Approach

The diagnosis of PANS is clinical, based on careful review of symptoms, a comprehensive medical and psychiatric history, and a thorough physical exam.[20] General laboratory tests are recommended to evaluate for infections, inflammation, and co-occurring inflammatory disorders.[2][20][33]

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is an overlapping criteria with PANS, defined by an acute onset of tics or obsessive-compulsive symptoms and specific neuropsychiatric symptoms with a temporal association with group A streptococcus (GAS) infection.[2][6][54][55] PANDAS criteria, however, should be used only as a research tool since it misses cases where the patient presents past the window of opportunity to detect GAS infection.[6]​ See Criteria.

A diagnosis of PANS may be missed due to the overlap of symptoms with other psychiatric conditions, such as obsessive-compulsive disorder (OCD), tic disorders, attention deficit hyperactivity disorder (ADHD), depression, and bipolar disorder.[20] It is the acuity of onset and simultaneous presentation of symptoms across multiple domains (i.e., restricted food intake, motor and sensory symptoms, and increasing urinary frequency) that differentiates PANS from these psychiatric conditions.[56]

PANS is a diagnosis of exclusion and other causes for the neuropsychiatric symptoms, such as Sydenham chorea, systemic lupus erythematosus, or autoimmune encephalitis, should be ruled out at initial presentation.[2][20] In patients with severe disease or if autoimmune encephalitis is being considered as a differential diagnosis, further investigations such as lumbar puncture, magnetic resonance imaging (MRI), and electroencephalography (EEG) should be considered.[20] Polysomnography and swallowing studies may be appropriate in patients with sleep disturbances and restricted food intake, respectively.[20]

Clinical presentation

Suspect PANS in a child (typically from age 3 years to the beginning of puberty) presenting with:[1]

  • Abrupt and dramatic onset (<72 hours) of obsessive-compulsive symptoms or severely restricted food intake

    AND

  • Concurrent presence of additional neuropsychiatric symptoms, with similarly severe and acute onset, from at least 2 of the following 7 categories:

    • Anxiety

    • Emotional lability and/or depression

    • Irritability, aggression, and/or severely oppositional behaviors

    • Behavioral (developmental) regression

    • Deterioration in school performance

    • Sensory or motor abnormalities

    • Somatic signs and symptoms including sleep disturbance, enuresis, or urinary frequency.

The obsessive-compulsive symptoms must meet Diagnostic and statistical manual of mental disorders, 5th edition, text revision (DSM-5-TR) criteria for OCD.[1][57] In addition, the criteria for PANS require that symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham chorea, systemic lupus erythematosus, Tourette disorder, or others.[1]

The acuity of onset and initial severity of the obsessive-compulsive symptoms are hallmarks of the diagnosis.[1] Parents may describe their child as "a changed child."[7]

Children with PANS:[20]

  • May appear hypervigilant, highly anxious, and in the "fight or flight" mode during an acute episode.

  • Often cannot recall details of their symptoms or their impact on functioning.

  • Present with mood-incongruent involuntary and often uncontrollable episodes of crying or laughing (emotional lability is a distinctive symptom of PANS). Depression is common, particularly during the later stages of the illness; the child may present with a flat or depressed affect.[3][7]

  • Commonly present with agitation, irritability, aggression, and temper tantrums/rage episodes. Severe impulsivity and compulsive behaviors posing danger to self, others, or properties may be present.[3][58]

  • Often have their speech affected; changes are various and may include "baby talk" secondary to developmental regression, a lack of speech, selective mutism, or new-onset stuttering.

  • Are often acutely conscious of, and even embarrassed or frightened by, their unwanted intrusive thoughts and obsessions. They need reassurance that they do not have to reveal their content before acknowledging the OCD thoughts.

  • May experience auditory or visual hallucinations, violent imagery, and suicidal or homicidal ideation.[59]

Children with PANS are typically moderately to severely ill. Severely ill children may present with:[20]

  • Extreme compulsions (licking shoes, barking)

  • Severe tics (whooping, wringing hands, self-injury behaviors)

  • Terrifying episodes of extreme anxiety or aggression

  • Violent imagery

  • Strong irritability, aggression, and/or violence (against self, others, or property)

  • Extreme sleep and sensory disturbances.

It is rare to present with PANS as an adolescent without having had a history of early childhood episodes. Rarely, patients present with primary chronic or secondary chronic course.[51] In the experience of the authors of this topic, single episodes are also very rare; however, these patients may not present to academic centers, thus are not represented in academic cohort reports.

Symptoms overlap with a variety of psychiatric disorders such as OCD, tic disorders, attention deficit hyperactivity disorder (ADHD), depression, and bipolar disorder.[20] It is the acuity of onset and simultaneous presentation of symptoms across multiple domains (i.e., restricted food intake, motor and sensory symptoms, and increasing urinary frequency) that differentiates PANS from these psychiatric conditions.[56] See Differentials.

Psychotic symptoms such as delusional thinking and visual or auditory hallucinations are often transient, whereas severe OCD persists.[59] In patients with persistent psychosis, evaluate for other disorders including autoimmune encephalitis and neuropsychiatric lupus.

PANS follows a relapsing-remitting course, in which patients experience acute psychiatric symptom flares between periods of relative symptom quiescence.[3] Flares are defined as abrupt deteriorations in neuropsychiatric symptoms, lasting an average of 12 weeks.[1][3][4][5]

History

Take a careful medical and psychiatric history. Patient and family history should cover:[20]

  • Neurologic diseases such as movement disorders or any neurologic conditions linked to autoimmune and autoinflammatory processes

  • Psychiatric disorders, including common psychiatric conditions in all ages such as anxiety, OCD, depression, bipolar disorder, and psychotic disorder

  • Developmental disorders such as ADHD, sensory disorder, learning disability, autism spectrum disorder, handwriting problems, or speech delay[50]

  • Inflammatory conditions including acute rheumatic fever, Sydenham chorea, psoriasis, inflammatory back pain symptoms, arthritis and/or symptoms (joint stiffness or pain in morning or with stationary positions), enthesitis, inflammatory bowel conditions, thyroiditis, psoriasis

    • Comorbid inflammatory conditions can affect up to one third of children with PANS over their childhood and are also commonly present in first-degree family members.[3][49][50][53] Investigations and screening for these conditions should be conducted over time.[4][21][48][60]

  • History of immunodeficiency in the patient or a first-degree family member (i.e., severe prolonged infections or infections that do not resolve with standard treatment)

  • Current or past episodes of GAS infection or recurrent streptococcal pharyngitis.

A thorough psychiatric assessment by a pediatric psychiatrist should be performed in all patients to understand the onset and extent of symptoms.[2][20]

  • The Children’s Yale-Brown obsessive compulsive scale (CYBOCS) symptom checklist in children and adolescents (ages 6 to 17 years) and the Nine-Item Avoidant/Restrictive Food Intake Disorder (ARFID) screen or Eating Disorders in Youth-Questionnaire (EDYQ) can be used to elicit the details of OCD and restricted eating pattern, respectively. The CY-BOCS is the most widely used measure of pediatric OCD severity.[61]

  • Baseline individual and family functioning and other concurrent psychiatric symptoms should be evaluated as this is important to establish the diagnosis.

Physical exam

In patients with new-onset disease and in newly relapsed patients, evaluate for signs of infection such as pharyngitis, sinusitis, otitis media, skin abscesses, perianal streptococcal infection, and infected in-grown toenail.

  • Psychiatric symptoms may be overwhelming and the child may not spontaneously mention these symptoms. Specifically ask about headaches and facial pressure worse with inverting head; check for tenderness over sinuses including ethmoid sinuses (pinch bridge of nose).[33][62]

  • In most cases, PANS is likely to be a postinfectious entity, so the infection may have passed by the time the patient presents with signs and symptoms. However, it is still important to perform a thorough physical exam since treating a clear and active infection can improve the patient's mental health.[20][33][62]

Exclude acute rheumatic fever.

  • Signs of acute rheumatic fever include migratory arthritis with or without pseudoparalysis of the joint, erythema marginatum, and tachycardia without fever and with PR elongation on ECG. See Rheumatic fever.

Check for signs of basal ganglia dysfunction, vasculopathy/inflammation of small blood vessels, and other signs of inflammation. These are common in patients with PANS but are not required for the diagnosis:

  • Signs of basal ganglia dysfunction: positive glabellar tap, hung-up reflexes, tongue fasciculations, weak grip with subtle milkmaid grip, choreiform movements of fingers, and overflow dystonia

    • As with Sydenham chorea, patients with PANS may be clumsy during episodes and can have subtle difficulty with sustaining tetany in the tongue (tongue fasciculations) and hands (milkmaid grip).[20][56] Consider Sydenham chorea and other disorders such as autoimmune encephalitis in patients presenting with frank chorea, darting tongue, strongly abnormal milkmaid grip, and hung-up reflexes.

  • Signs of vasculopathy/inflammation of small blood vessels: palatal petechiae (may indicate current or recent GAS pharyngitis), periungual redness, prominent onychodermal bands (the point of strongest attachment between the nail and the underlying digit), and livedo reticularis. The meaning of each of these findings is currently poorly understood. Palatal petechiae can be observed at presentation; however, streptococcal cultures at this time are commonly absent.[62]

  • Other signs of inflammation that can present at initial onset or develop over time include:

    • Arthritis (typically dry; there is no evidence of swelling on exam, which is similar to that seen in acute rheumatic fever)

    • Enthesitis: tenderness over the site of tendon and ligament insertion (i.e., Achilles tendon insertion, plantar fascia insertion, the inferior or superior pole of the patellar bone, and sides of the proximal interphalangeal joints)

    • Dactylitis and distal interphalangeal (DIP) joint tenderness: especially in patients with psoriasis or a first-degree family member with psoriasis. Patients with DIP tenderness will typically also have periungual redness

    • Limited forward bend (Schober test) in patients with back pain and stiffness in the morning and with stationary positions.

Pseudoparalysis of a joint is atypical for PANS but common in Sydenham chorea and acute rheumatic fever.

Check for signs of dehydration, low body mass index, and low body fat.

  • Children with severely restricted food and fluid intake (usually because of fears of contamination, choking, vomiting) present with significant low body weight (<10% body weight), dehydration, and vital sign instability.[51][63]

Initial investigations

Order the following investigations in all patients:

A throat culture or polymerase chain reaction (PCR) for GAS

  • Throat culture is the recommended test for patients and close contacts (regardless of report of a sore throat) as it is the most sensitive (90% to 95%) and specific test.[2][20][64]

  • PCR testing has high sensitivity and specificity, comparable to that for throat culture for GAS infection, but it is more expensive and less readily available than rapid antigen detection test (RADT) for GAS.[65]

  • RADT for GAS, if available, offers the advantage of immediate point-of-care testing, but about 15% of GAS pharyngitis is missed with RADTs.[33] If the RADT is negative, follow up with a throat culture.[20][33][64]

Blood tests

  • Antistreptococcal serology (i.e., antistreptolysin O titer [ASO] and antideoxyribonuclease B [ADB]) at two timepoints separated by 2 weeks for patient and close contacts[33]

    • Order near the time of infection and then repeat to demonstrate a serologic rise. A rise in serial antibody level, regardless of RADT or throat culture result, supports recent immunologic response to GAS infection.[33] Another sign of a recent infection is a falling titer around 6-8 weeks after the infection.[33] However, note that documenting the presence of preceding GAS infection may be difficult, since GAS is common in elementary school children and infection may go undetected (some children have minimal or no symptoms of streptococcal pharyngitis). In some cases, the child may be diagnosed on the basis of a history of exposure to known GAS infection (particularly in a sibling or overnight stay with a friend/relative).

  • CBC with differential[2][20]

  • Inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)[2][20]

  • Comprehensive metabolic panel[20]

  • Ferritin (iron) and transferrin saturation[2]

  • Antinuclear antibodies (ANA)[2][20]

  • Immunoglobulins (IgG, IgA, IgM, IgE) with IgG subclasses.[2][20][66]

Other investigations

Consider ordering the following investigations in selected patients:

  • Urinalysis in patients with urinary symptoms to assess hydration, and to rule out inflammation and infection[2][20]

  • Brain magnetic resonance imaging (MRI), electroencephalogram, and lumbar puncture in patients with severe new-onset psychiatric symptoms and when autoimmune encephalitis is being considered as a differential diagnosis, especially if one of the following is present:[20]

    • Cognitive/memory dysfunction (formal testing can pick up on more subtle problems)

    • New-onset severe headache

    • New-onset severe sleep disturbance

    • Behavior regression

    • Seizures.

  • These evaluations are not necessary if the clinical course has already been established to be relapsing-remitting. Findings are typically normal in patients with PANS. If the patient has pleocytosis, IgG bands, high IgG index, or highly elevated protein or serum albumin quotient (Qalb), consider other inflammatory brain diseases.[67]

Consider further investigations on a case-by-case basis if additional signs and symptoms are identified, for example:

  • Polysomnogram to evaluate new-onset sleep disturbances, such as reverse-cycling, severe insomnia, restless sleep, new-onset nightmares, and rapid eye movement (REM) sleep without atonia[2][20][48][68][69]

  • Swallowing studies for children with restricted food intake, for example, when associated with fear of choking or vomiting[20]

  • Musculoskeletal imaging in patients with aches, pain, and stiffness in the morning or with prolonged stationary positions. Patients who have overwhelming psychiatric symptoms may not be able to appreciate or convey the subtle signs of arthritis. The rate of arthritis, enthesitis, and inflammatory back pain is high in patients with PANS and their family members.[20] Most forms of arthritis in people with PANS are dry and therefore imaging is often needed to establish the diagnosis.[53]

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