pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections/pediatric...

NPBR-138; No. of Pages 6

Pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections/pediatricacute-onset neuropsychiatric syndromes vs.pediatric bipolar disorder—A possible connection?

Rosalie Greenberg *

Medical Arts Psychotherapy Associates, P.A., 33 Overlook Road, Suite 406, Summit, NJ 07901, United States

n e u r o l o g y , p s y c h i a t r y a n d b r a i n r e s e a r c h x x x ( 2 0 1 4 ) x x x – x x x

a r t i c l e i n f o

Article history:

Received 25 September 2013

Received in revised form

19 May 2014

Accepted 18 June 2014

Keywords:

Streptococci

Pediatric bipolar disorder

Inflammation

a b s t r a c t

Many studies on the causality of mental illness are currently focusing on the interplay of

genetics, environment, inflammatory processes, and immunologic changes. Select diagnos-

tic groups with extant data from some of these domains may provide etiological insight and

suggest novel therapeutic paradigms. This article compares and discusses two diagnostic

groups with accumulating evidence about the role of genetic, environmental and immuno-

logical factors: pediatric autoimmune neuropsychiatric disorders associated with strepto-

coccal infections (PANDAS) and the related pediatric acute-onset neuropsychiatric

syndromes (PANS) and pediatric bipolar disorder. These entities are increasingly reported

in children and adolescents. Clinical observation and review of the literature suggest

similarities between these diagnostic groupings including: early onset; mood dysregulation;

irrational and unpredictable temper outbursts; high comorbidity with anxiety disorders

(including obsessive compulsive disorder), school refusal, attention deficit hyperactivity

disorder, sensory hypersensitivity; unpredictable responses to psychotropic medications

and a waxing and waning course that can become chronic with repeated exacerbations.

Neurologic symptoms such as tics, rapid jerky movements or other movement abnormalities

seen in PANS/PANDAS are not part of the bipolar presentation. A case demonstrating the

importance of recognizing both diagnostic groupings is presented. The phenotypic common-

alities discussed raise intriguing questions about whether or not illness in a child or adolescent

who is genetically predisposed to bipolar disorder can be triggered by infection and subsequent

inflammatory and/or immune responses. Additionally, the symptomatic overlap between the

two disease groupings, even if not causally related, may have implications for therapy.

Treatment of inflammation may ameliorate bipolar symptoms in some patients.

© 2014 Elsevier GmbH. All rights reserved.

Available online at www.sciencedirect.com

ScienceDirect

jo u rn al h om epag e: ww w.els evier .c o m/lo c at e/np b r

1. Introduction

The exploration of the interactions of genetics, environmentalstress, inflammation, and the body's immunologic response in

* Tel.: +1 908 598 0200; fax: +1 908 598 0924.E-mail address: [email protected].

Please cite this article in press as: Greenberg R. Pediatric autoimmune npediatric acute-onset neuropsychiatric syndromes vs. pediatric bipolar disdx.doi.org/10.1016/j.npbr.2014.06.004

0941-9500/$ – see front matter © 2014 Elsevier GmbH. All rights reserhttp://dx.doi.org/10.1016/j.npbr.2014.06.004

the precipitation of mental illness is part of an exciting newfrontier in psychiatry. Although the details about multifacto-rial determinants that come into play to precipitate a mentaldisorder remain unclear, there are many important clues tobe pursued in each of these areas mentioned. For example:

europsychiatric disorders associated with streptococcal infections/order—A possible connection?. Neurol Psychiatry Brain Res (2014), http://

ved.

http://dx.doi.org/10.1016/j.npbr.2014.06.004

mailto:[email protected]



http://www.sciencedirect.com/science/journal/09419500


Table 1 – Symptoms commonly associated with PANDAS.

� Sudden unexplained rages� Intense moodiness (emotional lability)� Personality changes� Symptoms of ADHD (attention deficit hyperactivity disorder) i.e.hyperactivity, distractibility, inattention and/or impulsivitythat is new or suddenly worse

� Refusal to eat or difficulty surrounding eating (often because ofa fear of choking, or fear of throwing-up)

� Nervous system disorders in addition to tics including otherrapid, jerky movements

� Age inappropriate behaviors (such as bedtime fears/rituals,baby talk)

� Separation anxiety (e.g. fear of sleeping alone, refusal to be ina different room than their parent or school refusal)

� Sensory hypersensitivity (i.e. heightened sensitivity to touch,taste, smell, sound or light)

� Noticeable decline in handwriting or math skills� Frequent daytime urination, recurrent or increased bedwettingor repeated complaints that the child still feels wet despiteoveraggressive toileting

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(1) having a parent with a mood disorder significantlyincreases the chances of the offspring being samely affected,1

(2) infections such as H. influenza during pregnancy have beenassociated with schizophrenia in the offspring2 and (3) invulnerable individuals infection by toxoplasmosis gondii canbe linked to the subsequent development of bipolar disorder inadults.3 These observations are valuable in identifying newperspectives on causation and treatment of mental disorders.Finding a clinical group to study that combines informationalready available in some of these areas may provide a fertilepopulation for research. It is from this vantage point that theillnesses of pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections (PANDAS)/pediatricacute-onset neuropsychiatric syndromes (PANS) and pediatricbipolar disorder (PBD) are examined in this paper.

PANDAS and PBD are considered controversial diagnoses inboth the psychiatric and medical communities.4–7 Somebelieve these illnesses are underdiagnosed and often gounrecognized. Others doubt that either one is very prevalent,if they exist at all; or feel that one or both of these disorders areoverdiagnosed. Adding to this list of questionable disorders isthe newer diagnostic category of PANS.4 Unlike PANDAS,which is a disorder or constellation of symptoms feltsecondary to a streptococcal infection, PANS refers to thesudden onset of obsessive–compulsive disorder (OCD) but doesnot indicate the pathophysiologic cause of the syndrome.PANDAS can be viewed as a subgroup of PANS. Reviewingthese two sets of illnesses: PANDAS/PANS and PBD, bydemonstrating their symptomatic and clinical overlap, mayadd a new element in our understanding and approach tochildhood mental illness.

2. Method

Based upon information drawn from clinical practice and themedical literature on PANDAS, PANS and PBD, definitions andcharacteristics associated with each disorder are discussedseparately, and then compared, focusing on areas of overlapand those of differentiation. A clinical case will be presented todemonstrate the importance of proper diagnosis for maximiz-ing treatment outcome.

3. Results

In the initial paper published in the journal Pediatrics inFebruary 1994 by Dr. Susan Swedo and colleagues, the namePANDAS was given to the sudden onset of obsessive–compulsive disorder (OCD) and/or tic disorders that werepostulated to be precipitated by a Group A Beta HemolyticStreptococcal (GABHS) infection, which then led to aninappropriate autoimmune response. Instead of the immuneattack being focused on the invading bacteria, it is mistakenlydirected against certain areas of the brain (e.g. basal ganglia),leading to neuro-behavioral changes.

Five criteria needed to be met before the diagnosis ofPANDAS could be given:

(1) Presence of OCD and/or tic disorder

Please cite this article in press as: Greenberg R. Pediatric autoimmune

pediatric acute-onset neuropsychiatric syndromes vs. pediatric bipolar disdx.doi.org/10.1016/j.npbr.2014.06.004

(2) Pre-pubertal onset(3) Sudden onset or episodic course of symptoms(4) Temporal association with GABHS infections(5) Association with neurological abnormalities (e.g. motoric

hyperactivity, or choreiform movements)

In addition to the more familiar signs of OCD or tics,children suffering from PANDAS might also exhibit some or allof the symptoms listed in Table 1.8

The concept of infection playing an important role in thegenesis of psychological symptoms (e.g. mood disturbances,impulsivity, obsessions/compulsions) as well as tic disordersand Tourette's syndrome has been demonstrated for otherpathogens e.g. Borrelia burgdorferi9,10 and mycoplasmapneumonia.11,12,13 The majority of research has focused onPANDAS, and a variety of characteristics in these youngstershave been described in the literature. There is some evidencethat children with PANDAS ``have a substantial prevalence'' ofautoimmune disorders in their family history compared withthe general population.14,15

Swedo and colleagues8 found that children suffering fromPANDAS were highly comorbid for ADHD (40%), affectivedisorders (42%) and anxiety disorders (32%).

In 2012, the broader diagnostic category of PANS wasproposed4 which significantly expanded the possible etiolo-gies of the illness. The primary focus was shifted to OCD andrestricted oral intake, with tics removed as a necessarycomponent. The accompanying possible neuropsychiatricsymptoms are not very different (see Table 2).

Pediatric bipolar disorder (PBD), previously known asmanic-depression, is a mental illness in which the childexperiences unusual shifts in mood, energy, and activity levelthat interfere with his/her ability to function in daily life.Although previously felt to be a disorder of late adolescence oradulthood, in the past 2 decades support for an earlier onsethas come from a variety of sources.16–18 There is no questionthat there has been a significant increase in the number of

neuropsychiatric disorders associated with streptococcal infections/order—A possible connection?. Neurol Psychiatry Brain Res (2014), http://



Table 2 – Criteria for PANS.

I. Abrupt, dramatic onset of obsessive–compulsive disorderor severely restricted food intake

II. Concurrent presence of additional neuropsychiatric symptoms,with similarly severe and acute onset, from at least 2 of thefollowing 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 disturbances,enuresis or urinary frequency

III. Symptoms are not better explained by a known neurologic ormedical disorder, such as Sydenham chorea, systemic lupuserythematosus (SLE), Tourette's disorder or othersa

a Note: The diagnostic work-up of patients suspected of PANS mustbe comprehensive enough to rule out these and other relevantdisorders. The nature of the co-occurring symptoms will dictatethe necessary assessments, which may include MRI scan, lumbarpuncture, electroencephalogram or other diagnostic tests.

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children given this diagnosis in recent years.19 But are they allreally bipolar?

The symptoms required by the Diagnostic and StatisticalManual IV-TR in order to make the diagnosis of bipolardisorder are seen in Table 3.20

By applying developmental modifications to the adultcriteria similar symptoms can be observed in children.21

Adult manics can be fairly jovial, very entertaining andoverly effusive unless they are irrationally irritable or highlyinappropriate or psychotic. A child in a manic state oftenshows excessive anger as the main mood state and can haveoutrageous temper outbursts.16,22,23

The majority of youth with BPD also show times (even ifonly very brief periods) of excessive silliness, or inappropriateelation. It is the increased frequency and intensity of the moodstate (either excessive elation or irritability) that makes itstand out enough for it to be considered a sign of hypomaniaor mania.

Table 3 – DSM IV-TR criteria for mania.

The Individual must have a manic or hypomanic mood i.e. Onedistinct episode of elevated, expansive, or irritable mood thatlasts a week, or less, if hospitalization is necessary

During the period of disturbed mood, three or more of thefollowing symptoms must be present (four if the moodproblem is only irritability):� Inflated self-esteem or grandiosity� Decreased need for sleep (e.g. feeling rested afteronly 3 h of sleep)

� Unusual talkativeness� Racing thoughts� Distractibility� Increased goal-directed activity (either socially, at work orschool, or sexually)

� Doing things that have a high potential for painfulconsequences – e.g. unrestrained buying sprees, sexualindiscretions or foolish business investments


Youth with BPD often exhibit ``mixed states'' i.e. signs ofthe manic and depressive moods at the same time. Alsochildren with BPD, unlike adults, are more likely to show rapidcycling (i.e. at least 4 episodes of significant mood swings in ayear). Bipolar youth often experience mood shifts multipletimes over the course of a day or a few days.

Bipolar youngsters can experience racing thoughts andexhibit very rapid speech.

Grandiosity, bragging and boastful behavior is not uncom-mon in children, in general, but in bipolar youth it is muchmore frequent, and often seems quite irrational.21

Features shared between pediatric bipolarity andPANDAS/PANS include::

(1) Emotional lability(2) Heightened anxiety symptoms especially separation

anxiety and obsessive–compulsive behavior.(3) An increase in impulsivity or immaturity.8,24

(4) Obsessively demanding behavior in pursuit of a goal.(5) Severe temper tantrums.8,21

(6) Often abusive to family at home, yet well behaved inschool. Some children struggle in both environ-ments.

(7) Keeping up with schoolwork can be difficult becauseof problems with concentration.

(8) Depression.8,24

(9) Highly comorbid with other psychiatric disorders –

especially ADHD.8,24

(10) Sensory hypersensitivity.(11) Nightmares are not uncommon.(12) Somatic symptoms – insomnia, appetite change,

etc.4,21

(13) Very sensitive to treatment with standard psychiat-ric medications.21,25,26

(14) Course of illness. Although children with BPD oftenappear to have chronic difficulties, generally there isan episodic quality to their major mood episodes.In PANDAS/PANS there is an acute onset and thepattern goes from saw tooth to chronic withrepeated infections.

One clear difference between PBD and PANDAS/PANSis that PANDAS patients have neurological symptoms e.g.tics, choreiform movements, etc. that are not part of a mooddisordered picture. On the other hand, tics disorders are themost frequent movement disorder in childhood27 so theirpossible presence in a child with pediatric bipolar disorder as asecond unrelated diagnosis is not necessarily so unusual.

3.1. A case example

S. is a 17 year old female who has been in treatment since age 6when she was referred for evaluation of excessive anxiety andmild oppositional behavioral both at home and at school.

Birth and early developmental history were remarkable forsevere separation anxiety between age 9 months and 3 years,and she was described as a ``high energy'' toddler.






Medically between ages of 8 months and 3 years she had afew episodes of otitis media treated with antibiotics. At age 3 1/2she had infectious mononucleosis.

S. exhibited a significant change in behavioral andemotional regulation by age 4: i.e. her separation anxietyincreased creating problems sleeping alone in her own bed,not wanting to go to nursery school, emotionally more labile,easily tearful, oppositional, impulsive, felt easily rejected byothers, and began having temper tantrums both at home andin public settings. Escalation in these behaviors over the nexttwo years prompted the psychiatric assessment.

Positive Family Psychiatric History: depression in 3 gen-erations including at least one member with postpartumdepression; bipolar I disorder; ADHD; alcoholism; and anxietyand panic disorder.

Initial diagnoses: (1) Separation Anxiety Disorder, (2)probable ADHD – inattentive type and (3) possible mooddisorder R/O bipolar disorder.

Treatment included individual therapy and parentalcounseling as well as pharmacotherapy. Low dose paroxetineresulted in rapid mood shifts between agitation, irritability,depression, overactivity and increased silliness. Upon with-drawal of the selective serotonin reuptake inhibitor (SSRI), S.became very depressed.

Over time, it became clear that S. had a Bipolar MoodDisorder Not Otherwise Specified in addition to her separationanxiety symptoms (refusal to fall asleep alone, excessive fearof separation from her parents, reluctance to go to school andleave her mother, etc.). Depressive symptoms includedtearfulness, low energy, increased irritability, temper tan-trums, feeling others did not like her, and social withdrawal(not solely due to anxiety). When hypomanic she could beoveractive, inattentive, silly, use more ``bathroom words,''show increased irritability, bossiness, heightened impulsivityand grandiosity (acted like she knew more than her elders).

Within 6 weeks after starting on a trial of oxcarbazepine sheshowed significant improvement. S. no longer appeared tostruggle with major mood shifts and ADHD symptoms (morefocused and motorically calmer), but still remained immatureand mildly anxious. There also was a Seasonal Affectivecomponent to her mood disorder characterized by depressiveepisodes each fall (mid October), and hypomania in the spring(March/April). Seasonal adjustments in her oxcarbazepinedosage (increased when depressed and decreased whenhypomanic) were effective in achieving mood restabilization.

Following a gastrointestinal virus in 4th grade, shedeveloped an obsessional fear of emesis: i.e. fear she wouldthrow up or fear that another classmate would vomit and thenshe would have to do the same. This fear overwhelmed herand became the focus of her future intermittent recurrentanxiety. Her academic performance suffered when she wasunable to concentrate due to internal distraction by obses-sional thoughts and anxieties.

In winter of 8th grade, she developed an acute intenseexacerbation of psychiatric symptoms and was subsequentlydiagnosed with recurrent infectious mononucleosis.

Mood instability and increased obsessional anxiety duringher high school years minimally responded to the addition ofbuspirone to the oxcarbazepine. The diagnosis of PANS wasthen considered.



Of note, family history of immunologic dysfunction waspositive for: ulcerative colitis, celiac disease, asthma, eczema,and possible thyroid disease.

Laboratory testing checking for evidence of a GABHSinfection including Anti-streptolysin O (ASO) and anti-DNAaseB Streptococcal titers was unremarkable. S. had positiveMycoplasma Pneumonia Antibody titers, both for IgM = 3.15(nl < 0.9) and IgG = 5.12 (nl < 0.9). Within 3 days of placementon a 2-week course of azithromycin for the mycoplasmainfection her worrying decreased and she reported resolutionof psychiatric symptoms by day 12.

Over the next few months, whenever she was physically ill,S. experienced an increase in her psychiatric symptomatology.Different antibiotics were tried as her mycoplasma pneumoniaIgG and IgM titers came down very slowly. The addition ofibuprofen 800 mg/day to the antibiotic treatment (for sus-pected inflammation) helped speed improvement. Stoppingantibiotics on a few occasions resulted in an increase inpsychiatric symptoms with fairly rapid resolution of symp-toms with resumption of treatment.

On 4-month follow-up, she remains euthymic with mini-mal anxiety on a regimen of an antibiotic, oxcarbazepine, andbuspirone. Plans are to taper her antibiotic at some time aftershe transitions to her senior year in high school.

An important treatment issue in the long run will be thelength of time antibiotic treatment is necessary, as she hasbeen on one form or another for the majority of the last 10months. Also, if over time this approach proves ineffective,other more aggressive interventions aimed at correcting herimmune dysfunction (e.g. intravenous gamma globulin orplasmaphoresis) may need to be considered.

4. Discussion

Oxcarbazepine is an anti-convulsant that has not beenapproved for treatment of bipolar disorder but data from avariety of studies indicate it has potential mood stabilizingproperties.28,29 In adult bipolar disorder it is usually prescribedfor prophylaxis of depression and mania/hypomania. Wagnerand colleagues30 found no benefit from treatment withoxcarbazepine in bipolar youth compared to placebo. Giventhe possibility of effectiveness, relatively benign side effectsprofile, and S.'s anxiety over bloodwork, S. was initially placedon oxcarbazepine. This resulted in a good response. Accordingto Norman Rosenthal M.D. an expert on SAD, it appears thatsome individuals with a seasonal component to their bipolardisorder respond to small changes in their oxcarbazepine doseduring their seasonal mood shifts.31 This is consistent with theauthor's clinical experience.

There has been a great deal of interest in the interplay ofinfectious illness, immunologic changes and psychiatricillness.32–34 There is some evidence to support that in PANDASthe individual's immune system, initially triggered by a GABHSinfection creates antibodies that mistakenly act as anti-neuralantibodies in the central nervous system.35,36

Furthermore, mood disorders, especially depression, arecommonly seen in patients with autoimmune disease, e.g. SLE,multiple sclerosis, Crohn's disease, etc. The details of theimmune/mental illness connection in these disorders have yet




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to be uncovered. In addition, our increased awareness ofillnesses such as anti-NMDA receptor encephalitis shows howimmune dysfunction can affect the brain causing dramaticemotional and behavioral manifestations.37 Just as shortnessof breath on exertion may be caused by heart damage fromrheumatic carditis that began with a streptococcal sore throat,it may be that the psychiatric symptoms, e.g. the intense ragessome children have, may be the end result of an aberrant bodyimmune response that began with a simple infection.

Focusing on children who have this combination of geneticvulnerability, early onset of mood disorder, with a possibleinfectious trigger may help us isolate a more homogenousgroup in which to study the interplay of these factors incausing bipolar disorder.

In addition as seen in the case of S., recognizing thecommonality in the symptom picture between PANDAS/PANSand PBD can play an important role in the approach totreatment. If the onset of mood disorder symptoms occursafter a youngster has been ill, this can be a potential etiologicclue in the diagnostic process. This sequence of eventsnecessitates a careful and detailed evaluation to determineif the prior illness is relevant to the child's problems or just ared herring.

Screening for the evidence of an infectious and/orimmunologic process in select pediatric patients might be ofetiologic and therapeutic benefit. These patients wouldinclude: (1) those with the sudden onset of mood disordersand/or anxiety symptoms, (2) those with sudden onset of aneating disorder or (3) those that have been somewhattreatment refractory. In general, testing should be done tocheck for (1) GABHS infection (ASO titer, Anti-DNAse B titer,streptozyme) in addition to obtaining a throat culture; (2)mycoplasma pneumonia (IgM and IgG antibody titers); (3)Lyme disease (ELISA and Western Blot) as well as (4) looking forpotential Lyme coinfections: babesiosis, bartonellosis, erli-chiosis or anaplasmosis (IgM and IgG antibody titers for eachdisorder). Other titers may be indicated depending on thechild's previous symptoms (e.g. Epstein Barr antibody titers) orwhatever other viral, bacterial, or parasitic infections areendemic to a particular geographic region.

5. Conclusions

In comparing the criteria, course, and response to treatment itappears that there are significant overlaps between PANDAS/PANS and PBD. These commonalities may in part contribute tothe present state of confusion and heightened concern aboutthe overdiagnosis of PBD. One hypothesis based on theinformation presented in this paper is that in some individualstheir bipolar disorder may be the result of a complex series ofinteractions i.e. genetic predisposition, triggered by an infec-tion, the subsequent neuro-inflammation resulting in animmune reaction (possibly autoimmune) in the CNS which isthen manifested in the form of emotional and behaviordisturbances. Repeated inflammatory stimuli or chronicinflammation may help the disease process progress suchthat at some point this disturbance become an intrinsiccondition in the CNS and contributes to the development ofbipolarity. Studies exploring these issues in the future may


help us understand much more about the biologic under-pinnings of mental disorders. Focusing on youth with a veryearly onset of their bipolar disorder, that also have laboratoryand clinical evidence of PANDAS or PANS may provide aninroad into the biologic basis of pediatric mood disorder.In addition this work may generate biomarkers that areindicative of an increased risk for mental illness at a veryyoung age.

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