Schrodinger’s PANDAS

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The existence of PANDAS and other Paediatric Acute Onset Neuropsychiatric Syndromes has been controversial for the last two decades.

What is PANDAS?

Paediatric Acute-Onset Neuropsychiatric Disorder Associated with Streptococcal infection, is a concept first mooted by Swedo, an American paediatrician in 1998, as a formé fruste (or incomplete form) of Sydenhams Chorea.

Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998 Feb;155(2):264-71.

She postulated that Group A Beta-Haemolytic Strep infection caused sudden onset explosive OCD symptoms with choreiform movements in prepubertal children. The criteria is: (click for quotes from Swedo’s original wording)

1. Must have OCD or Tic Disorder.

Presence of OCD and/or a tic disorder: The patient must meet lifetime diagnostic criteria (DSM-III-R or DSM-IV) for OCD or a tic disorder.”

2. Pre-pubertal.

 “Pediatric onset: Symptoms of the disorder first become evident between 3 years of age and the beginning of puberty (as is generally true for rheumatic fever).”

3. Abrupt/Explosive Onset.

 “Episodic course of symptom severity: Clinical course is characterized by the abrupt onset of symptoms or by dramatic symptom exacerbations. Often, the onset of a specific symptom exacerbation can be assigned to a particular day or week, at which time the symptoms seemed to “explode” in severity. Symptoms usually decrease significantly between episodes and occasionally resolve completely between exacerbations.”

4. Association with GABHS infection.

Association with GABHS infection: Symptom exacerbations must be temporally related to GABHS infection, i.e., associated with positive throat culture and/or elevated anti-GABHS antibody titers. Of note, the temporal relationship between the GABHS infection and the symptom exacerbation may vary over the course of the illness. In rheumatic fever, there is often a delay of 6–9 months between the last documented GABHS infection and the appearance of symptoms of Sydenham’s chorea; however, recrudescences follow the GABHS infections at a much shorter interval, often with a time lag of only several days to a few weeks . It appears that the pattern is similar for PANDAS. It should be further noted that because fever and other stressors of illness are known to increase symptom severity, the exacerbations should not occur exclusively during the period of acute illness. Furthermore, as in Sydenham’s chorea and rheumatic fever, some symptom recurrences may not be associated with documented GABHS infections, so the child’s lifetime pattern should be considered when making the diagnosis.

5. Abnormal neuro exam, but NOT chorea.

”Association with neurological abnormalities: During symptom exacerbations, patients will have abnormal results on neurological examination. Motoric hyperactivity and adventitious movements (including choreiform movements or tics) are particularly common. Of note, children with primary OCD may have normal results on neurological examination, particularly during periods of remission. Further, the presence of frank chorea would suggest a diagnosis of Sydenham’s chorea, rather than PANDAS. It is particularly important to make this distinction, since Sydenham’s chorea is a known variant of rheumatic fever and requires prophylaxis against GABHS; PANDAS does not.”

Think of it as rheumatic fever for the brain; specifically, the basal ganglia.

So, a specific set of patients, with a well-stated mechanism and a clear symptom cluster. That said, this diagnosis and its criteria have been mired in controversy throughout the last twenty years, due predominantly to incongruity, poor external validity and erratic reproducibility in a number of trials.

Given the many billions of words on the topic, there have been some agreed points and areas of controversy. Hence, it is generally agreed that;

  1. Children with signs and symptoms compatible with Gp A H Beta-Haemolytic Strep (GAS) infections should be evaluated for same.
  2. GAS is one of several factors that can exacerbate OCD or tic disorder in a subset of patients.
  3. Children with GAS infection and OCD/tic disorder require standard treatments for these problems (regardless of whether GAS and OCD/tic disorder are causally associated)
  4. There is no indication for routine administration of the following therapies for children who meet PANDAS criteria; prophylactic antibiotics, steroids, plasma exchange, IVIG.

Controversy exists regarding;

  1. It is unclear whether PANDAS is a discrete neuropsychiatric disorder sufficiently different from OCD/tic disorder to be considered a separate entity.
  2. The role of GAS as a precipitant of OCD/tic disorders (+/- PANDAS), and whether this is a causal or incidental relationship.
  3. The etiology of PANDAS as an autoimmune disorder.
  4. The clinical utility of seeking evidence of GAS infection in children with OCD/tic disorders.

In 2010, the PANDAS criteria was redefined and re-labelled to Paediatric Acute Onset Neuropsychiatric Syndrome (PANS). This widened the age range to <17 years, added restricted food intake as an alternative major symptom, and postulated a much broader aetiology, including a larger number of infectious causes including mycoplasma, HIV, VZV, HSV and the common cold.

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 Feb;25(1):3-13. doi: 10.1089/cap.2014.0084. Epub 2014 Oct 17.

By 2013, Singer proposed a move away from the term PANS to Childhood Acute onset Neuropsychiatric Syndrome (CANS), further amending the diagnostic criteria to broaden the causality and focus investigations on the exclusion of treatable causes. When none are found a diagnosis of Idiopathic CANS can be made.

Singer, HS., Gilbert DL., Wolf, DS., et al. Moving from PANDAS to CANS. J Pediatr. 2012 May;160(5):725-31. doi: 10.1016/j.jpeds.2011.11.040. Epub 2011 Dec 22.

 

So, what are the challenging parts of this diagnosis?

Firstly, it looks like OCD, and OCD is very common. 1 in 60 kids have an OCD diagnosis

CANS is extremely rare by comparison. Actually, it’s unclear the actual incience, but it is less prevalent than either choreiform disorders or Munchausen’s By Proxy, which are around 1 per 100,000.

Secondly, it’s supposed to be foudroyant, which means literally strikes as with lightning, sudden and overwhelming in effect, stunning and dazzling.”

This in itself is a challenge to identify, as everything must start somewhere. It is the point of noticeable symptoms that really matters. To extend the metaphor, we don’t actually have random lightning strikes, as realistically the weather changes, a storm rolls in, thunder is heard in the distance and then… bang.

Thirdly, Sydenham chorea, obsessive compulsive disorder, and tic disorders share common anatomic areas: the basal ganglia of the brain and the related cortical and thalamic sites. Some patients with Sydenham’s chorea display motor and vocal tics, obsessive-compulsive symptoms, and ADHD symptoms, adding support to the possibility that, at least in some instances, these disorders share a common etiology.

Fourthly, a review by Murphy notes a study of PANS-OCD versus Non-PANS OCD which identifies an association between Non-PANS OCD and a Family history of same.

Murphy TK, Gerardi DM, Leckman JF. Pediatric acute-onset neuropsychiatric syndrome.Psychiatr Clin North Am. 2014 Sep;37(3):353-74. doi: 10.1016/j.psc.2014.06.001.

Murphy and colleagues suggest this could be seen as an association between the infectious/autoimmune trigger for PANS-OCD. The countervailing argument is that this is instead representative of tolerability of OCD symptoms within families. That is, by the time the child is functionally impaired and the diagnosis made, it’s not controversial and there is acceptance of the diagnosis within the family.

Fifthly, it’s worth noting that the data for most studies is from the USA, where entry into the health system is very different to Australian, New Zealand or UK, particularly around self-referral to specialists. I’d speculate that it is much more socially acceptable for a child to have a neurologic than a psychiatric condition. Thus, children with OCD with or without tics are might present to a neurologist and be more likely to receive a CANS diagnosis.

Pragmatically for general paediatricians, the diagnostic dilemma here is two-fold;

  1. How much to investigate?
  2. How can we treat it?

And this is where Schroedinger comes in. Every time this box is opened, unless we are able to do so in an incisive, foudroyant manner, the child risks becoming medicalised. Indeed, we risk leading them on that journey. By simply looking into the box, we’re disproportionately more likely to find PANDAS than a child with OCD.

I don’t know how to prevent this happening. I do know that the best care for patients with suspected CANS could include general paediatrics, psychiatry, neurology and rheumatology. Ideally, these teams would collaborate to consider diagnosis and management on a case by case basis.

Medical treatments for this constellation of diagnoses have included antibiotics, steroids, immunoglobulins and plasmapheresis. Recent recommendations have highlighted the paucity of evidence for any of these therapies.

Psychiatric treatments include clomipramine, SSRI and Cognitive Behavioural therapy, as for obsessive compulsive disorder; I have not yet seen robust evidence with these interventions specifically for CANS (if you have some, please link in the comments!)
In summary, a child with explosive onset obsessions, compulsions with or without tics might have CANS. Although, on balance, they are more likely to have OCD, considering the prevalence in the population. We need to keep an open mind about these presentations.

 

References:

Murphy TK, Gerardi DM, Leckman JF. Pediatric acute-onset neuropsychiatric syndrome.Psychiatr Clin North Am. 2014 Sep;37(3):353-74. doi: 10.1016/j.psc.2014.06.001.

Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry. 1998 Feb;155(2):264-71.

Pichichero, ME. PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci. UpToDate [Online database]. Accessed 22 Feb 2017.

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 Feb;25(1):3-13. doi: 10.1089/cap.2014.0084. Epub 2014 Oct 17.

Singer, HS., Gilbert DL., Wolf, DS., et al. Moving from PANDAS to CANS. J Pediatr. 2012 May;160(5):725-31. doi: 10.1016/j.jpeds.2011.11.040. Epub 2011 Dec 22.

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A Paediatric Trainee based in Queensland, Australia, Henry is passionate about Adolescent Medicine & General Paediatrics, with a strong interest in Medical Education & Clinical Teaching. An admitted nerd & ironman with a penchant for Rubik's Cubes & 'Dad jokes'.

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