Approach

The key goals of management are to:[2][85]

  • Target the most impairing neuropsychiatric symptoms (e.g., obsessive-compulsive disorder [OCD], tics, severe food restriction, anxiety) and symptoms resulting from neuroinflammation or postinfectious autoimmunity

  • Address underlying etiologies, such as infections, inflammation, psychosocial trauma, and other medical causes.

Treatment may include:[2][33][51][86]

  • Education, supportive and behavioral therapies, and psychotropic drugs for neuropsychiatric symptoms

  • Antibiotics for identified infections (e.g., otitis media, tonsillitis, sinusitis)

  • Anti-inflammatory or immunomodulatory therapies for symptoms resulting from neuroinflammation or postinfectious autoimmunity.

Psychiatric interventions should begin once the diagnosis is confirmed and should occur simultaneously with treatments for infections or inflammation. Timely control of and minimizing psychiatric symptoms is essential to reduce immediate suffering, enhance the child's capacity to receive further treatments, and improve long-term recovery.

Treatment needs to be individually tailored, with the intensity of the therapeutic intervention matched to the severity of the symptoms and disease trajectory.[33][51][86]

Due to the rarity and heterogeneity of PANS, much of the evidence for treatment approaches is based on case reports, observational studies, and expert consensus rather than high-quality randomized controlled trials. Where the evidence is lacking, recommendations are based on consensus expert opinion and/or the experience of the authors of this topic. Use of interventions such as prophylactic antibiotics in patients with recurrent episodes triggered by group A streptococcus (GAS), and anti-inflammatory and immunomodulatory treatments are considered controversial and provisional.[2][33][51][60] European guidelines recommend that the decision to use these treatments is taken by a multidisciplinary team consisting of psychiatry, neurology, infectious disease, rheumatology, immunology, and neurogenetics/neuroimmunogenetics.[2]

Effectiveness of treatment should be evaluated at frequent intervals and modified accordingly. Treatment can be tapered down or stopped when symptoms resolve. However, treatment may be necessary again due to the relapsing-remitting nature of symptoms.[85]

Follow-up is recommended at 1, 3, 6, and 12 months if symptoms resolve or stabilize and immunomodulatory/antibiotic treatment options have been sufficiently tried.[2]

Infections

GAS infection

Following confirmation of the diagnosis of PANS:[33]

  • Give antibiotics targeted at GAS (e.g., penicillin or amoxicillin [or equivalent]) to any patient and their close contacts with laboratory-confirmed GAS infection (e.g., GAS pharyngitis, impetigo, perianal streptococcal infection). For full details of treatment, see Acute pharyngitis, Impetigo

  • Consider an initial 2-week course of antibiotics for all patients while waiting for laboratory results.

Based on clinical experience, the authors of this topic suspect that GAS is the most common trigger and recommend following the typical treatment approach used for Sydenham chorea, including testing and treating all family members with positive GAS infection.

Many PANS cases are thought to be caused by GAS; however, the window of opportunity to diagnose GAS infection may be missed (as is true with many cases of Sydenham chorea). The PANS/PANDAS Consortium consensus guideline recommends an initial course of antibiotics for all newly diagnosed PANS patients, including those without documented GAS infection, as is done for patients with acute rheumatic fever.[33] However, due to the limited available evidence, the authors of this topic consider (based on their clinical experience) that the decision to give antibiotics in these patients should be made by the clinician and the family after a discussion of the risks and benefits. Scenarios where the benefits likely outweigh the risks include:

  • Families where recurrent streptococcus and/or poststreptococcal inflammatory diseases are common

  • Child has severely deteriorated, where the risk/harms of giving a 2-week course of antibiotics (with the possibility of dramatic benefit) is not as great as the risk of missing an opportunity to reverse a life-threatening situation (including suicide risk, starvation risk, risk of impulsive dangerous behavior). This recommendation is based on the clinical experience of the authors of this topic.

Carefully consider prophylactic antibiotics only in selected patients where benefits are deemed to outweigh the risks. The use of prophylactic antibiotics in patients with recurrent episodes of PANS triggered by GAS or in patients without documented infections is controversial.

  • The PANS/PANDAS Consortium consensus guideline recommends considering prophylactic antibiotics in patients with two or more recurrent episodes triggered by GAS infection and a severe course.[33]

  • However, European guidelines recommend against the use of prophylactic antibiotics in this scenario as it is not supported by high-quality evidence.[2]

Non-GAS infection

Treat early any identified non-GAS bacterial infection, such as sinopulmonary infections (e.g., sinusitis, otitis media, mastoiditis, mycoplasma pneumonia), skin infections (abscesses), and Lyme disease as per standard of care for that infection.[33][86]

Viruses have been observed to be coincident with some presentations. These are generally self-limiting and are unlikely to need treatment.

Treat underlying infections before giving corticosteroids for inflammatory symptoms.

Acute symptoms: mild impairment

Mild impairment due to PANS may be defined as obsessive-compulsive symptoms that are significant but occur for only 1 or 2 hours a day and cause minor disruption at home or school.[51] The following treatments are recommended for new-onset PANS or new flare.[51] Flares are defined as abrupt deteriorations in neuropsychiatric symptoms, lasting an average of 12 weeks.[1][3][4][5]

Psychiatric interventions

Refer the patient for cognitive behavioral therapy (CBT) and provide other interventions, such as educational and supportive therapies.[86] These are the most appropriate therapies for management of OCD symptoms in children with mild impairment.[86] Psychotropic drugs are usually not required in this patient group.[86] However, psychotropic drugs may be considered on a case-by-case basis as an alternative to corticosteroids (see corticosteroids below), for example, in children who do not tolerate corticosteroids.[86][87]

Anti-inflammatory therapy

Consider a nonsteroidal anti-inflammatory drug (NSAID) if symptoms continue beyond 2 weeks (especially if symptoms are worsening and/or impairing function).[51]

  • NSAIDs may shorten the episode to 8 weeks and minimize symptoms during this time.[23]

  • If the initial NSAID does not improve symptoms, consider switching to a different NSAID (e.g., switch from naproxen to ibuprofen).​[24][51]

If symptoms persist despite NSAID treatment or the patient has poor response to NSAIDs, consider a short burst (brief course) of an oral corticosteroid.[51]

  • Short bursts of an oral corticosteroid may also shorten flares/episodes.[25]

  • Always make sure infection (e.g., low-grade sinusitis, perianal streptococcal infection) is cleared before starting corticosteroids. Corticosteroids may prolong elimination of triggering infections.

  • The authors of this topic typically only give oral corticosteroids in patients with post-GAS infection PANS, using the same approach and rationale as for Sydenham chorea, and only after elimination of infection. Controlled trial data are lacking for the effectiveness of corticosteroids in both these conditions, and therefore other approaches (i.e., psychiatric interventions, elimination of infection) should be considered and preferred by clinicians.

Note that European guidelines recommend NSAIDs in patients with mild impairment only if symptoms persist following psychiatric interventions and elimination of infection, and only recommend corticosteroids if the patient has severe symptoms after treatment with an NSAID and there is a strong suspicion of inflammation.[2]

Based on the experience of the authors of this topic, immunomodulatory therapy may not be needed in this patient group, since most episodes (especially in early childhood) resolve in 12-16 weeks and the risks of using immunomodulators should be weighed against benefits.

Acute symptoms: moderate to severe impairment

Moderate-to-severe impairing symptoms may be defined as symptoms that are distressing and impairing that interfere with daily life, but not overwhelming or incapacitating. The obsessive-compulsive symptoms may occupy 50% to 70% of waking hours, but there are periods of relief.[51] The following treatments are recommended for new-onset PANS or new flare.[51]

Psychiatric interventions

Refer the patient for CBT and provide other interventions such as educational and supportive therapies.[86] Refer the patient to a pediatric psychiatrist. Management of the most impairing neuropsychiatric symptoms should be prioritized.[86]

  • For some children, PANS-related separation anxiety and obsessive thoughts create the most distress and interference. For others, the most troubling symptoms are emotional lability, rages, and impulsivity. The management of these symptoms should be the same as the treatment for those psychiatric conditions.[2][86] See Obsessive-compulsive disorder, Anorexia nervosa, Tic disorders, and Generalized anxiety disorder.

  • Standard evidence-based interventions for neuropsychiatric symptoms may include CBT, educational and supportive therapies, and the use of psychotropic drugs (e.g., selective serotonin-reuptake inhibitors [SSRIs], benzodiazepines, and alpha-2 agonists).[2][86]

  • As with other inflammatory brain conditions, patients may be sensitive to psychotropic drugs; starting at a lower than typical dose (e.g., up to one fourth to one half of the typical starting dose) should be considered. A slower and closely monitored dose escalation than typical should be employed to avoid activation, agitation, akathisia, and other adverse effects.[87] Based on the experience of the authors of this topic, patients tolerate and have better responses to psychotropic drugs after addressing underlying infection and postinfectious inflammation.

Anti-inflammatory therapy

Consider a corticosteroid (oral bursts or pulse doses) to shorten flares/episodes in patients with moderate to severe impairment.[51] Corticosteroids are usually sufficient for this purpose, particularly if given within a few days of symptom onset.[51]

  • The authors of this topic suggest considering a 1-2 month course of oral or intravenous corticosteroids in patients with post-GAS infection PANS, using the same approach and rationale as for Sydenham chorea. Controlled trial data are lacking for the effectiveness of corticosteroids in both these conditions, and therefore other approaches (i.e., psychiatric interventions, elimination of infection) should be considered and preferred by clinicians.

  • For more severe impairment, prolonged corticosteroid courses (with gradual taper) or repeated high doses of corticosteroids may be indicated.[51] Temporary or permanent adverse effects can occur with prolonged courses, frequent oral bursts, and high doses (e.g., blurry vision, weight gain, Cushingoid appearance, altered glucose metabolism, dyslipidemia, hypertension, cataracts, glaucoma, osteoporosis, diabetes). The decision to give corticosteroids should be weighed against these potential toxicities.[51]

Note that many patients have transient worsening of psychiatric symptoms after initiation of corticosteroids.[51] This is almost always followed by improvement. If the patient does not improve, or only has a transient improvement, re-evaluate for underlying infection. Prepare families for worsening symptoms so that they can ensure adequate resources to manage the child.

Always make sure infection (e.g., low-grade sinusitis, perianal streptococcal infection) is cleared before starting corticosteroids.

It is unclear whether corticosteroids are helpful in viral-triggered episodes and may prolong clearance of viruses.

Immunomodulatory therapy

High-dose intravenous immune globulin (IVIG) may be considered instead of corticosteroids or if there is no long-term improvement in symptoms following cessation of corticosteroids.[2][51]​ IVIG may be given alone or in combination with a corticosteroid for patients with moderate to severe PANS.[51]

  • IVIG is considered an experimental treatment for PANS; the decision to treat with IVIG should always rely on a highly specialized team after full consideration of the case, evaluation of autoimmune encephalitis and other inflammatory brain diseases, and demonstration of evidence for inflammation/autoimmunity.[2][51]

  • IVIG can address underlying infections; however, it is not readily available to most clinicians and patients.[51]

  • One randomized controlled trial showed improvements in obsessive-compulsive symptoms, anxiety, and overall functioning in patients receiving IVIG compared with those receiving placebo after 1 month of treatment, but its effect was unclear in another trial.[26][88] An ongoing trial is evaluating the efficacy of IVIG (primary outcome: improvement of neuropsychiatric symptomatology and behavior) in patients with PANS.[89]

Refer the patient for a full workup for other inflammatory diseases before starting immunomodulatory therapy.[51]

  • Starting corticosteroids or IVIG before a complete inflammatory disease workup is complete may mask tell-tale signs of other autoimmune diseases (e.g., autoimmune encephalitis, arthritis).

Patients may have transient worsening of psychiatric symptoms occasionally after initiation of immunomodulators. If the patient has extreme symptoms such as rage/violence, life-threatening impulsivity, mood instability, or suicidality, ensure that a safe environment can be maintained in case the patient's behavior escalates.[51]

Acute symptoms: extreme or life-threatening impairment

Extreme or life-threatening impairing symptoms may be defined as obsessive-compulsive symptoms that occupy 90% to 100% of waking hours. Children experience profound distress from separation anxiety, generalized anxiety, depression, and emotional lability.[51] The following treatment is recommended for new-onset PANS or new flares.[51]

Psychiatric interventions

Consider arranging admission to an inpatient psychiatric setting, particularly where the combination of escalated impulsivity, behavioral regression, mood lability, and irrational fears can lead to life-threatening impulsive actions.[51] If the child has severe separation anxiety, accommodations for a parent to stay with the child may be required.[51]

  • Crisis management in PANS is similar to that for other disorders presenting risk of self-harm. Impulsivity, physical violence, or aggression, refusal to eat or drink, suicidality, and sometimes acute psychosis, need to be carefully assessed and managed in a timely manner. An ideal inpatient unit for children with symptoms of PANS requires staff skilled in behavioral management and should be equipped to perform necessary medical procedures (e.g., lumbar puncture, intravenous fluid administration, tube feeding, ECG monitoring).[86]

As with moderate-to-severe impairment PANS, treatment of extreme or life-threatening psychiatric symptoms, such as OCD, restricted eating, and anxiety symptoms, should follow the usual standard of care for those conditions.[2][86] Refer the patient for CBT and provide other interventions, such as educational and supportive therapies.[86]

Anti-inflammatory and immunomodulatory therapies

Plasmapheresis (therapeutic plasma exchange) may be considered as first-line therapy, given either alone or in combination with high-dose intravenous corticosteroids, IVIG, and/or rituximab.[51] Plasmapheresis removes autoantibodies triggering immune response leading to brain inflammation.[51]

  • Plasmapheresis followed by IVIG may be considered in life-threatening cases which are not responsive to psychotropic drugs since treatment response is typically rapid.[27] However, rebound worsening after apheresis is discontinued is not unusual (as is typical for many inflammatory conditions), hence, IVIG or other maintenance anti-inflammatory treatments should be considered.[51]

  • Note that European guidelines recommend plasmapheresis or rituximab only in patients with clinically probable or definite autoimmune encephalitis.[2]

  • This is an experimental treatment for PANS; the decision to treat should always rely on a highly specialized team after full consideration of the case, evaluation of autoimmune encephalitis and other inflammatory brain diseases, and demonstration of evidence for inflammation/autoimmunity.[2][51]

Refer the patient for a full workup for other inflammatory diseases before giving immunomodulatory therapy.[51]

  • Starting corticosteroids or IVIG before a complete inflammatory disease workup is complete may mask tell-tale signs of other autoimmune diseases (e.g., autoimmune encephalitis, arthritis).

Always make sure infection (e.g., low-grade sinusitis, perianal streptococcal infection) is cleared before starting corticosteroids.

It is unclear whether corticosteroids are helpful in viral-triggered episodes and may prolong clearance of viruses.

Note that many patients have transient worsening of psychiatric symptoms after corticosteroids, and occasionally after initiation of immunomodulators. If the patient has extreme symptoms such as rage/violence, life-threatening impulsivity, mood instability, or suicidality, ensure that a safe environment can be maintained in case the patient's behavior escalates.[51]

Disease trajectory

The vast majority of patients have relapsing-remitting symptoms with initial episodes lasting 4 weeks to 4 months. Although rare, some patients may progress to a chronic course.[51]

Relapsing-remitting

The management of relapsing-remitting episodes is typically the same as for acute symptoms (new-onset or new flare) according to symptom severity.[51] In addition, consider evaluating patients for:[51]

  • The possibility of recurrent infections/exposures triggering flares

    • If GAS infection is a frequent trigger for relapses, the patient and close contacts should be treated. Consider giving prophylactic antibiotics.[33] However, European guidelines recommend against the use of prophylactic antibiotics in this scenario as it is not supported by high-quality evidence.[2]

  • Underlying immunodeficiency and autoimmune/rheumatologic conditions.

Chronic symptoms

Rarely, patients present with primary chronic or secondary chronic course.

  • Primary chronic course. After 6 months, patients with a high burden of symptoms (with no or little signs of an improving trajectory) likely have one of the following: ongoing infection, autoimmune/inflammatory condition (arthritis or other autoimmune condition), underlying neurogenetic/neuroimmune genetic condition, or a combination of these.[51]

  • Secondary chronic course. These are patients with relapsing-remitting course who do not return to baseline between episodes. These patients tend to have more severe flares and take longer to recover from each flare. They may also have more frequent flares and stacked flares.

Patients with chronic symptoms and their families can benefit from a multidisciplinary team approach including psychiatrist with expertise in OCD and other behavior disorders, behavioral therapist, social work support, neurodevelopmental specialist, infectious disease expert, rheumatologist, immunologist, and geneticist with expertise in neurogenetics/neuroimmunogenetics.[3]

Other considerations

Due to the acuity, severity, and rapid change of psychiatric symptoms, consider:[86]

  • Writing educational plans. Many children with PANS require modified educational plans to ensure their educational needs are met due to severe separation anxieties, OCD symptoms, tics, frequent urination, attention-deficit disorder symptoms, handwriting difficulties, poor cognitive and physical stamina, difficulties with math and processing speed, memory issues, and pain. Children's needs may change day to day and month to month. Writing the plans with the most difficult days in mind will assure that the child can receive adequate accommodations.

  • Avoiding chasing symptoms but allowing time for drugs to take effect. Symptoms of PANS can change very fast.

  • Ensuring that families are given early support and coaching since the illness is abrupt and severe and most parents do not have the skills, resources, or network to manage these new-onset severe psychiatric/behavior issues. Some parents and siblings may develop symptoms of post-traumatic stress disorder (PTSD) after witnessing the sudden decompensation of their child/sibling. In practice, adapting trauma treatment models for parents/siblings may be helpful.[90]

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