Anxiety disorders

OVERVIEW: What every practitioner needs to know

Anxiety disorders in youth are among the most common mental health issues in children and adolescents, with prevalence estimates for this group of disorders ranging from 6%-20%. These disorders can often be difficult to diagnose. Specific fears and worries are part of normal development and disentangling normal developmental variants of anxiety from true anxiety disorders can be difficult.

Because of their internalized nature, these problems are often undiagnosed and untreated in youth. Because anxiety disorders are often accompanied by somatic symptoms (e.g., headaches, stomachaches), children with anxiety disorders often present first to primary care physicians for initial diagnosis and management.

Are you sure your patient has an anxiety disorder? What are the typical findings for this disease?

List of Anxiety Disorders in Children

There are nine specific types of anxiety disorders in youth recognized by the Revised 4th Edition of the Diagnostic and Statistical Manual (DSM-IV-TR) of the American Psychiatric Association, including panic disorder (with or without agoraphobia), separation anxiety disorder (SAD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), agoraphobia (without panic disorder), posttraumatic stress disorder (PTSD), social phobia, selective mutism, and specific phobia.

Anxiety disorders can also be caused by substance use or pharmacologic treatment (substance-induced anxiety disorder) or many different medical conditions (anxiety disorder due to a general medical condition). The common presenting signs and distinguishing characteristics for each of these disorders are covered briefly in this segment.

Youth may be able to identify anxiety or worries, but may have little insight into the cause, irrationality, or impairment of the problem.

Key Features of the Nine Types of Anxiety Disorders affecting youth

Phobias:

These are persistent, irrational fears. Specific phobias are specific fears of certain objects (e/g., blood/injection), creatures (e.g., animals or insects), or situations (e.g., heights, small enclosed spaces). Fear must be associated with functional impairment to be considered a disorder.

Social phobia is an intense fear of social situations in the core fear is of being negatively evaluated by others. When anxiety in social situations leads to the child becoming extremely withdrawn and nonverbal, this is further classified as selective mutism.

Panic attacks:

Panic attacks are manifested as a sudden rush of fear or terror during which the patient feels that they are losing control of their mind and body. Profound physical symptoms, including rapid heart rate, chest pain, vision changes (e.g., tunnel vision), and shortness of breath, are perceived by the patient as evidence of something being terribly wrong (e.g., very sick, dying).

Panic attacks can accompany any of the other anxiety disorders, but when they occur uncued by anxiety-provoking situations or thoughts and when they are associated with avoidance of potential triggers of and worry about future attacks they are classified as panic disorder.

When panic disorder is accompanied by avoidance of situations or places where panic attacks could occur, the diagnosis is panic disorder with agoraphobia. Agoraphobia can lead to patients becoming homebound and in children is often associated with unwillingness to separate from parents.

Separation anxiety disorder (SAD):

SAD is typified by excessive fear about being away from parental/attachment figures. Anticipatory anxiety about impending separations and worries about health and safety of self and attachment figures is central to the presentation. Somatic complaints on separation or anticipated separation are common, as is refusal to attend school.

Generalized anxiety disorder (GAD):

GAD consists of a long-term pattern (≥6 months) of excessive worry, often about mundane daily events. The pattern of rumination is often associated with physical complaints (e.g., poor sleep, tension, fatigue, restlessness).

Obsessive compulsive disorder (OCD):

OCD is typified by the presence of obsessions and/or compulsions. Obsessions are unwanted recurrent thoughts, images. or impulses. Common obsessional themes are fears of contamination, aggressive themes, and scrupulosity.

Compulsions are repetitive behaviors or mental acts that are aimed at alleviating anxiety. Typical compulsions include rituals to ensure cleanliness of self or environment, counting, rearranging items, and checking. Although compulsions are conceptualized as reducing the anxiety associated with obsessional thinking, the connection between the obsession and the compulsion may not make logical sense.

Posttraumatic stress disorder (PTSD):

PTSD is a complex of symptoms that occurs as a direct result of exposure to a traumatic event in which one feels like one’s life is threatened. This event leads to marked fear, horror, or agitation. There are three categories of symptoms: intrusive recollections, numbing/avoidance, and hyperarousal. These symptoms must persist beyond the immediate aftermath of the traumatic event to be considered PTSD.

Assessment Instruments for Child Anxiety Disorders

Formal psychological testing and questionnaires are not required to make the diagnosis of anxiety disorders in youth, but there are several instruments that can be helpful adjuncts to a detailed clinical interview:

The Anxiety Disorders Interview Schedule for DSM-IV–Child Version (ADIS-C) is a structured diagnostic interview that covers allof the major anxiety disorders in children and provides detailed questions that tap all of the typical manifestations of each illness.

The Children’s Yale-Brown Obsessive Compulsive Scale (C-YBOCS) is a clinician-administered instrument for assessing OCD severity that provides a checklist of the most common obsessions and compulsions as well as rating scales of associated interference and impairment.

The Multidimensional Anxiety Scale for Children (MASC) is a self-report questionnaire measure for children aged 8 years and older.

The Screen for Child Anxiety Related Emotional Disorders (SCARED) is a questionnaire that offers self- and parent-report versions.

What other disease/condition shares some of these symptoms?

Differential Diagnosis

Other medical causes of anxiety symptoms:

Cardiac— angina or myocardial infarction, arrhythmias, heart failure, shock

Endocrine—Cushing’s disease, hyperkalemia, hypo- or hyperthyroidism, hypoglycemia, tumors (insulinoma, pheochromocytoma)

Hematologic—anemia

Neurologic—essential tremor, encephalitis, seizure disorders, vertigo, trauma/concussion, intracranial mass

Respiratory—asthma/chronic obstructive pulmonary disease (COPD), pulmonary edema, pulmonary embolism

Other psychiatric conditions that share some of these symptoms:

Attention Deficit Hyperactivity Disorder (ADHD)—restlessness, difficulties with attention

Pervasive developmental disorders—social awkwardness, repetitive behaviors, adherence to routines

Learning disabilities—worries about academic performance

Depression—difficulty sleeping and concentrating, somatic complaints

Drugs or medications (prescribed or over-the-counter) can also induce anxious states. Typical offending agents include:

Stimulants (including cocaine and methamphetamine)

Anticholinergic agents

Hypotensive agents

Bronchodilators

Hallucinogens

Antipsychotic agents or chlorpromazine (can be associated with akathisia)

Significant anxiety symptoms can also be caused by withdrawal from medication or drugs, such as alcohol, benzodiazepines, barbiturates, or serotinergic agents.

What caused this disease to develop at this time?

The causal models for anxiety disorders are multifactorial. Both genetic and environmental factors have received empirical support. In most cases, a diathesis (genetic/temperament)/stress (environmental conditions) model is likely operating.

In someone with a vulnerable genetic diathesis/inhibited temperament, the following environmental factors are relevant:

Escape and avoidance learning:

Anxious behavior is maintained when people remove themselves from situations that make them anxious before their anxiety has had a chance to attenuate and when they avoid situations that make them anxious. Environmental factors that support escape and avoidance from anxiety triggers cause exacerbations.

Observational learning/modeling:

Anxious parents not only pass on their genes to their children but also often model worry or anxious behavior for their children, and they are often less able to cope with anxious behavior in their children. These factors lead them to provide excessive reassurance and to teach children to avoid anxiety triggers.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

No laboratory data are needed to diagnose anxiety disorders. Laboratory values of neurotransmitters, such as decreased serotonin levels in cerebrospinal fluid, are not used in clinical practice.

Laboratory studies may be useful to rule out other causes of anxiety. Several laboratory tests, such as urine screen, pregnancy test, basic metabolic profile, and complete blood count (CBC) are often part of the work-up in psychiatric emergency rooms and inpatient settings to screen for a potential medical cause of anxiety.

Would imaging studies be helpful? If so, which ones?

Imaging studies would be helpful only if you have a strong suspicion of an underlying medical cause that may be diagnosed by imaging, such as a pulmonary embolism or tumor.

Confirming the diagnosis

This algorithm (Figure 1) is designed to help determine which of the anxiety disorders is most consistent with a patient’s presenting symptoms. Determining severity of symptoms and degree of functional impairment is also important, as it has treatment implications.

Figure 1.

If you are able to confirm that the patient has an anxiety disorder, what treatment should be initiated?

Severity of symptoms and degree of functional impairment and associated risk/safety issues determine the appropriate context for care.

High safety risk:

Although not as common as in other psychiatric conditions, it is possible for youth with anxiety disorders to become a danger to themselves or others, in which case immediate referral to an emergency department to assess the need for more intense levels of care (i.e., inpatient or partial hospitalization/day treatment program) is warranted.

High severity and/or functional impairment with low safety risk (e.g., not attending school):

For youth who are less at risk of harm to self or others but who are experiencing debilitating symptoms, referral to a crisis evaluation with a psychiatric provider is warranted.

Lower safety risk, moderate to mild severity and/or functional impairment:

These symptoms can more likely be managed in an outpatient pediatric or psychiatric setting.

Specific treatment approaches include:

Psychotherapy:

Although there are some data on other approaches to psychotherapy for anxious youth, cognitive behavioral therapy (CBT) is the psychotherapy with the most data supporting its efficacy. For mild to moderate cases of anxiety, it is common to use CBT monotherapy as first-line treatment. The key components of CBT for anxiety follow:

Psychoeducation about the fact that anxiety is normal and not something to be completely removed from one’s life; the goal of treatment is to not let the anxiety make the child avoid or take less pleasure in his/her life.

Cognitive tools that teach the child how to identify automatic anxious self-talk to make it more likely that they will avoid anxious triggers and cognitive restructuring techniques that teach the child how to transform those automatic anxious thoughts into coping thoughts.

Behavioral tools are designed to encourage approach of feared situations and stimuli. Some behavioral tools focus on developing skills to manage somatic symptoms of anxiety (e.g., relaxation of deep breathing exercises), whereas other tools focus on building the child’s tolerance for increasing levels of anxiety through hierarchy-driven exposure exercises.

During exposure exercises, the child is asked to remain in contact with the anxious stimulus until the anxious state has attenuated on its own. In this manner the child learns that escape from or avoidance of the anxious triggers is not necessary in order to feel calm. These exercises are done gradually and with a lot of collaboration between child and therapist in designing the exercises. For OCD, a special variant of exposure exercises is used called exposure with response prevention.

Pharmacotherapy:

Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line agents for moderate or severe anxiety symptoms in youth. Ideally they are used in combination with psychotherapy, such as CBT, but they can be used instead of psychotherapy or before beginning a course of psychotherapy if psychotherapy cannot be tolerated by the child/family.

The six SSRI medications are fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, and paroxetine. The only US Food and Drug Administration (FDA)-approved use of SSRIs in anxious youth is for OCD, which has FDA approval for fluoxetine, sertraline, and fluvoxamine for children as young as 6 years. Additionally, a tricylic antidepressant, clomipraine, also has an FDA indication for pediatric OCD, but it is less commonly used as a first-line agent because of its side effect profile and the need for electrocardiography before dosing.

All other use of SSRIs in anxious youth (e.g., among those with GAD, SAD) is considered off-label, non-FDA approved use. However, practitioners often use all of these agents for treatment of anxiety. In general, child psychiatrists will often start with fluoxetine, sertraline, or citalopram because there is more efficacy data for their use, and in general a better side effect profile than with the other SSRIs.

Anxiety disorders often require a higher dose of SSRIs compared with typical doses used for depressive disorders.These medications often take 4-6 weeks to reach maximum benefit/efficacy. If clinical improvement is not seen in 2-3 weeks after titration, an additional dose increase may be warranted. Treatment with SSRIs is usually continued until 6-9 months after symptoms abate at which point a therapeutic taper/cessation of medication with careful monitoring for rebound anxiety may be indicated.

Other pharmacologic agents sometimes used in anxious youth include:

Benzodiazepines, such as clonazepam, lorazepam, and alprazolam, can be used in children. The only one with FDA approval in youth is lorazepam for those aged 12 years and older. These medications are often prescribed “as needed” to manage breakthrough anxiety symptoms or as “stop-gap” medications until therapeutic levels are obtained with an SSRI.

Benzodiazepines are generally avoided in younger children because of potential disinhibition or agitation. Additionally, patients can become physiologically dependent on these medications, so it is important to use them judiciously and to taper the dose of the medication if taking consistently for over 1-2 weeks.

Hydroxyzine can be used for anxiety in children less than 6 years of age and offers a way to treat breakthrough anxiety symptoms without prominent physiologic dependence.

What are the adverse effects associated with each treatment option?

Adverse effects from psychotherapy:

Overall, psychotherapy is a very low-risk type of treatment and is usually well tolerated in youth. In severe cases of anxiety disorders, psychotherapy, especially exposure-based CBT, may heighten symptoms of anxiety. For children/families who are extremely avoidant of anxiety triggers, facing these fears or worries may induce so much anxiety that compliance with treatment may become a problem. In these instances, combining exposure-based CBT with pharmacotherapy is indicated. When treatment calls for or produces changes in the larger family system other family or marital issues can be unmasked.

Adverse effects from SSRIs:

Antidepressants are usually well tolerated but can produce some side effects, many of which will abate after 1-2 weeks of continued use.

Common side effects:

Stomachache, nausea, headache, mild sedation, or sleep initiation difficulties, and the potential for weight gain are common. SSRIs can cause initial feelings of heightened anxiety, especially if started at a high dose. Anxious children can be especially sensitive to side effects. Therefore, starting at a very low subtherapeutic dose with more frequent, smaller dose titrations may be effective in mitigating this side effect.

Although less often discussed among child psychiatrists, sexual dysfunction (decreased sex drive, anorgasmia) is another possible side effect of these medications and it is important to screen for this in older adolescents/young adults.

Black box warning:

Before starting an SSRI trial it is vital to discuss the FDA’s 2004 “Black Box Warning” with parents/caregivers of children and adolescents (up to age 24 years). The evidence that led to this warning, in summary, was based on a 2003 meta-analysis in which SSRIs were associated with a higher risk for suicidal thinking than was placebo or no treatment (4% vs. 2%) in children with depression.

It is important to note that no children or adolescents in the study attempted or completed suicide. To guard against this risk, the FDA recommends weekly follow-up for the first month of SSRI treatment, and then every other week for the next month, and then monthly thereafter.

Activation:

Activation can occur with this class of medication. Therefore it is important to monitor for decreased need for sleep, increased energy, agitation/irritability, increasing goal-oriented activity, or impulsive behaviors. SSRIs should be avoided or used very carefully in youth with characteristics or a diagnosis of bipolar disorder because of the risk of mania induction.

Serotonin syndrome:

SSRIs should be avoided in combination with other serotonergic agents (e.g., tramadol, tricyclic antidepressants, St. John’s wort) because of the risk of serotonin syndrome. The cardinal symptoms of serotonin syndrome are tachycardia, hemodynamic instability, confusion, and fever. If this syndrome occurs, serotonergic agents should be stopped and immediate medical attention should be sought because of potential hemodynamic instability, which can lead to death.

Adverse effects from benzodiazepines:

These agents can cause significant sedation or symptoms of intoxication if overdosed; hallmark symptoms are slurred speech, ataxia, impulsivity, and poor decision making (similar to alcohol intoxication). Benzodiazepines can also cause irritibility or activation in youth, especially in younger children.

Adverse effects from hydroxyzine:

Similar to diphenhydramine, hydroxyzine can cause sedation and antihistaminic side effects (e.g., dry mucosa, tachycardia). Additionally, hydroxyzine can cause a paradoxic reaction in children, as evidenced by activation, hyperactivity, and impulsivity.

What are the possible outcomes of anxiety disorders in youth?

There are no long-term studies to date that have investigated the natural course and chronicity of child anxiety disorders. In the absence of empirical evidence, clinical evidence suggests that early detection and intervention is vital in limiting the negative consequences of these illnesses.

There are retrospective reports from adult patients that support the fact that without intervention, anxious children grow up to be adults with multiple psychiatric problems, depression being the most common.

Some anxiety disorders are more likely to persist than others (e.g., OCD, GAD), and some anxiety disorders are more likely to remit in childhood spontaneously (e.g., separation anxiety disorder) but may take another form in adulthood.

Treatment in childhood is also important because it minimizes “collateral damage” that can come from missing out on important normal developmental events and milestones secondary to anxious avoidance of the situations in which these occur (e.g., peer activities, school activities).

As a group, the treatment outcome data for child anxiety disorders are very promising, with as many as 80% of youth achieving symptom remission. Multiyear follow-up studies suggest that these gains are fairly well maintained.

What causes this disease and how frequent is it?

Prevalence

Symptoms of anxiety are common in normal childhood development. True anxiety disorders that meet full diagnostic criteria develop in 6%-20% of youth. This risk is increased by a family history of anxiety symptoms, which causes genetic loading for the illnesses as well as contributing to an environment in which anxiety is modeled and rewarded on a regular basis.

Overall, females are at higher risk than males for the development of anxiety disorders, especially when looking at prevalence statistics for separation anxiety disorder, specific phobias, panic disorder, and agoraphobia. In general, if anxiety symptoms are more severe at onset, there is a greater likelihood that they will persist into adulthood.

Anxiety disorders in childhood increase the risk of additional mental health issues in adolescence/adulthood (especially if untreated), including depression, substance abuse, and other anxiety disorders.

Lifetime prevalence rates of specific anxiety disorders in youth are:

Separation anxiety disorder: 4%

GAD: 5%

Social phobia: 3%-13% (varies based on criteria used)

OCD: 1%-2%

How do these pathogens/genes/exposures cause the disease?

of the multifactorial nature of psychiatric disorders, including anxiety, finding a single aberrant gene or mutation as the root of the disorder is not possible. Family studies on anxiety dating back to the 1970s demonstrate a clear genetic component in the transmission of these illnesses within families. Generally speaking, first-degree relatives of someone with an anxiety disorder (panic disorder, OCD, GAD, phobias) have a four- to sixfold increased risk of acquiring the disorder.

Twin studies have demonstrated a concordance rate of 4%-15% for dizygotic twins and 12%-26% for monozygotic twins.

Gene linkage studies for anxiety disorders have implicated several regions, which have been inconsistent across studies. The candidate gene that is most widely studied in anxiety disorders is the serotonin transporter gene.Research has demonstrated the presence of a polymorphism that causes a “short” allele of this transporter region, which is found in up to 45% of Americans of European descent.

This gene has been linked to some symptoms of OCD, PTSD, and social phobia, but this research has been complicated by several negative studies, inconsistent results, and difficulty linking these genes in association studies.

Recently, functional MRI (fMRI) has been used to link these genetic alterations to neural circuitry changes in the brain. Anxiety disorders have been associated with changes in limbic reactivity when processing emotions.

The previously described polymorphism of the short allele of the serotonin transporter gene has been linked to potential heightened fear reactivity due to increased amygdala reactivity to high-emotion situations and decreased connectivity between the anterior cingulate and the amygdala.

What complications might you expect from the disease or treatment of the disease?

Complications from the disorder itself:

Anxiety disorders in children are often diagnosed several years after the onset of symptoms. Because the often internalizing nature of the illness, families have often accommodated such symptoms for a long time before bringing the chlid for treatment.

Anxiety can cause significant issues in multiple spheres of life, including school (e.g., avoidance, underperformance), family (e.g., conflict with parents, siblings, accommodation and associated alterations in family routine, and peer interactions (e.g., isolation).

Patients and their families often present with great despair, worry, and/or animosity toward the affected child. It is vital to address both the child’s symptoms and the family’s response to those symptoms in an effort to stimulate change.

Anxiety disorders, especially those that have festered without treatment for some time, often co-occur with other psychiatric disorders, including depression, substance abuse, oppositional defiant disorder, ADHD, and learning disorders. Screening and treatment for comorbid conditions has been shown to improve anxiety symptoms as well.

Complications from treatment:

Psychotherapy, which is often the first line of treatment, may be too difficult initially for the child or family. If engagement in psychotherapy is problematic, consider augmenting treatment with a psychopharmacologic agent. Monitoring for potential side effects of psychopharmacologic treatment is vital (see section on “adverse effects”).

How can anxiety be prevented?

There are no primary prevention programs for child anxiety disorders. The best evidence for prevention is secondary prevention (i.e., in youth who are already showing subsyndromal levels of anxiety). There have been several research studies of school-based prevention programs (e.g., the FRIENDS program from Australia).

Among children at risk for anxiety disorders, care should be taken to model positive coping strategies and nonavoidance of anxious triggers. Helping parents or caretakers with profound anxiety problems of their own seek treatment can often be one of the most helpful prevention strategies.

There are no preventive medications or genetic tests/counseling to prevent or predict anxiety disorders.

What is the evidence?

Walkup, JT, Albano, AM, Piacentini, J. “Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety”. N Engl J Med. vol. 359. 2008. pp. 2753-66. (This is the largest (N = 488) randomized placebo-controlled combined-treatment trial for youth aged 7 to 17 years with anxiety disorders (GAD, SAD and social phobia) conducted to date. It was a multisite (N = 6) study that compared four different treatments: manualized CBT monotherapy, sertraline monotherapy, the combination of CBT and sertraline, and pill placebo. Independent evaluators blinded to treatment conditions assessed anxiety severity and impairment at baseline and at weeks 4, 8, and 12. After 12 weeks of treatment, using intent-to-treat analyses, remission rates were 81% in the sertraline + CBT group (n = 140), 60% in the CBT group (n = 139), 55% in the sertraline group (n = 133), and 24% in the pill placebo group (n = 76). The authors concluded that the combined treatment was superior to either of the monotherapies alone, and that both monotherapies were superior to placebo.)

March, JS, Foa, E, Gammon, P. “the Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavioral therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: The Pediatric OCD Treatment Study (POTS) randomized controlled trial”. JAMA. vol. 292. 2004. pp. 1969-76. (This is the largest (N = 112) randomized placebo-controlled combined-treatment trial for youth aged 7 to 17 years with OCD conducted to date. It was a multisite (N = 3) study that compared four different treatments: manualized CBT monotherapy, sertraline monotherapy, the combination of CBT and sertraline, and pill placebo. The CBT emphasized exposure with response prevention strategies. Independent evaluators blinded to treatment conditions assessed anxiety severity and impairment at baseline and at weeks 4, 8, and 12. After 12 weeks of treatment, using intent-to-treat analyses, remission rates were 54% in the sertraline + CBT group (n = 28), 39% in the CBT group (n = 28), 21% in the sertraline group (n = 28), and 4% in the pill placebo group (n = 28). The authors concluded that CBT + an SSRI or CBT alone should be first-line treatment approaches for youth with OCD.)

Hetrick, SE, Purcell, R, Garner, B. “Combined pharmacotherapy and psychological therapies for posttraumatic stress disorder (PTSD) 2010”. (The purpose of this Cochrane review was to determine whether the combination of psychological therapy and pharmacotherapy provides a more efficacious treatment for PTSD than either of these interventions delivered separately. Four trials met the inclusion criteria for the review, only one of which (sample size n = 24) was with children and adolescents. All four trials used an SSRI plus exposure or a CBT intervention. The authors of the review concluded that there was not enough evidence to support or refute the efficacy of combined CBT and SSRI compared with the monotherapies. Further large randomized controlled trials are needed in PTSD in general and in youths in particular.)

Smoller, JW, Block, SR, Young, MM. “Genetics of anxiety disorders: The complex road from DSM to DNA”. Depress Anxiety. vol. 26. 2009. pp. 965-75. (This article summarizes the evidence base for genetics and animal models from 114 studies of anxiety disorders in general [i.e., not specific to the pediatric population]).

Seligman, LD, Ollendick, TH. “Cognitive-behavioral therapy for anxiety disorders in youth”. Child Adolesc Psychiatr Clin N Am. vol. 20. 2011. pp. 217-38. (This article reviews the findings of 66 studies that have examined the efficacy of CBT for child anxiety disorders.)

Kircanski, K, Peris, TS, Piacentini, J. “Cognitive-behavioral therapy for obsessive compulsive disorder in children and adolescents”. Child Adolesc Psychiatr Clin N Am. vol. 20. 2011. pp. 239-54. (This article reviews the literature for treatment of OCD with CBT in children, providing overview of all research studies on the subject.)

Ongoing controversies regarding etiology, diagnosis, treatment

In pediatric OCD, there is an ongoing controversy as to whether some cases of pediatric OCD may be caused by an autoimmune reaction to a group A beta-hemolytic streptococcal infection. This hypothesis, called pediatric autoimmune disorders associated with streptococcal infections (PANDAS), has received much research attention in the past decade.There has been no conclusion to date as to whether the temporal association between the streptococcal infection and the onset/exacerbation of symptoms is based on an autoimmune mechanism (which the supporters endorse) or other factors such as stress (as the detractors believe).

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