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PANDAS



Introduction

PANDAS ( Paediatric Autuimmune Neuropsychiatric Disorder associated with group Streptococcus) is a group of disorders seen in the paediatric population which consist of either tics or obsessive compulsive disorder either exacerbated or brought on by a common bacterial infection called Group A streptococcus (GAS). This infection may present with a sore throat or chest infection.

This group of disorders has been given a International classification of disease (ICD-11) code in the next set of codes to be released.

This group of disorders is thought to occur after the body produces an antibody to fight a common everyday infection.  This antibody then goes on to stimulate a part of the brain involved with movement control (or regulation of obsessive compulsive behaviours) which in turn results in the abnormal movement, noise, feeling or compulsion.

PANS (Paediatric acute-onset neuropsychiatric syndrome)  describes a clinical syndrome that may be caused by noninfectious or infectious triggers.  Proposed diagnostic criteria for PANS include: the sudden onset of OCD or severely restricted food intake,  severe neuropsychiatric symptoms (eg, anxiety, depression, emotional lability, etc) or symptoms not better explained by a known neurologic or medical disorder. The key words in this are “sudden onset”. Symptoms appear dramatically and there is a rapid shift in the child’s behaviour.

Background

Rheumatic fever has been a less commonly recognised condition over the past 30-40 years. Part of the diagnostic criteria for rheumatic fever included a condition called “Sydenham’s chorea” or ‘St. Vitus dance” . This was an abnormality of movement which was associated with streptococcal infection. Individuals diagnosed with rheumatic fever were given long term prophylactic penicillin to treat the condition and prevent disease relapse.

Dr Susan Swedo during her research into Sydenham’s chorea realised that there were a sub-group of patients with tics & obsessive-compulsive behaviour that had a sudden onset of symptoms. This was very different to the movements seen with rheumatic fever. Crucially the symptoms had a very rapid pace of onset. The video below shows how this condition has evolved.

Dr Swedo 2014

Signs & symptoms

PANDAS symptoms typically start abruptly, almost as if a switch has been thrown. Symptoms include tics, sleep disturbance, obsessive compulsive behaviour, deterioration in handwriting, eating disorders (including anorexia but the problems appear to be more centred on difficulty in coordinating swallowing), behavioural regression and urinary incontinence. By definition these occur following a streptococcal infection which then results in the stimulation of antibodies which stimulates the part of the brain involved in movement and behaviour regulation (the basal ganglia). Examination of the child reveals a child who is “trapped” or “psychologically burdened”. They may have reduced muscle power and may show abnormal movements.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is defined by the rapid onset of obsessive–compulsive disorder (OCD) or eating restrictions and comorbid symptoms from at least two of seven categories:

  1. Anxiety (particularly separation anxiety)
  2. Emotional lability or depression
  3. Irritability
  4. Aggression, and/or severely oppositional behaviors
  5. Deterioration in school performance related to ADHD-like behaviors, memory deficits, and cognitive changes
  6. Sensory or motor abnormalities
  7. Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary frequency (Swedo et al. 2012; Chang et al. 2015). Acute onset cases that are triggered by Group A streptococcal infections may meet diagnostic criteria for both PANS and PANDAS.

Diagnosis & Investigations

Criteria for diagnosis of PANDAS include:

  1. Prescence of OCD and/or Tics
  2. Pre-pubertal onset
  3. Acute onset of symptoms with an episodic (saw-tooth) pattern
  4. Association with a neurological abnormality
  5. Temporal relationship with Group A strep infection

Examination of the child should include looking at the throat, ears, skin (eg for impetigo or guttate psoriasis),examining the peri-anal area and genitals for infection, checking for a heart murmur and assessing weight and height.

Investigations that the Children’s e-Hospital views as useful in helping to make a diagnosis include:

Investigation
Comment
Throat swab & swab of suspicious sites  Also swab family members
Full blood count
Immunoglobulins with IgG sub-sets
Anti-nuclear antibody (ANA)
Anti DS DNA antibody
Vitamin D levels
C-reactive protein
Copper & caeruloplasmin Only if Wilson’s is considered likely
ESR
ASOT
Mycoplasma titres
Anti-Dnase B
Cunningham panel The current evidence (September 2017) is not supportive of this test
MRI/PET Scan Some research suggests that PET scanning is more useful
EEG
ECG
Lumbar puncture  To screen for encephalitis & meningitis together with specific antibodies (eg anti-neuronal antibodies).

*Consider checking IgA levels prior to giving IVIG.

There have been lots of questions about a panel of investigations called “the Cunningham panel” which has been developed by Moleculera labs. This panel test looks at measuring five different variables:

  1. Anti-dopamine receptor D1 antibodies
  2. Anti-dopamine receptor D2 antibodies
  3. Anti-lysoganglioside  antibodies
  4. Anti-tubulin antibodies
  5. Calmodulin protein kinase II (Cam kinase II) levels

The value of the Cunningham panel is still being debated so it is not universally performed (and indeed it is quite expensive). For completeness we have included details on this group of tests so that parents can make up their own minds on whether they would like to have it done or not but the latest data that we have available (September 2017) does not support this test.

What is the Cunningham panel?

Disease monitoring

The free downloadable form that we have supplied on this page will allow parents to score their child’s symptoms on a daily basis. You can download this form by clicking on “Patient Information Leaflet” above or by clicking on the following link; PANDAS symptom monitoring chart. This scoring sheet also allows  parents to add detail such as whether or not a child is receiving antibiotics or anti-inflammatories. This information is invaluable in assessing the patients that we see using the Children’s e-Hospital on-line service but can also be used to help parents with any health professionals they see. If you need any support in using this tool please conact us at: admin@e-hospital.co.uk

Treatment of PANDAS

Treatment can be divided into several stages which are described below. For a 1st episode without any dangerous behaviours it is reasonable to give a month of antibiotic treatment and if there is no response to then add in 3-4 weeks of prednisolone treatment (be cautious with adrenal suppression and ensure the dose is tapered off). Also give vitamin D supplementation.

If there are concerning or dangerous behaviours , then some workers would advocate avoiding steroids (as they may induce a psychosis) and moving quickly from antibiotics to IVIG and then plasmapheresis. Experience has shown that SSRI’s should be used with caution in this group. If used at all, you should start at a very low dose (Dr Swedo recommends 1/10th the normal paediatric dose) and increase slowly according to response.

If there is life threatening anorexia then plasmapheresis should be considered early on as flare’s following IVIG may occurr.

  1. Induction of disease remission

    • Anti-inflammatory treatment
      • Non-steroidal anti-inflammatory drugs (eg ibuprofen)
      • Steroid pulse therapy (e.g. prednisolone)
    • Anti-microbial treatment
      • Azithromycin (Zithromax)
      • Penicillin V
      • Cephalexin
      • Amoxicillin (Augmentin)
    • Intravenous immunoglobulin
      • Intravenous immunoglobulin (IVIG) can be used to induce disease remission. Drs. Perlmutter and Swedo used IVIG in the 1999 study published in the Lancet where nearly all of the children benefitted from its use. The sampling was small (30 of children). In PANDAS an autoimmune irregularity is causing encephalitic-like inflammation and the use of IVIG interrupts this process. The PANDAS IVIG study (run by the PANDAS physician network) administered 1gram/kg of the child’s body weight per day on 2 consecutive days. Preliminary results were positive but not conclusive. Prophylactic antibiotics should be continued thoughout treatment if IVIG is given. The following link gives access to the NHS IVIG guidelines: NHS IV Immunoglobulin Guidelines
    • Plasmapharesis
      • In this process the harmful auto-antibodies are removed from the blood system itself. Compared to IVIG the success rate for this procedure is very good but it does need to be done in a specialist setting. This technique is therefore usually reserved for severely affected patients with symptoms that would be considered “life threatening”. What is not clear is if the child’s autoimmune system will recreate the negative antibodies. It has been reported that PEX has had to be repeated (as with IVIG) in a few cases.  Prophylactic antibiotics should be maintained throughout treatment. The following link gives access to the UK blood transfusion & tissues transplantation services professional advisory committee recommendations for therapeutic plasma exchange : Therapeutic Plasma Exchange Recommendations
  2. Cognitive behaviour therapy

    • The onset of PANDAS or PANS symptoms can be extremely distressing for the child and family members. It is therefore essential that psychological support with cognitive behaviour therapy (CBT) is initiated at an early stage. On-line CBT in children has been shown to be more effective than face to face therapy and also allows flexibility in seeking consultations. Using CBT gives parents the tools to manage their child during a crisis.
  3. Maintainance therapy

Once disease remission has been achieved the antibody level will gradually fall and symptoms will slowly improve unless the immune system is restimulated eg with another infection. In order to reduce the risk of further streptococcal infections, current recommendations include the use of preventative (prophylactic) antibiotics which are given long term to prevent further streptococcal infections.

Final words

This article has been written to try and help parents in the UK get the best treatment for their child. The Children’s e-Hospital is working with others to try and establish a UK PANDAS Doctors Network to raise the profile of this condition and ensure safe and effective management. It must be remembered that this is an evolving disease in the paediatric population and therefore other conditions must be excluded before you embark on a pursuit of a diagnosis of PANDAS or PANS.

If you would like to discuss your child’s diagnosis further or wish to know more about PANDAS & PANS please contact the Children’s e-Hospital admin team at admin@e-hospital.co.uk

 

  • Recent updates
  • Published evidence
  • References
  • Author
  • The following review articles were released in 2017 to attempt to obtain a consensus view on the diagnosis & treatment of PANDAS & PANS

PANDAS & PANS Review Article 1

PANDAS & PANS Review Article 2

PANDAS & PANS Review Article 3

  • Current work involves looking at IL17/TH1 ratios. IL17 is a marker for multiple sclerosis whilst TH1 is involved in the immune pathway that kills bacteria

1. Internet survey of PANDAS treatment

Treatment of Pediatric Acute-Onset Neuropsychiatric Disorder in a Large Survey Population.

Calaprice D, Tona J, Murphy TK.

J Child Adolesc Psychopharmacol. 2017 Aug 23. doi: 10.1089/cap.2017.0101

Abstract

OBJECTIVE: 

The goal of this study was to investigate treatment histories and outcomes in a large community sample of youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), and, where appropriate, to examine the impact of immune deficiency on treatment outcomes.

METHODS: 

A comprehensive internet-based survey was completed by parents or guardians of youth who had received physician diagnoses of PANS, or by young adults (age 18+) who had themselves been diagnosed by a physician (N = 698). Data regarding the treatment histories of these patients, including the variety of medical and psychological treatments employed and the caregiver- or self-reported response to each, are presented.

RESULTS: 

The PANS patients in this study had commonly been treated with antibiotic (N = 675), anti-inflammatory (N = 437), and/or psychotropic therapy (N = 378). Response to antibiotic treatment was best when treatment was relatively aggressive, with broad-spectrum antibiotics and courses of >30 days generally producing the best results (i.e., up to 52% of patients achieving a “very effective” response). For immune-deficient patients (caregiver-reported laboratory studies below normal limits; N = 108), use of broad-spectrum antibiotics appeared to be particularly desirable. Anti-inflammatory therapies, including over-the-counter medications such as ibuprofen, were at least “somewhat effective” for most patients. Intravenous immunoglobulin (IVIG) had been used to treat PANS in 193 (28%) of the patients and was at least “somewhat effective” for 89%, although for 18% of these, the effect was not sustained. The highest rate of sustained response to IVIG treatment was seen in immune-deficient patients who received doses of at least 0.8 g/kg IVIG on a regular basis. Psychotropic medications, most commonly SSRIs (38% reported a trial), were commonly employed, but were often ineffective (e.g., 44% found SSRIs “somewhat” to “very effective”). Many patients (N = 473) had received some form of psychotherapy with some benefit, with cognitive behavioral therapy found to be at least somewhat effective in a majority of those treated with this modality.

CONCLUSION: 

Among the PANS patients represented in this study, relatively aggressive treatment courses targeted at eradicating infection and modulating the inflammatory response appeared to provide the best caregiver-reported therapeutic results, and to be generally well tolerated. Given its relative efficacy and tolerability, treatment targeting the inflammatory response may represent an underutilized approach in this population. The results of this study should be considered in light of the limitations inherent in a self-selected and administered online

 

1. Swedo SE, Leckman JF Rose NR. From research subgroup to clinical syndrome: Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr Therapeut 2012, 2:2.

2. Swedo SE, Leonard HL, Garvey M, Mittleman D, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections: Clinical description of the first 50 cases. Am J Psychiatry 155:2, February 1998; pp265-271.

3. Allen AJ, Leonard HL, Swedo SE. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry. 1995 34: 307-311.

4. Snider LA, Swedo SE. PANDAS: current status and directions for research. Mol Psychiatry. 2004 Oct;9(10):900-

5. Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med. 2002 Apr;156(4):356-61.

6. Murphy TK, Storch EA, Lewin AB, Edge PJ, Goodman WK. Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Pediatr. 2012 Feb;160(2):314-9.

7. Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999 Oct 2;354(9185):1153-8.

 

Dr Tim Ubhi

September 2018