Diagnosis and Management of PANS and PANDAS

Educational Objectives

The goal of this program is to improve the management of pediatric postinfectious neuropsychiatric diseases. After hearing and assimilating this program, the clinician will be better able to:

1. Perform an appropriate workup for patients with suspected pediatric acute-onset neuropsychiatric syndromes (PANS) or pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).
2. Avoid exacerbation of flares of PANS and PANDAS.
3. Choose the most effective treatment strategies for PANS and PANDAS.

Summary

Pediatric acute-onset neuropsychiatric syndrome (PANS): children with PANS show acute onset of symptoms (within 3 days), such as obsessive-compulsive disorder (OCD), suicidal and disturbing thoughts, irritability, hyperactivity, aggressiveness, or disturbed sleep; testing for streptococcal infection (SI) is negative

PANS flares: periodic relapses of PANS may occur after exposure to eg, an illness, inflammatory process, vaccine; some relapses are idiopathic; if not infectious, periodic flares can be treated with prednisone; although many children outgrow relapses during the peripubertal period (possibly because of changes in the brain or immune system), a large proportion do not

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) vs PANS: PANDAS presents similarly to PANS but is associated with positivity for SI; the PANS diagnosis was created to describe a syndrome in which the cause of the symptoms is unknown and tests for SI are negative; symptoms of PANDAS and PANS overlap almost completely; both fall within the category of postinfectious neuropsychiatric disease (PIND)

Sydenham chorea (SC): a PIND that has been known for centuries; patients show chorea-like behavior (eg, writhing motions, inability to sit still) several weeks after an SI; in the 1800s, SD was linked to rheumatic fever and endocarditis; children were described as having perseverative behavior, now known as OCD; studies at the National Institute of Mental Health found that 75% of children with SC had OCD; children with SC have emotional lability and suddenly become restless, irritable, extremely sensitive, abusive, and/or violent; some children diagnosed with disruptive mood dysregulation disorder (DMDD) may have PANS or PANDAS

Streptococcal infections: the most common infectious cause of neuropsychiatric disease; Orlovska et al (2017) — a population-based study found that streptococcal throat infections increased the risk for any mental disorder, specifically OCD and tic disorders; increased risk is seen with nonstreptococcal throat infections (eg, mycoplasma, viral) as well, but less so than with pharyngeal SI

Diagnosis of PANDAS: the acute onset OCD that occurred in children after any infection (including SI) was initially labeled “pediatric infection triggered autoimmune neuropsychiatric disorders” (PITANDs); original diagnostic criteria — laboratory confirmation of SI; abrupt and severe onset of OCD or motor or vocal tics, separation anxiety, attention problems, mood lability, enuresis, or handwriting changes following SI; usually prepubertal

Diagnosis of PANS: primary criteria include OCD, food restriction (<10%), and onset of ≥2 specified symptoms, ie, anxiety, emotional lability, irritability, aggression, oppositional behaviors, behavioral regression, deterioration of school performance, cognitive issues (math and handwriting may become more difficult), sensory or motor abnormalities (tics are a secondary criterion; possibly associated with Tourette syndrome), psychosis (auditory or visual hallucinations), sleep disturbance (eg, rapid eye movement [REM] behavioral disorder [frequent waking; involuntary motor movements during REM]), and/or enuresis or urinary frequency (believed to be associated with basal ganglia dysregulation)

Features of PANS: incidence is estimated at 1 in 200 children; PANS is distinct from functional neurological symptom disorder or conversion; a survey suggests that onset is typically at 6 to 10 yr of age, with greater prevalence in boys, and is acute (defined as 3 days for research purposes, but may be longer in some cases); triggers — largely infections, including SI (50%); also vaccinations (children with PANS are highly sensitive to vaccinations; these should be avoided during a PANS flare; give separately when possible)

Causes of PANS and PANDAS: animal models and neuroimaging suggest PANS and PANDAS are caused by an inflammatory process (antibodies directly cross-reacting with brain tissue or inflammatory factors crossing the blood-brain barrier and affecting the basal ganglia); Cunningham panel — measures 4 antineuronal antibodies (eg, anti-dopamine receptor 1, anti-dopamine receptor 2) and 1 enzyme activated by the antibodies; levels are elevated in children with PANS and PANDAS and decrease with treatment; although these antibodies are not specific or diagnostic, these suggest an inflammatory cause; Zheng J et al (2020) performed a diffusion-weighted imaging (DWI) study and found an increased diffusion coefficient in PANS, indicating disruptions in the basal ganglia that could be caused by inflammation; Frankovich has reported findings of systemic inflammation and autoinflammation, as well as response to immunomodulatory therapy, in children with PANS or PANDAS

Treatment of PANDAS and PANS: controversial; guidelines have been published (Chang K et al [2015], Swedo et al [2015], Swedo et al [2017]); some experts believe that the data are inconclusive and suggest treating children with selective serotonin reuptake inhibitors (SSRIs) to relieve symptoms of OCD; 3-armed treatment approach — includes antimicrobial agents, immunomodulation (eg, steroids, intravenous immunoglobulin [IVIG]), and psychiatric treatment (medications and support)

Diagnostic workup for PANS and PANDAS: psychiatric evaluation — essential to understand the onset; family history often reveals autoimmunity on one parent’s side and OCD on the other; medical examination — should include neurologic testing; look for “soft signs,” including the glabellar tap sign, and chorea (eg, piano-playing movements on Romberg examination); consider evaluation by a neurologist or infectious diseases specialist (ones who accept these conditions as true disease entities); magnetic resonance imaging is typically negative if symptoms have been present ≥1 wk; lumbar puncture can help to rule out autoimmune encephalitis but is usually negative (ie, the striatum is affected rather than the entire brain)

Laboratory studies: should include streptococcal and mycoplasma titers (positive results for mycoplasma may indicate an overactive immune system); children with PANS and family history of Hashimoto disease may have elevated thyroid antibody titers, suggesting a tendency toward autoimmune reactions; consider measuring markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein); check levels of ferritin (an acute-phase reactant; decrease in response to inflammation) and vitamin D (levels are typically low in children); thyroid hormone levels are usually normal; if positive findings are reported or symptoms increase, rule out other conditions, including tick-borne and mold-related illnesses; a positive antibody test necessitates further immunologic studies

Key points: the first step is determining whether the patient is having an active inflammatory episode; despite symptoms suggesting inflammation, laboratory tests may be negative; the Cunningham panel may be helpful; history may suggest an episode of PANDAS in the past; if current infection is ruled out, determine whether symptoms occur after vaccinations (suggesting an autoinflammatory condition); confirmed infections should be treated with antibiotics (some antibiotics also have anti-inflammatory effects); nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen) are often effective when infection has been ruled out

Psychiatric support: SSRIs and antipsychotic agents — avoid during an acute flare (the exception is olanzapine, but it may cause torticollis); inhibition of dopamine (the main neurotransmitter in the basal ganglia) worsens the condition because PANS and PANDAS are caused by derangement of dopamine signaling; lithium — a neuroprotectant; can be used to stabilize severe mood dysregulation; benzodiazepines — as needed lorazepam 0.5 mg may be administered to manage the condition acutely; cognitive behavioral therapy — ineffective during an acute flare but beneficial in the long term

Pharmacotherapy: antibiotics — studies have demonstrated superiority of azithromycin (Murphy et al [2017]), cefdinir (Murphy et al [2015]), and ceftriaxone over placebo for decreasing tics; all family members and contacts should be tested for SI; NSAIDs — some data suggest NSAIDs shorten the duration of flares (from 12 wk to 4 wk) if used early (Brown et al [2017]); corticosteroids — shorten flares (from 16 wk to 10 wk); adverse effects are short term; well tolerated by ≈90%; the dose may be increased to ≤2 mg/kg to ensure effect, followed by a slow taper

IVIG: Perlmutter et al (1999) reported that IVIG and plasmapheresis are more effective than sham infusion; a more recent trial (Williams et al [2016]) did not show efficacy from baseline to week 6 after 1 IVIG infusion vs a sham infusion (response improved after a second dose); Melamed et al (2021) found that ≥6 IVIG doses are required for good response

Other therapies: data on use of rituximab, methotrexate, mycophenolate mofetil (CellCept) are accumulating; psychiatric care and family support remain important; adjunct psychotropic agents may be tried; SSRIs may be used to manage residual OCD after resolution of inflammation; clozapine — may be effective when other agents have failed; has immunosuppressive as well as antipsychotic effects

Readings

Brown KD, Farmer C, Freeman GM Jr, et al. Effect of early and prophylactic nonsteroidal anti-inflammatory drugs on flare duration in pediatric acute-onset neuropsychiatric syndrome: An observational study of patients followed by an academic community-based pediatric acute-onset neuropsychiatric syndrome clinic. J Child Adolesc Psychopharmacol. 2017;27(7):619-628. doi:10.1089/cap.2016.0193; Chang K, Frankovich J, Cooperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25(1):3-13. doi:10.1089/cap.2014.0084; Gamucci A, Uccella S, Sciarretta L, et al. PANDAS and PANS: Clinical, neuropsychological, and biological characterization of a monocentric series of patients and proposal for a diagnostic protocol. J Child Adolesc Psychopharmacol. 2019;29(4):305-312. doi:10.1089/cap.2018.0087; Hajjari P, Oldmark MH, Fernell E, et al. Paediatric acute-onset neuropsychiatric syndrome (PANS) and intravenous immunoglobulin (IVIG): comprehensive open-label trial in ten children. BMC Psychiatry. 2022;22(1):535. Published 2022 Aug 6. doi:10.1186/s12888-022-04181-x; Melamed I, Kobayashi RH, O'Connor M, et al. Evaluation of intravenous immunoglobulin in pediatric acute-onset neuropsychiatric syndrome. J Child Adolesc Psychopharmacol. 2021;31(2):118-128. doi:10.1089/cap.2020.0100; Orlovska S, Vestergaard CH, Bech BH, et al. Association of streptococcal throat infection with mental disorders: Testing key aspects of the PANDAS hypothesis in a nationwide study. JAMA Psychiatry. 2017;74(7):740-746. doi:10.1001/jamapsychiatry.2017.0995; Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354(9185):1153-1158. doi:10.1016/S0140-6736(98)12297-3; Shimasaki C, Frye RE, Trifiletti R, et al. Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms. J Neuroimmunol. 2020;339:577138. doi:10.1016/j.jneuroim.2019.577138; Swedo SE, Frankovich J, Murphy TK. Overview of treatment of pediatric acute-onset neuropsychiatric syndrome. J Child Adolesc Psychopharmacol. 2017;27(7):562-565. doi:10.1089/cap.2017.0042; Swedo SE, Seidlitz J, Kovacevic M, et al. Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings. J Child Adolesc Psychopharmacol. 2015;25(1):26-30. doi:10.1089/cap.2014.0073; Thienemann M, Murphy T, Leckman J, et al. Clinical management of pediatric acute-onset neuropsychiatric syndrome: Part I-psychiatric and behavioral interventions. J Child Adolesc Psychopharmacol. 2017;27(7):566-573. doi:10.1089/cap.2016.0145; Vreeland A, Thienemann M, Cunningham M, et al. Neuroinflammation in obsessive-compulsive disorder: Sydenham chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, and pediatric acute onset neuropsychiatric syndrome. Psychiatr Clin North Am. 2023;46(1):69-88. doi:10.1016/j.psc.2022.11.004; Williams KA, Swedo SE, Farmer CA, et al. Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Am Acad Child Adolesc Psychiatry. 2016;55(10):860-867.e2. doi:10.1016/j.jaac.2016.06.017; Zheng J, Frankovich J, McKenna ES, et al. Association of pediatric acute-onset neuropsychiatric syndrome with microstructural differences in brain regions detected via diffusion-weighted magnetic resonance imaging. JAMA Netw Open. 2020;3(5):e204063. Published 2020 May 1. doi:10.1001/jamanetworkopen.2020.4063.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Chang has been a consultant for AbbVie, COMPASS, and Human Health and on the Speakers' Bureau for Sunovion. Members of the planning committee reported nothing relevant to disclose. Dr. Chang’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Chang was recorded at the 28th National Psychopharmacology Update, held February 15-18, 2023, in Las Vegas, NV, and presented by the Nevada Psychiatric Association. For information on upcoming CME activities from this presenter, please visit NPAUpdate.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

NE141601

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Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

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To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

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