Pediatric acute-onset neuropsychiatric syndrome (PANS)

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Pediatric Acute-onset Neuropsychiatric Syndrome “PANS” is a clinically defined disorder characterized by the sudden onset of obsessive-compulsive symptoms “OCD” or eating restrictions, concomitant with acute behavioral deterioration and/or motor/sensory changes in at least two of eight domains.[1][2] Additional psychiatric symptoms include anxiety (typically separation anxiety), attention deficit, hyperkinesis, emotional lability and/or depression, irritability, aggressiveness or oppositional behavior, and academic as well as cognitive decline. Associated neurologic findings include thought disorders, mental impairments, motor or vocal tics, increased sensory sensitivities, choreiform finger movements, deteriorating penmanship, and urinary frequency and/or enuresis. Sleep disruptions (disturbed REM sleep) are also characteristic. The definitive diagnosis also necessitates a course that follows a relapsing-remitting pattern. In case of postpuberty chronicity residual symptoms and their severity increases.[3][4]

Symptoms[edit]

Patients with PANS may present with a new onset or acute flare and follow a relapsing-remitting course, chronic-static course, or a chronic-progressive course.[2]

PANS Criteria include the following:

I. Abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake

II. Concurrent presence of additional neuropsychiatric symptoms, (with similarly severe and acute onset), from at least two of the following seven categories:

  1. Anxiety
  2. Emotional lability and/or depression
  3. Irritability, aggression, and/or severely oppositional behaviors
  4. Behavioral (developmental) regression
  5. Deterioration in school performance (related to attention deficit/hyperactivity disorder ADHD-like symptoms, memory deficits, cognitive changes)
  6. Sensory or motor abnormalities
  7. Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency.[5]

2017 survey[edit]

According to the 2017 "Survey of Pediatric Acute-Onset Neuropsychiatric Syndrome Characteristics and Course" these symptoms may occur in PANS patients:[3]

  • General anxiety (non-psychological)
  • Disordered thinking (OCD like)
  • Mood lability (moodiness) Irritability
  • Excessive worry
  • Rage/meltdowns
  • Sadness (non-psychological)
  • Sensory defensiveness (e.g., to sound, light, clothing)
  • Handwriting deterioration
  • Defiance
  • Fatigue
  • Specific phobias
  • Tics and hyperkinesia
  • Bizarre thoughts or behavior
  • Insomnia
  • REM-sleep disturbances
  • Hyperactivity
  • Loss of math skills
  • Stomach/abdominal pain
  • Brain fog/confusion
  • Social anxiety (non-psychological)
  • Aggression toward others
  • Panic attacks (non-psychological)
  • Nightmares
  • Frequent urination, bedwetting, incontinence
  • Joint pain
  • Restrictive eating and eating fears
  • Obsession with weight gain
  • Loss of appetite
  • Muscle pain
  • Self-injurious behavior
  • Night terrors
  • Speech disfluencies (e.g. stuttering, stammering)
  • Mania/hypomania (grandiose or high behavior or feelings)
  • Hallucinations/hearing or seeing things that are not there
  • Mutism (no speaking at all)
  • Bulimia/binge eating
  • other

Chronic/Deteriorating Course[edit]

Some patients meet criteria for PANS, but have a severe presentation and/or follow a chronic static or chronic deteriorating course. These patients warrant more aggressive evaluations, as they may also meet criteria for Autoimmune Encephalitis, Steroid Responsive Encephalitis with Thyroiditis, CNS vasculitis, antiphospholipid antibody syndrome, or lupus cerebritis, and thus may qualify for aggressive immunomodulatory therapy.[1]

Pain[edit]

While not often volunteered as a complaint, upon questioning, it has been found that pain is a common co-morbidity. Pains may include joint pain, muscle aches, headaches and stomachaches. Clinical experience has shown that after the OC and other psychiatric symptoms have improved, some children report pain for the first time. When widespread pain is present, patients often report other forms of sensory amplification and poor sleep. Physical exam may reveal areas of tenderness to palpation in the classic distribution for fibromyalgia. Patients who report both pain and stiffness upon awakening or after prolonged stationary positions should be assessed for arthritis. A small fraction of patients with PANS have been afflicted by an arthritis condition (inflammatory back pain, reactive arthritis, psoriatic arthritis, and juvenile idiopathic arthritis). Reactive arthritis (most commonly in the ankles, knees, and hips) has been reported before PANS onset. Involvement of the pediatrician, pediatric rheumatologist, pain specialist, occupational therapist, and physical therapist may help the course of the illness, alleviate pain and likely, improve emotional functioning.[5]

Causes[edit]

The initial onset and subsequent exacerbations are usually incited by a variety of recognizable infections. Alternatively, these conditions may be associated with life stresses. In other cases, there is no clear inciting factor.[1]

Infections[edit]

A variety of inciting infections have been observed. The most common infection sites are in the upper respiratory tract: including rhinitis, sinusitis, and pharyngitis. The specific microbe most commonly recognized has been group A Streptococcus. Mycoplasma pneumonia, influenza, and other common viruses have also been noted. Influenza has often been well-documented anecdotally at both initial onset and exacerbations of PANS.[4]

A number of additional infections, including gastrointestinal infections, dental infection, herpes simplex, varicella, Epstein-Barr virus, enterovirus, Kawasaki disease, and anaphylactoid purpura, have been mentioned to be associated with the onset or exacerbation of PANS symptoms in a small number of cases.[1]

Environment[edit]

At the time of first PANS presentation, note any family history of pharyngitis, impetigo, perianal dermatitis, and GAS infections. If possible, family members should have a throat swab cultured for GAS. Ongoing vigilance against GAS infections in any of the patient’s close contacts is important, as symptom exacerbations have been reported following exposure to a sibling with GAS (even when the PANDAS patient had no evidence of infection). Prompt medical attention to symptoms suggestive of streptococcal infection is important not only to protect the patient, but also siblings, who may be at an increased genetic risk for PANS.[6]

Inflammation[edit]

Additionally, studies have shown a high rate of concurrent autoimmunity in patients with PANS and their first degree family members further supporting a role for inflammation in PANS.[2]

Subtypes[edit]

PANDAS (“Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections”) is a subset of PANS and was first reported by Dr. Swedo at the National Institute of Mental Health in 1998. PANDAS has 5 distinct criteria for diagnosis, including:

  1. abrupt “overnight” OCD or dramatic, disabling tics;
  2. a relapsing-remitting, episodic symptom course;
  3. young age at onset (average of 6–7 years);
  4. presence of neurologic abnormalities;
  5. and temporal association between symptom onset and Group A streptococcal (GAS) infection.

The 5 criteria usually are accompanied by similar comorbid symptoms as found in PANS.[7]

The etiology and pathogenesis of PANDAS is not completely understood. Some postulate it to be similar to that of Sydenham's chorea, in which genetically susceptible individuals produce cross-reactive antibodies (Abs) in response to untreated infections with GAS. The Abs are produced against components of the GAS cell wall, and through molecular mimicry, cross-react with neuronal components of cells in the basal ganglia (caudate, putamen, and internal segment of the globus pallidus) in animal models.[8]

Management[edit]

Mainstays of treatment include psychoeducational, psychotherapeutic, behavioral, family, school-based and pharmacological interventions, which reduce suffering and improve functioning until the immunologic and infectious processes are addressed.[5]

Accommodations[edit]

The majority of children with PANS/PANDAS require some type of school accommodation. Anxieties, OCD symptoms, tics, frequent urination, attention deficit disorder symptoms, handwriting difficulties, poor cognitive/physical stamina, difficulties with processing speed, memory issues, pain, and frequent absences create great challenges to the children and their teachers.[5]

Many schools have scarce resources, so persistence and creativity in the school and family will yield better outcomes. The IEP should provide specific, individually-tailored accommodations that will help the child with PANS/PANDAS attend and benefit from school. These might include:

  • General—Excusing the child’s absences, and not requiring make-up assignments or tests,
  • Separation anxiety—allowing a parent to be in or near the classroom (perhaps helping out),
  • OC symptoms – excusing the child from certain activities, allowing him to complete assignments using alternate methods (e.g., typing homework, rather than erasing and rewriting repeatedly; listening to audio books, rather than reading and rereading),
  • Urinary urgency/frequency – leaving the class without asking permission
  • Dysgraphia/handwriting difficulties—having a note-taker in class, dictating tests and homework, enlarging worksheets, writing on large grid paper, using a keyboard, voice-recognition software or audio recorder,
  • Dyscalculia/math difficulties – using a calculator or times table and working with a resource teacher or tutor,
  • Slowed processing speed – decreasing the number and length of assignments, allowing extra time for tests and in-class assignments and giving directions in written and oral form,
  • Poor physical and cognitive stamina/pain – shorter school day with reduced academic load, less homework, rest periods during the day (perhaps in the nurse’s office), omitting or adapting physical education requirements.

When acute exacerbations of PANS/PANDAS symptoms have abated, these accommodations should be re-evaluated. Attending school and doing school work may be part of an appropriate psychotherapeutic plan.[5]

Treatments[edit]

For treatment guidelines, refer to the PANDAS Physicians Network. PPN’s goal is to help medical professionals understand, diagnose and treat PANS and PANDAS. The network provides research, diagnostic, and treatment tools. PPN Guidelines for Diagnostics and Therapeutics are developed by PPN committees and advisors from the top academic medical institutions in the United States. The members have worked with, treated, and studied the patients and the disorder. PANS and PANDAS are interdisciplinary disorders, so the relevant disciplines are represented on the PPN committees and special advisory council. Some of the disciplines include: Psychiatrists, Pediatric Neurologists, Immunologists, Microbiologists, Rheumatologists, Geneticists, Otolaryngologists, etc.[9]

Studies[edit]

Immunomodulatory Therapy Study[edit]

A placebo-controlled trial of plasmapheresis and IVIG for PANDAS was conducted at the NIH in the late 1990’s, with children randomly assigned (by the NIH pharmacy) to receive plasmapheresis (unblinded) or IVIG/sham IVIG (double blinded). At one month evaluations, placebo infusions produced no improvements in OC or tic symptoms, while 100% of the children receiving IVIG or plasmapheresis improved. The average improvement in OC symptoms was 45% for the group receiving IVIG and nearly 65% for the children receiving plasmapheresis. The results of the trial were sufficiently robust to cause the American Society of Apheresis to include plasmapheresis as a treatment option for PANDAS, as well as for Sydenham chorea.[10]

Animal Studies[edit]

Animal studies have shown that infusion of the Abs into the basal ganglia of rats produces abnormal behaviors.[11][12] More recently, researchers at Columbia University demonstrated that passive transfer of the Abs is able to induce the abnormal movements and behaviors in recipient mice.[13] Among PANDAS patients, high Abs concentrations are found in acute serum samples; Abs titers are decreased during periods of symptom remission.[8]

PANS/PANDAS Research Consortium[edit]

A consortium of academic clinicians and scientists was convened in 2013 to develop more defined diagnostic guidelines for this disorder in anticipation of furthering research, clinical trials, and clinical care for this patient subgroup.[1] A second consortium meeting was convened at NIMH in 2014 to develop preliminary treatment guidelines. The following are the members of the PRC:

  • Kiki Chang, MD (Stanford University School of Medicine): Professor of Psychiatry & Behavioral Sciences
  • Michael Cooperstock, MD, MPH (University of Missouri School of Medicine): Pediatrics Infectious Diseases
  • Jim Crowley, PhD (University of North Carolina School of Medicine): Research Assistant Professor of Genetics
  • Madeleine Cunningham, PhD (University of Oklahoma College of Medicine): Professor of Microbiology & Immunology
  • Jennifer Frankovich, MD (Stanford University School of Medicine): Clinical Professor of Pediatric Rheumatology
  • Mady Hornig, MD, MA (Columbia University, Mailman School of Public Health): Professor of Epidemiology
  • Elizabeth Latimer, MD (Latimer Neurology Center): Pediatric & Adolescent Neurology
  • Tanya Murphy, MD (University of South Florida): Professor of Pediatrics & Psychiatry
  • Mark Pasternack, MD (Massachusetts General Hospital): Associate Professor of Pediatrics Infectious Disease
  • Susan Swedo, MD (National Institute of Mental Health): Chief Pediatrics & Developmental Science Branch
  • Margo Thienemann, MD (Stanford University School of Medicine): Clinical Professor of Psychiatry & Behavioral Sciences
  • Jolan Walter, MD (Massachusetts General Hospital): Assistant Professor of Pediatrics Allergy & Immunology
  • Kyle Williams, MD (Massachusetts General Hospital): Instructor in Psychiatry

References[edit]

  1. ^ a b c d e Chang, K; Frankovich, J (2015). "Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference". Journal of Child and Adolescent Psychopharmacology. 25 (1): 3–13. 
  2. ^ a b c Frankovich, J (2015). "Five Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome of Differing Etiologies". Child Adolesc Psycopharm. 25: 31–37. 
  3. ^ a b Tanya K. Murphy u.a. (2017): A Survey of Pediatric Acute-Onset Neuropsychiatric Syndrome Characteristics and Course. Journ of Child and Adolesc Psychopharm. Jan 17. (doi:10.1089/cap.2016.0105)
  4. ^ a b Cooperstock, M; Murphy, T.K. (2016). "Clinical Management of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Part III-Treatment and Prevention of Infections.". PANS PANDAS Management If Infection. 27: 1–33. 
  5. ^ a b c d e Thienemann, M. "Consensus Guidelines for Psychiatric and Behavioral Interventions for Pediatric Acute-‐Onset Neuropsychiatric Syndrome and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection". PANS Psychiatric and Supportive Therapy: 1–13. 
  6. ^ Lewin, Adam B.; Storch, Eric A.; Murphy, Tanya K. (2011-04-01). "Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus in Identical Siblings". Journal of Child and Adolescent Psychopharmacology. 21 (2): 177–182. ISSN 1044-5463. doi:10.1089/cap.2010.0085. 
  7. ^ Swedo, Susan E.; Snider, Lisa A.; Garvey, Marjorie A. (2004-01-01). Rose, Noel R., ed. Infection and Autoimmunity. Amsterdam: Elsevier. pp. 333–343. ISBN 9780444512710. doi:10.1016/b978-044451271-0/50027-2. 
  8. ^ a b Kirvan, CA; Swedo, SE (2006). "Streptococcal mimicry and antibody-.‐mediated cell signaling in the pathogenesis of Sydenham's chorea". Autoimmunity. 39: 21–29. 
  9. ^ "PANS Diagnostic Criteria | PPN". PPN. 2013-12-18. Retrieved 2016-12-07. 
  10. ^ Weinstein, Robert (2008-01-01). "Therapeutic apheresis in neurological disorders: A survey of the evidence in support of current category I and II indications for therapeutic plasma exchange". Journal of Clinical Apheresis. 23 (6): 196–201. ISSN 1098-1101. doi:10.1002/jca.20178. 
  11. ^ Hallett, JJ; Kiessling, LS (2000). "Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction". Neuroimmunology. 111: 195–202. 
  12. ^ Taylor, JR; Peterson, BS (2002). "An animal model of Tourette's syndrome". Psychiatry. 159: 657–660. 
  13. ^ Yaddanapudi, K; Villar, G (2009). "Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection". Mol Psychiatry. 15: 712–726. 

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