PANDAS

General paediatrics, Neurology

=Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) – tics and obsessive-compulsive disorder that have an acute onset and relapsing course, related to streptococcal infection.

Swedo first reported 4 cases of acute onset/exacerbation (2 with evidence of strep), treated successfully with immunosuppression, in 1995. Term first suggested in 1998 by National Institute of Mental Health. Presumed to be causative of course, mediated by inflammation. Has ICD code (8E4A) and everything, but still in 2019 “substantial controversy regarding a role for inflammation in tics and OCD”.

Because many children with similar presentations did not have evidence of streptococcus, a broader category of PANS, paediatric acute onset neuropsychiatric syndrome, was created, which is agnostic to cause. But such a broad category, almost unhelpful.

Finding evidence of previous streptococcal infection is not hard, nor uncommon. Tics and OCD are relatively common too. Although evidence of basal ganglia antibodies, these are non-specific. Lots of neurological problems have acute onset, not least epilepsy. 2020 US study found 91.4% of PANDAS cases had at least 1 of 4 neuronal antibodies, and most at least 2, cf 32% of normal controls. Levels dropped over time, as did symptoms. CaMKII (synaptic protein) activity higher too. [Frontiers in Psychiatry, 24 June 2020 – US study, including Swedo – compares PANDAS with Tourettes and OCD]

Neuropsychiatric problems are well recognised in and after Sydenhams chorea so it is not without basis (but other organ systems involved, and good evidence for inflammation). Encephalitis lethargica is an encephalitic illness with parkinsonism, dyskinesias, and psychiatric disturbance as dominant features. It is assumed to be autoimmune. NMDA-R encephalitis is an encephalitis with dramatic psychiatric disturbance, dyskinesias, cognitive alteration, and seizures, associated with autoantibodies against NMDA-R (originally described in relation to ovarian cancer).

Movement disorders are also described associated with systemic lupus erythematosus and antiphospholipid syndrome.

Diagnosis

PANS –

  • 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 behaviours
    • 4. Behavioural (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
  • III. Symptoms are not better explained by a known neurologic or medical disorder, such as Sydenham’s chorea.

So typically very ill, and usually referred urgently to psychiatric services. NB part III – PANS is a “diagnosis of exclusion”. [Swedo, 2012]

Family history is interesting – mental health issues including tic disorders often run in families, but so do autoimmune conditions, and Sydenham’s chorea.

Kiki Chang’s clinical evaluation guideline defines chorea-like movements seen in PANS as “piano playing movements of fingers when arms extended and eyes closed”, which is very specific. Also states this is only valid over age 8?! But then distinguishes this from “full chorea” (not specified), which should prompt search for a different diagnosis.

For PANDAS, specifies history of scarlatiniform rash, impetigo but also perianal/perivulval dermatitis. ASOT should show rise of at least 58% over 4-8 weeks, or else a single reading more than double the upper limit of normal.

Role of Cunningham panel stated as “useful ancillary information” for PANDAS, but unclear role in PANS.

[Chang 2015]

Treatment

Lack of controlled treatment trial with more than 50 patients.

2 studies looking at exacerbations and throat cultures in Acute onset and non acute onset, non relapsing tics/OCD.  V similar patterns of exacerbations and no obvious link to strep infection.

Controlled trials of antibiotics in PANDAS have not provided strong evidence. Large symptom improvements reported in placebo arm too, for example. No evidence for tonsillectomy. 2016 controlled trial of IVIG showed no benefit (n=35, doi: 10.1016/j.jaac.2016.06.017).

Groups often self selected so at risk of bias. No evidence for 4/52 azithromycin in PANS. 

2017 PANS/PANDAS guidelines (PANS/PANDAS Consortium) are not based on high impact journal research, mostly expert opinion.  Table 1 lists “treatment approaches” but in the foot notes it states “this is not a definitive treatment algorithm; rather, it is a framework to aid in clinical decision making. Before initiating any of the therapies, clinicians must consider the risk/benefit ratio for their individual patients and provide careful/informed counseling about risk of side effects”.

Parental anxiety can be increased by the theory that “the brain is under inflammatory attack” which also fuels demands for treatment.

Is PANS/PANDAS diagnosis more acceptable than idiopathic psychiatric problem? Perverse incentives to diagnose, investigate and treat, of course.  Vaccines get blamed…

Useful perhaps that more research into inflammation getting done, even if putative triggers still unclear. Still v rare however to see high profile research in psychiatric conditions related to inflammation.

Just as interesting to research effect of parental anxiety and expectations on pattern of exacerbations and prognosis. 

[Donald Gilbert, J Child Neurology 2019]

BPNA statement

In response to increasing demands for PANDAS services, the British Paediatric Neurology Association published a consensus statement (2021) that was then criticised by PANDAS groups. When the BPNA then conducted a priority setting exercise, PANDAS came in at number 8. There is now a BPNA PANDAS working group. The latest statement highlights that –

  • all children presenting with acute onset neuropsychiatric symptoms should receive a full medical evaluation.
  • referrals from primary care should not be rejected on the basis that a MDT service may not currently be in place, nor on the basis that there are limited RCTs applicable to PANS or PANDAS.
  • [use] proficiency and judgment, acquired through clinical experience and clinical practice