V and ICD-11. Therefore, it is critical to conduct a thorough patient and family history, physical and psychiatric examination, and a phased laboratory and imaging workup.When a child presents with one or more of the symptoms that make up the criteria for PANS, it is also critical to remember the ages at which primary psychiatric syndromes tend to first present in the context of normal pediatric development. Anxiety disorders occur in 7.1% of children 3 to 17 years of age,18 and transient tics may occur in as many as 20% of school-aged children.19 OCD-a key criterion of PANS-occurs in 1% to 3% of all children and adolescents, although less commonly in younger children compared with adolescents.20,21 In contrast, disease-related OCD, such as with PANS, occurs more frequently in prepubertal children-an age group with much lower rates of OCD in isolation. Regardless of the child's age, anxiety, tics, and OCD are more likely to be a primary psychiatric disorder that is unrelated to PANS. This consideration will aid pediatric health care clinicians in differentiating PANS from other mental health conditions.When assessing a child for potential PANS, pediatric health care providers are encouraged to initially discuss a broad but individually tailored differential diagnosis-including acute-onset OCD or other anxiety disorders, tic disorder, Tourette syndrome, Sydenham chorea, or AE. A complete medical history and review of symptom longevity are required to assess these potential diagnoses.The patient's medical history and physical examination should address the signs and symptoms characteristic of PANS-including whether they occurred abruptly or over time as well as their duration, severity level, and impact on normal life functioning.9 This symptomatology is the most important part of the history. The history and examination should assess for signs and symptoms of disorders that must be excluded, including Sydenham chorea, Tourette syndrome, AE, and anorexia nervosa. Although nearly all children with PANS have OCD, the presence of OCD alone should not lead to a PANS workup unless the onset is extremely abrupt. Because children with Tourette syndrome (which is estimated to occur in 0.3% to 0.6% of school-aged children)18 may have tics in combination with OCD and attention-deficit/hyperactivity disorder (ADHD), they could be confused with children with PANS. The sudden onset of symptoms distinguishes children with PANS from those with Tourette syndrome.The patient history should thoroughly assess previous mental health problems, because patients with preexisting mental health challenges may have symptoms related to that condition rather than to a new, acute-onset syndrome such as PANS and because patients with PANS frequently have mental health comorbidities including anxiety, ADHD, and autism spectrum disorder. These comorbidities include previous OCD or anxiety (especially separation anxiety), mood disorders, psychological trauma, tic disorders, ADHD, oppositional defiant disorder, and learning issues in school. History of symptomatic pharyngitis (not just asymptomatic carrier status for GAS infection) and other upper respiratory infections should be noted, along with treatment with antibiotics for episodes of symptomatic GAS infections. A review of primary health care and school records is often helpful and may disclose prior neurodevelopmental or neuropsychiatric evaluations and issues that family members might not recognize as being relevant to the current history.Most children with PANS have a normal neurologic examination except for the presence of tics, inattention, or choreiform finger movements (eg, fine piano-playing movements when the child has arms and hands extended and eyes closed). These choreiform finger movements should be differentiated from more generalized chorea, defined as random-appearing, continuous, involuntary movements (while awake) that can affect the entire body and often include the face and tongue. If present, chorea should prompt the clinician to evaluate the child for Sydenham chorea and AE.9 Choreiform movements of the hands are often considered 'overflow' movements and may be observed in typically developing children who do not have PANS. These movements seem to be a sign of cortical immaturity of systems involved with automatic inhibition, tend to decrease as the child matures, and are reported to be observed more often in children who have learning disorders.22Children with PANS usually have normal cognition, although school performance may deteriorate because of inattentiveness, anxiety, OCD, and/or perfectionism. Assessing the child's actual cognitive abilities includes both a detailed history and neuropsychological examination to identify any specific deficits; this assessment may lead to formal neurocognitive testing if deficits are suspected. More significant cognitive or memory impairment suggests the possibility of AE or other brain disorders.9A comprehensive evaluation by an experienced child and adolescent psychiatrist or psychologist is necessary to eliminate other disorders that present with similar neuropsychiatric syndromes.7 If psychiatric evaluation is not available, then assessment by the primary care pediatrician should, at a minimum, focus on the psychiatric and behavioral symptoms seen in PANS.The family history may be contributory but is not conclusive either in supporting the diagnosis of PANS or suggesting the presence of other diagnoses. First-degree relatives of patients with PANS have been reported to have increased rates of OCD, tics, acute rheumatic fever, and maternal autoimmune disorders.9 It is not known whether these conditions suggest a genetic cause of PANS or whether families with these symptoms are more likely to recognize PANS symptoms in their children.Extensive workups and testing are not necessary in most cases of suspected PANS. A phased workup is recommended with stop points to mitigate the risk of the child (and family) having to endure an unnecessary major diagnostic odyssey.Because it is theorized that Streptococcus pyogenes infection or colonization, in conjunction with other factors, may be a trigger for PANS, some have proposed that testing all children with new onset abrupt neuropsychiatric symptoms consistent with PANS undergo a diagnostic test for S pyogenes (ie, throat culture, throat swab for S pyogenes polymerase chain reaction [PCR] or antigen tests) at the time of the diagnosis. Current recommendations are to perform this test only for children who otherwise are recommended to undergo streptococcal diagnostic tests (those with pharyngitis consistent with streptococcal infection). The only study to address this question is a case series of children at a single site who presented with both new onset abrupt neuropsychiatric symptoms consistent with PANS and some degree of pharyngeal symptoms consistent with GAS pharyngitis. The 12 children who tested positive for GAS were treated with oral antibiotics recommended for symptomatic GAS pharyngitis and were reported to have significant improvement in neuropsychiatric symptoms. Given that these are the only data in support of routinely testing for and treating children found to harbor GAS organisms, since the study had a small sample size, had a select population, included children with pharyngeal findings, and provided no control group for comparison or longer term follow-up, the AAP does not believe the data are strong enough to support universal testing of all cases of acute onset neuropsychiatric symptoms consistent with PANS. The AAP recognizes that there are theoretical analogies between PANS triggered by GAS infection and acute rheumatic fever (ARF) manifested as Sydenham chorea, but without additional empiric evidence of benefit and recognizing the potential for harm, the AAP does not endorse universal GAS testing and subsequent antibiotic treatment of children who are positive. For children who otherwise meet criteria for testing for GAS infection because of signs and symptoms consistent with current recommendations for whom to test, the AAP recommends testing and appropriate treatment. The AAP also endorses and supports further research to evaluate the causes of PANS and the efficacy of interventions to reduce its subsequent morbidity.Because of well-described problems with sensitivity and specificity, antistreptococcal serologic testing (ie, anti-streptolysin O and anti-DNAase B levels) is not recommended to evaluate for GAS infection.4 Sustained high or low titers are difficult to interpret and do not support a recent episode of GAS infection.Additional evaluation is recommended when the child displays focal neurologic signs and symptoms or specific signs and symptoms that may indicate the potential for AE, including17: Symptoms of psychosis (eg, hallucinations, catatonia);Persistence of symptoms over months (ie, not relapsing-remitting, which is characteristic of PANS);Altered level of consciousness;Cognitive impairment (including confusion, aphasia, amnesia, memory deficits) that are not attributable to anxiety, OCD, or depression23;Seizures that are not associated with a preexisting seizure disorder; andMovement disorders other than tics, such as chorea, dystonia, tremor, myoclonus, and/or ataxia.The presence of the above symptoms should lead to additional evaluation, which may include: Electroencephalography (EEG);Brain MRI with contrast;Lumbar puncture with cell count, protein, and glucose measures to evaluate for signs of CNS inflammation as well as auto-antibodies to targets associated with AE (eg, NMDAR, myelin oligodendrocyte glycoprotein);Blood tests to evaluate for signs of inflammation (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], complete blood cell count [CBC]), thyroid function, antineuronal antibodies, and markers for other systemic autoimmune conditions (such as lupus erythematosus, vasculitis, etc);Neurocognitive evaluations; a comparison to any previous evaluations is critical; andA complete autoimmune panel of autoantibodies commonly associated with AE.Some groups recommend that children with potential PANS have a CBC with differential, ESR, CRP, metabolic panel, and urinalysis.9 There is no evidence for the utility of these tests in deciding on either diagnosis or treatment; therefore, they should not be routinely performed.15 In addition, there is no evidence for the following tests; their use is not recommended for diagnosing PANS: PCR assay for Mycoplasma infection (pharynx): Although some have hypothesized that M pneumonia infection may be a cause of PANS, good evidence to support this hypothesis does not exist. In addition, the PCR test result is usually positive only for a few weeks at the beginning of the infection and may also be positive in asymptomatic children.24,25Antinuclear antibody test: In isolation, this test result may be positive in healthy children, especially at low levels; its high false-positive rate makes the test problematic to use for autoimmune disorder screening.26 If a positive antinuclear antibody result occurs in the context of systemic signs and symptoms suggestive of rheumatologic disease as well as other positive laboratory markers that indicate inflammation, the patient should be referred to a rheumatologist for consideration of an alternate diagnosis to PANS.Cunningham panel: This commercially available set of assays purports to measure levels of biomarkers that are related to autoantibodies to dopamine receptors and other components found in basal ganglia. Current literature documents that the Cunningham panel has very high positive rates among children who are generally healthy and, therefore, very low specificity (eg, 6% for PANS and 10% for PANDAS).15,27 The panel is not recommended, because results will neither confirm nor eliminate PANS and will not alter planned treatment.Workup for other conditions: Myriad other conditions have been mentioned in association with PANS, either for the initial onset or for exacerbations. These include viruses (eg, influenza, Epstein-Barr, herpes simplex, enterovirus, and varicella-all of which are known to have neurologic complications), Lyme disease, sinusitis, dental infections, and gastrointestinal infections. Workups for these conditions are rarely, if ever, helpful. For example, there are only anecdotal case reports that claim an association with sinusitis; these are probably the simultaneous occurrence of a common and an uncommon event. Some advocates recommend workups to rule out AE, neuropsychiatric systemic lupus erythematosus, and acute disseminated encephalomyelitis using EEG, MRI, and lumbar puncture. These conditions have specific clinical presentations that are usually different from PANS. Hence, such a workup should not be performed in a patient being evaluated for PANS unless symptoms of encephalopathy, seizures, myelitis, or other focal neurologic deficits are present or there is overlap of other neuropsychiatric symptoms typical of these syndromes.Obtaining imaging is not warranted unless CNS or orbital complications are being evaluated.Treatment recommendations for PANS are generally grouped into 3 types of interventions7: 1) psychiatric and behavioral interventions for OCD, other types of anxiety, tics, or avoidant/restrictive food intake disorder (ARFID); 2) antibiotic treatment for GAS infection; and 3) aggressive therapies for presumed underlying neuroinflammation and autoimmune problems. Treatment is complicated by the fact that there are no well-designed trials that provide evidence-based guidance on treatment for PANS' symptoms-except for specific psychiatric and behavioral symptoms such as OCD, tics, and anxiety that can be seen without PANS. Effective treatments are described below. Families may ask pediatric care providers about other treatments they have heard about, including immunomodulatory therapies. Despite the lack of evidence for these treatments, they are also described in order to fully inform providers who may be considering these unproven treatments for potential PANS. As has been noted throughout this clinical report, more evidence is needed to identify the best possible treatment(s) for children in whom PANS has been diagnosed.There are evidence-based recommendations for psychiatric and behavioral interventions for children with PANS across a spectrum of symptoms observed.20,21 These treatments include psychosocial; psychiatric; physical therapy/occupational therapy; and other traditional, symptom-based, and function-based interventions. They should be started early in the course of symptoms in children with PANS, whether or not other treatments for infectious agents or immune modulation are being considered or given. In particular, because medications take time to work, especially in children with severe symptoms, it is important not to delay treatment. Treatments for some of the common psychiatric and behavioral problems seen in children with PANS are described below.OCD is the most common symptom complex in PANS and can be the most troubling. Standard evidence-based behavioral and medication treatments are available. The studies of treatments for OCD were in patients who were referred for OCD that was unrelated to PANS; nonetheless, it is reasonable to expect these treatments will be effective in PANS. In fact, pilot studies suggest that the treatments are effective.28First-line treatment for children with OCD is cognitive behavioral therapy (CBT) and SSRIs, usually sertraline or fluoxetine. The specific type of CBT is exposure and response prevention (ERP), in which the patient is exposed to actual situations, imagined situations, or the sensations associated with the discomfort attributable to those situations and then guided to resist (prevent) performing the compulsions that relieve their anxiety. This exposure is performed on a graded basis from least anxiety-producing to most anxiety-producing.29 Although both CBT and SSRIs are individually helpful in reducing symptoms, in children, the combination of the 2 has been shown to be more effective than the use of either alone (50% to 70% response in 12 weeks vs 40% for CBT alone and 20% to 30% for SSRIs alone).30,31 CBT/ERP is also intensive and may involve as much as 14 one-hour visits over 12 weeks; more severe cases may take even longer. Families may face barriers in accessing CBT because of insurance restrictions or shortage of available therapists in their area.Because SSRIs can cause activation in children (ie, a state of restlessness, lability, agitation, and anxiety), doses begin low and increase slowly with frequent monitoring. Once a therapeutic dose is reached, it may take up to 12 weeks to see a full response.32 Anecdotal evidence has suggested that children with PANS may be more sensitive to the adverse effects of SSRIs, making parents concerned about SSRI use.32 It is important for the physician to address and refute any concerns that SSRIs are contraindicated.32In addition to CBT and SSRIs, parent education to 'hold the line' and resist giving into or accommodating the child's compulsions (which frequently control the entire family's routines and escalate symptoms) has been shown to decrease OCD symptoms, family disruption, and family conflict.33Separation anxiety, which is commonly observed in children with PANS, can severely limit the child's and parent's activities. Parent accommodation of the child's anxiety for a limited time may be helpful, but escalation often occurs. Parent training should be offered to help the caregiver move the child back to normal sleeping arrangements and activities (including school) and to spend time with attachment figures other than parents (such as grandparents and other relatives, nannies, neighbors, and older siblings). CBT may also be helpful and may involve reappraisal of fears and problem-solving practice.28 Drug therapy is rarely necessary, but for severe cases, clinicians may consider use of an SSRI, especially in older children.Tics are very common in children with PANS and may range from simple motor tics to complex motor and phonic tics. When a triad of OCD, ADHD, and complex tics occurs, Tourette syndrome should be considered. In most cases, tics are not treated. Treatment may be considered if the tics interfere with the child's functioning or if the child experiences severe embarrassment, teasing, or bullying.28 Comprehensive behavioral intervention for tics (CBIT) has been shown to be effective. CBIT includes relaxation techniques, inhibition of tics with competing motor movements when the urge is felt (habit-reversal training), and awareness of situational antecedents or consequences of tics that may inadvertently reinforce them.34 Occasionally, medications are offered, of which the most common are alpha-2 agonists (guanfacine or clonidine). Antipsychotics are also effective, but significant adverse effects preclude their use to suppress tics in most children.Sleep disturbances are also common in children with PANS. They may be attributable to separation anxiety, OCD bedtime rituals, enuresis, nightmares, or rapid eye movement (REM) sleep behavior disorder.28 In general, the treatment for sleep disturbances includes counseling and implementation of the principles of good sleep hygiene. Occasionally, melatonin may be helpful. REM sleep behavior disorder consists of the lack of atonia (which is usually a hallmark of REM sleep), nightmares, and flailing of arms and legs that may be reenactment of dreams and are often violent enough to harm anyone who is sleeping with the child.35,36 There is some indication that SSRIs may be one of the inciting agents, leading parents to be concerned about their use. Most children with REM sleep behavior disorder are not on SSRIs, however.35,36 If REM sleep behavior disorder is of concern, psychiatry or sleep specialty consultation should be sought.Abrupt, dramatic onset of OCD or severely restricted food intake are the cardinal symptoms of PANS; severely restricted food intake may be the only symptom of PANS. Almost all children in whom PANS is diagnosed who have ARFID symptoms also have OCD. In these children, restricted food intake is usually attributable to obsessive fears of contamination, choking, or vomiting and, thus, is an extension of the child's OCD. In a 2015 case series of children diagnosed with PANS, all of the children had OCD; many also had separation anxiety, tics, and symptoms of ADHD.37 Two-thirds were restricting food secondary to contamination fears, with some restricting food for fear of choking or vomiting. In addition, the children also reported compulsive ways of preparing food or deciding what foods to restrict and/or refuse. Only a few had concerns about being overweight or body image; when present, these concerns were often concomitant with the fears described above.37Recommended treatment is two-pronged.28,38 First, a medical assessment should be performed including vital signs, electrocardiogram (EKG), electrolytes, and monitoring for weight loss. In children with significant weight loss, medical treatment may include hospitalization, feeding tubes, and intravenous fluids (if needed for nutrition, hydration, and correction of electrolyte abnormalities). Second, ERP should be offered to address the fears and compulsions with gradual exposure to foods and incremental expansion of diet and intake. SSRIs may also be added to the treatment regimen, similar to the treatment of OCD in children with PANS.28Children with PANS may have other psychiatric or behavioral symptoms, including irritable or aggressive behavior, mood lability, depression, and/or ADHD. These symptoms may or may not require treatment with behavioral interventions or medications; standard protocols for these problems can be used, in consultation with psychiatry or developmental-behavioral pediatrics.28Children with sudden and abrupt onset of behavioral symptoms of PANS (almost always OCD) with clinical pharyngitis should receive a diagnostic test for GAS infection-a throat culture, a rapid antigen detection test, or a nucleic acid amplification test. If a workup for GAS infection is performed in such patients and the result is positive, the child should be treated with appropriate antibiotics for a 10-day course (usually amoxicillin).36 In the absence of a positive culture, treatment is not recommended, even if an anti-streptococcal antibody test result is positive.15The AAP does not recommend follow-up tests, treatment for longer than 10 days, or prophylaxis if a follow-up test result is positive.39-41 There is no robust evidence basis for recommendations2 for long-term treatment with antibiotics for children with documented GAS pharyngitis. Nevertheless, some clinicians institute long-term streptococcal prophylaxis for patients who have either multiple GAS infection-associated exacerbations or are severely affected with symptoms of PANS. This practice may lead clinicians to offer or prescribe long-term antibiotics to children, perhaps for years or until adulthood, without any evidence of its effectiveness. In addition, because there is no evidence-basis for this practice, clinicians may create their own definition of 'long-term' (eg, months or years) and select a specific antibiotic based on their own opinion, using some hybrid definition of 'long-term' that includes extended treatment for an exacerbation (with or without documented GAS infection) and prophylaxis for future prevention. For a more detailed evaluation of the evidence base for antibiotic treatment, see Sigra, Hesselmark, and Bejerot, 'Treatment of PANDAS and PANS: A Systematic Review' (2018).42 Only 2 studies cited in that review included a placebo arm, both of which found no significant effect from antibiotics.In the age of the internet, caregivers are likely to search online for solutions and may seek information about the following unproven treatments. Because parents may ask about them, these treatments are described for the pediatric clinician's information. Treatment for Lyme Disease: Lyme disease has been suggested as a possible trigger for PANS because of its neuropsychiatric symptoms (including OCD).2 To-date, however, no clear-cut cases of PANS have been associated with Lyme disease. Testing or treatment for Lyme disease for children with PANS is not recommended at this time.Tonsillectomy and/or Adenoidectomy (T&A): T&A has been recommended to decrease incidence of GAS infections. A number of studies have evaluated the impact of T&A on exacerbations of PANS. Although no controlled studies have been conducted, 2 prospective observational studies found no helpful effect on symptom severity.42 T&A are not recommended treatments for PANS.Treatment for Sinusitis and/or Influenza: Although sinusitis and influenza have been labeled as 'inciting' agents for PANS, this connection is not supported by evidence. Sinusitis and influenza are common diagnoses in children and, therefore, frequently occur around the time of an initial PANS diagnosis or a subsequent exacerbation.43 The relationship is most likely coincidental and temporal. Both conditions have well-developed guidelines for diagnosis and treatment that should be followed.43 Treatment for sinusitis and influenza is not recommended outside of the usual criteria for respiratory disease.Unfortunately, concerns among patients and families about the influenza vaccine exist (especially the live-virus formulation) because of its anecdotal association with PANS. These fears may lead to concerns about vaccines in general.2 The AAP has long supported vaccines as one of the most effective medical advances of all time; vaccines are safe, are effective, and save lives. There is no reason to curtail their use in children with PANS. Pediatricians are encouraged to discuss and counter concerns about vaccination, in relationship to causing or exacerbating PANS, whenever they are raised by parents. Treatment for M pneumoniae: The focus on M pneumoniae is primarily because of its association with a number of other neurologic disorders, including encephalitis, transverse myelitis, Guillain-Barré syndrome, acute disseminated encephalitis, choreoathetosis, ataxia, and acute psychosis.2,44 No well-documented cases connecting M pneumoniae and PANS have been described. Because M pneumoniae is treated with macrolides, some clinicians have used macrolides (such as azithromycin) to either treat or provide long-term prophylaxis to children with PANS. Until a clear connection to PANS is demonstrated, however, there is no need to treat for M pneumoniae outside of the usual criteria for respiratory disease or other known neurologic complications.Treatment for Other Viruses and Infections: Treatment for a myriad of other conditions has been mentioned in association with potential PANS, either for the initial onset or for exacerbations. These include treatment for viruses (eg, Epstein-Barr, herpes simplex, enterovirus, and varicella, which are known to have neurologic complications), dental infections, and gastrointestinal infections. It is hard to know what to make of these potential triggers, because they are very common in all children. No treatment for these conditions is indicated at this time for children in whom PANS has been diagnosed.Invasive Therapies for Presumed Underlying Neuroinflammation and Autoimmune Problems: Patients and their families may ask about aggressive therapies that have been reported as helpful or recommended by experts and other parents. These may include IGIV; biologics, such as rituximab; immunosuppressives, such as mycophenolate mofetil; and therapeutic plasma exchange (TPE). These immunomodulatory therapies are the most controversial area of treatment for PANS. Some experts recommend their use, especially for children with moderate-to-severe or extreme neuropsychiatric symptoms and impairment of functioning.45 Many subspecialists and other medical experts are skeptical about the use of immunomodulatory therapies to treat patients with PANS, given the lack of demonstrated evidence of underlying CNS inflammation or autoimmunity for many children in whom PANS has been diagnosed. A 2018 systematic review of treatments for PANS found that the evidence for the benefit of treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, IGIV, and TPE was inconclusive because of poor study designs, small numbers of subjects, and conflicting results.42 The randomized controlled trial (RCT) of treatment with IGIV did not show efficacy for children in whom PANS was diagnosed.46 Because of the lack of evidence strength for autoimmunity and the potential for adverse effects, including immunocompromise, severe headaches, anaphylaxis, aseptic meningitis, thromboembolic phenomena, hemolysis, renal failure, among other serious reactions,6,15,45 treatment with invasive immunotherapies is not usually recommended.Children who have severe and incapacitating symptoms should be evaluated by a neurologist, rheumatologist, or immunologist who has expertise in assessing and treating autoimmune neuropsychiatric conditions. In children with severe and incapacitating neuropsychiatric symptoms, it is more difficult to distinguish PANS from other conditions, because the severity of a predominant symptom may mask other disease manifestations. If the symptoms are severe enough to warrant consideration of intravenous therapies such as IGIV, TPE, or immunosuppressant medications, a thorough workup to exclude other conditions should strongly be considered. The AAP believes that immunomodulatory therapies should only be used in rare cases and only after consultation with a multispecialty team that includes pediatric neurologists and rheumatologists who are experienced in the diagnosis of other conditions (such as AE) and in the use of these medications. These drugs should be administered in pediatric infusion centers/inpatient pediatric centers and not in a general office setting because of the need to monitor patients closely to ensure their safety. Further, these drugs are ideally only used in the context of clinical trials designed to improve our understanding of, and evidence for, effective treatment for PANS.Despite the lack of compelling evidence to support efficacy in treating PANS, advocacy for IGIV treatment is occurring across the country and becoming more widespread. Several states have passed laws mandating insurance coverage of IGIV for PANS/PANDAS treatment (including Arkansas, Delaware, Illinois, Indiana, Maryland, Minnesota, and New Hampshire). Pediatricians are encouraged to engage with their local chapters to learn more about the situation in their state and community.All children-including those with a potential PANS diagnosis-should receive care that is delivered in a medical home and involving a team of caregivers, that is family centered, and that includes resources and support as well as treatment.47 The AAP acknowledges that there is much to do before all children and families have equal access to the trusted services provided by the medical home.Medical homes facilitate the creation of team-based partnerships with parents and other caregivers. The trusted relationships and continuity of care provided by the medical home are helpful in supporting parents and children during challenging and frightening health crises-including when children are being evaluated for potential PANS. Clinicians must introduce the family to all of the team members who will be collaborating and communicating with the family about treatment options. Early engagement with partners who form the treatment team is critical to ensure that families get the help and support they need. As described, team members may include-depending on the child's symptoms-the medical home primary care clinician, psychiatry, psychology, neurology, rheumatology, physical therapy, developmental-behavioral pediatrics, and occupational therapy.A medical home is not a place. It is a way for children and families to receive health care from a primary care provider they know and trust. T...

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https://publications.aap.org/pediatrics/article/155/3/e2024070334/200384/Pediatric-Acute-Onset-Neuropsychiatric-Syndrome

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