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Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)/Pediatric Acute-onset Neuropsychiatric Syndromes (PANS) and Pediatric Bipolar Disorder (PBD) Is there a Connection?
by Rosalie Greenberg, M.D.
Both Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and pediatric bipolar disorder (PBD) are highly controversial diagnoses in the psychiatric and medical communities. Some believe these illnesses are under diagnosed and often go unrecognized. Others doubt that either one is very prevalent, if they exist at all, or feel that one or both of these disorders is over diagnosed. Adding to this list of questionable disorders is the newer diagnostic category of Pediatric Acute-onset Neuropsychiatric Syndromes or PANS. Unlike PANDAS, which is a disorder or constellation of symptoms felt secondary to a streptococcal infection, PANS refers to the sudden onset of obsessive compulsive Disorder (OCD) but does not indicate the pathophysiologic cause of the syndrome. PANDAS can be viewed as a subgroup of PANS. As noted on the NIMH website “”PANS and PANDAS are comparable to cancer and leukemia (respectively) as PANS is the large class of disorders and PANDAS is one specific type.
Having treated children with a variety of psychiatric disorders for over 30 years there is no question in my mind that many disorders presently falling under the heading of mental illness are biologically based. We are only at the very beginning of our journey to understand the biologic mechanisms through which this occurs. The views expressed in this article are mine. They are based on my clinical experience and my review of the literature. They are not etched in stone nor should they in any way substitute for a good comprehensive personal face-to-face biomedical psychiatric assessment.
In my practice I observed that a proportion of my patients parents said that the onset of the child’s mood shifts and behavioral changes occurred after the youngster had been physically ill (e.g. following an episode of mononucleosis in one child, and following a flu like illness in another etc.). This temporal association raised the question of whether or not these children had a PANDAS or PANS like quality to their illness?
For years, as part of a full psychiatric assessment of a child, families were routinely asked if there was any family history of mental disorders (bipolar disorder, depression, anxiety, substance abuse, etc.) as well as medical disorders (heart disease, thyroid disease, Diabetes Mellitus etc.). When I began asking if there were any blood relatives that suffered from autoimmune disorders on either side of the family tree, more than a few parents, related a positive family history of autoimmunity (e.g. systemic lupus erythematosus, rheumatic heart disease, rheumatoid arthritis etc.)
Because of this experience, autoimmune disorders have been added to my standard family history checklist.
With these experiences in mind, in recent years, when a child presented with the sudden onset of mood symptoms, signs of obsessive compulsive disorder (OCD), or tics (motor or vocal) post infection, I began checking immunoglobulin levels, streptococcal antibody titers, mycoplasma pneumonia immunoglobulin titers, as well as looking for evidence of other possible infections that might potentially be playing a role in the child’s problems.
Upon closer investigation, I became struck by the similarities exhibited in a variety of areas by children diagnosed with PANDAS or PANS and those diagnosed with pediatric bipolar disorder.
What I’d like to do in this article is to start to discuss these two groupings, and demonstrate how symptoms of these disorders can overlap, causing diagnostic confusion, and how for some children more than one of the diagnoses may need to be considered and addressed.
Since the initial paper published in the journal Pediatrics in February 1994 by lead author Dr. Susan Swedo, the existence of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections or PANDAS has been an area of division in the medical community. The authors proposed that there was a link between Group A streptococcal infections and the sudden onset of obsessive-compulsive disorder (OCD) and/or tic disorders in children. The suggested mechanism was felt to be an autoimmune response directed against certain targets of the brain leading to neuro-behavioral changes, similar to what happens in rheumatic fever, where the heart valve is the mistaken target of the body’s natural fight against infection. Five criteria needed to be met before a youngster could be given the diagnosis of PANDAS: 1) presence of OCD and/or tic disorder, 2) pre-pubertal onset, 3) sudden onset or episodic course of symptoms, 4) temporal association between streptococcal infections and 5) neuropsychiatric symptom exacerbations, and associated neurologic abnormalities (i.e. choreiform movements). Since the initial paper, studies conducted in other parts of the world, (e.g., Italy, France, England etc.) indicate that PANDAS is not a disorder that is limited to the United States.
In addition to the more familiar signs of OCD or tics, children suffering from PANDAS may also exhibit some or all of the following:
• sudden unexplainable rages
• Intense moodiness (emotional lability)
• Personality changes
• Symptoms of ADHD (Attention Deficit Hyperactivity Disorder) i.e. hyperactivity, distractibility, inattention and/or impulsivity that is new or suddenly worse.
• Refusal to eat or difficulty surrounding eating -(often because of a fear of choking, or fear of throwing-up).
• Nervous system disorders such as tics or other rapid, jerky movements
• Age inappropriate behaviors (such as bedtime fears/rituals, baby talk)
• Separation anxiety (e.g. fears of sleeping alone, refusal to be in a 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
bedwetting or the child complains that he/she still feels
wet despite overaggressive toileting.
The pattern of illness in PANDAS is described as episodic and saw-toothed. Patients may experience complete disappearance of symptoms between episodes. On the other hand if there has been multiple recurrent episodes, it may be harder to see an episodic pattern and the picture begins to appear more like one of chronicity.
Presently there are some indications that children with PANDAS often have a family history with an increased rate of autoimmunity in relatives, but this issue requires much more extensive exploration.
The issue of comorbidity also complicates the diagnosis of PANDAS. Comorbidity means that in addition to the primary disorder the child also has other significant problems that affect his or her functioning. In child psychiatry, this concept is more the rule than the exception. Often if a child has one diagnosis, they also have 1 or 2 or more other problems. Consistent with this observation, Dr. Swedo and colleagues found that children suffering from PANDAS were highly comorbid for Attention deficit hyperactivity disorders (ADHD) (present in 40%), affective (mood) disorders (42%) and anxiety disorders (32%).
The newer diagnostic category that has been proposed for Pediatric Acute-onset Neuropsychiatric Syndrome almost seems symptomatically to straddle the line between PANDAS and PBD. Unlike PANDAS, (which is due to a streptococcal infection) the causality of this neuropsychiatric syndrome is not identified in the name. This significantly broadens the possible etiologies of the illness. The criterion proposed for PANS include:
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 2 of the following 7 categories:
2. Emotional lability and/or depression
3. Irritability, aggression and /or severely oppositional behaviors
4. Behavioral (developmental) regression
5. Deterioration in school performance
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 chorea, systemic lupus erythematosus, Tourette’s Disorder or others.
Note: The diagnostic work-up of patients suspected of PANS must be comprehensive enough to rule out these and other relevant disorders. The nature of the co-occurring symptoms will dictate the necessary assessments, which may include MRI scan, lumbar puncture, electroencephalogram or other diagnostic tests.
A very dramatic and emotionally trying symptom for both the parent and child is the overwhelming anxiety that many of the children with PANS experience. Their intense separation fears often interfere with school attendance or the child being able to sleep alone at night. Fear of vomiting or choking, feelings of repulsion/anxiety from hypersensitivity to taste or smell of certain foods may lead to restricted oral intake. To the clinician the sudden onset of these types of symptoms should bring the possibility of PANS to mind. The frequency of comorbidity with PANS has yet to be determined and may be somewhat difficult to ascertain as many of the symptoms in criteria II are also seen in many other psychiatric illnesses. For example, irritability and aggressive behavior has been argued to be the common expression of pediatric mania. The potential primacy of these symptoms in both disorders can increase diagnostic confusion. It’s important to keep in mind that one symptom does not make a diagnosis in these situations. Irritability and aggression are non-specific but still of great importance when considering potential diagnoses and subsequent treatment approaches.
The existence and frequency of Pediatric Bipolar Disorder (PBD), is another hotly debated entity. Previously called manic – depression, bipolar disorder is a brain disorder that causes unusual shifts in the individual’s mood, energy, and activity level that interfere with his/her ability to function in daily life. In the past it was felt to be a disorder of late adolescence or adulthood, but generally considered very rare in childhood. More recent research indicates that many of the criteria used to make the diagnosis of bipolarity in adulthood can also be applied to children. There is no question that there has been a significant increase in the number of children given this diagnosis in recent years. But are they all really bipolar?
The symptoms that the Diagnostic and Statistical Manual IV-TR requires in order to make the diagnosis of bipolar disorder include:
The individual must have a manic or hypomanic mood-i.e. One distinct episode of elevated, expansive, or irritable mood that lasts a week, or less, if hospitalization is necessary.
During the period of disturbed mood, three or more of the following symptoms must be present (four if the mood problem is only irritability):
• Inflated self-esteem or grandiosity
• Decreased need for sleep (for example, feeling rested after only three hours of sleep)
• Unusual talkativeness
• Racing thoughts
• Increased goal-directed activity (either socially, at work or school, or sexually)
• Doing things that have a high potential for painful consequences — for example, unrestrained buying sprees, sexual indiscretions or foolish business investments
By applying developmental modifications similar symptoms can be observed in children. Inflated self esteem or grandiosity is seen in the child who brags about his abilities excessively, or claims his teacher or the book he’s reading is wrong and he know better. Bragging and boastful behavior is not uncommon in children, but in these youngsters it is much more frequent, and often seems quite irrational.
Bipolar kids seem to have hyperactive mouths with nonstop talking (and not necessarily always making sense).
When they have racing thoughts, it can seem like one thought distracts the child into another thought and it’s hard to get a handle on what he or she is really talking about.
Children with BPD can look very much like ADHD children as they can be highly distractible, impulsive, physically restless, and unable to stay still.
Youth suffering from BPD can be very obsessively demanding and overfocused when they want something and behave irrationally in their pursuit of getting what they want.
Impulsivity in juvenile mania or hypomania may be manifested by the youngster suddenly telling far out tales (grandiosity plays a role here too), stealing something he or she wants, lying, or showing more sexualized behaviors (e.g. frequent potty talk in little ones, excessive notice of the opposite sex in a six year old etc.).
Often a child in a manic state shows mainly excessive irritability as opposed to the elation or elevated mood that is more typically seen in adults with mania. The youngster can have angry outrageous temper outbursts and be verbally and/or physically out of control (boys are physical more often than girls).
The majority of youth with BPD also show times (even if only very brief periods) of excessive silliness, or inappropriate elation. These episodes can be misinterpreted as the child just having been “over stimulated,” “overtired” or perhaps he or she “ate too much sugar” that day. As almost all kids show this type of behavior at sometime in their childhood, this behavior alone is not necessarily pathological. It is important to remember that it is the increased frequency and intensity of the behavior (excessive elation or irritability) that makes it stand out enough for it to be considered a sign of mania.
Parents often describe the child as being abusive to family members at home and yet teachers may report the child is very well behaved in the classroom. Some children struggle in both environments.
The former situation can occur for a few reasons. Many kids with BPD have some boundaries and some control. They are more able to relax and be themselves at home. They know that out in public if they misbehave they will be rejected and ostracized by others. Believe it or not, often it is because of good parental teaching of societal rules that the child works hardest at self-control outside the home. The child feels safest with his parent and therefore freer or more comfortable to express his distress. After holding it together all day at school, he or she may feel overwhelmed and seem unable to continue to exert such intense control at home. In general, it may well be that the child is aware that if he behaves inappropriately the outside world will reject him a lot sooner than his parents might.
Youth with BPD often exhibit “mixed states” i.e. they show signs of the manic and depressive moods at the same time. Also children with BPD, unlike adults, are more likely to show a pattern referred to as rapid cycling. The means that the individual has at least 4 episodes of significant mood swings in a year. Bipolar youth often experience mood shifts multiple times over the course of a day or a few days.
Bipolar children in the manic or depressed phase can have outrageous temper tantrums. They are often very emotionally labile, i.e. changeable. The child can get overly focused on doing something or over focused on acquiring what he wants and there is a strong obsessional quality to his demands. Tantrums can be unpredictable or easily precipitated by a “no” response from the parent. Tantrums can occur in either the elevated or depressed mood state. After outrageous destructive tantrums the bipolar child may suddenly become very sad and guilty- as he realizes that his behavior is unacceptable and he doesn’t even understand the reasons for his actions. Children with PANDAS or PANS can share this excessive irritability and become violent and out of control for reasons that they don’t understand.
In addition, a bipolar youth may exhibit a reversion to speaking “baby talk” and act much younger than his/her biologic age.
It’s clear that schoolwork can be difficult for a bipolar child as his mind is so full of ideas, or it may feel the opposite i.e. empty with a paucity of thoughts, Just as seen in a child with PANDAS or PANS the ability to focus in school can be compromised.
It’s important to keep in mind the criteria for depression (as a disorder) when talking about kids within the PANDAS /PANS grouping or bipolar disorder because intense sadness or depressed mood is not uncommon in both sets of children.
To make the diagnosis of major depression an individual has to have a 2-week period in which some of the following signs and symptoms are present:
(1) depressed mood or in kids or adolescents it can be irritable mood
(2) loss of interest or pleasure in previously enjoyable activities
(3) significant change in weight or appetite - weight loss or weight gain, or decrease or increase in appetite, or failure to make expected weight gains.
(4) Insomnia or Hypersomnia (sleeping too much)
(5) motor restlessness or slowing
(6) fatigue or loss of energy
(7) feelings of worthlessness or excessive or inappropriate guilt
(8) diminished ability to think or concentrate, or indecisiveness
(9) recurrent thoughts of death or suicidal thoughts or actions
The importance of heightened anxiety is common to PANDAS/PANS and bipolarity (especially when the individual is in the depressed state). Affected children often show an increase in separation anxiety –e.g. unable to sleep alone at night, fearful of being alone in a room, very clingy and easily frightened, increase in obsessive compulsive types of behavior, wanting things just so, or their shoes need to be tied with equal tension and the socks of equal height before they will leave the house. They become more rigid and demanding, but they may also be harder to please and more indecisive.
In bipolar as well as PANDAS/PANS affected youngsters there can be an increase in sensory hypersensitivity, in any of the five main sensory modalities– touch, sound, smell, taste, and sight. Nightmares are not uncommon in these children. Somatic complaints -headaches, stomachaches etc. are common especially on school mornings. Within all three diagnostic groupings the child’s eating behavior may change and become much more limited-only certain foods are acceptable. Decision-making, remembering instructions, concentrating in school, may all become much more difficult. Of note, many of these symptoms or disorders disappear or significantly lesson when the bipolar child is no longer depressed.
As you can see, children with BPD and those with PANDAS/PANS, often experience a variety of overlapping primary symptoms. In addition they may share comorbid disorders including: anxiety issues, attention-deficit hyperactivity symptoms, autistic spectrum disorders, sensory hypersensitivity, learning problems and especially problems with math skills.
Bipolar kids as well as youth suffering from PANDAS are often able to show self control at school but are much more aggressive, irritable and negative in the safety of their own home.
Although the children with BPD often appear to have chronic difficulties, generally there is an episodic quality to their major mood episodes. Again, confusion with the course of illness as is seen in PANDAS is very possible. Genetically family trees of youth with early onset BPD have bipolar disorder, mood disorders, and alcoholism coming down both parents sides.
Clinically bipolar kids can be difficult to successfully treat with standard psychiatric medications that are more effective in adults with BPD. Antidepressants at doses typically used in depressed children may result in the bipolar child becoming more agitated, manic, more depressed or in a mixed state. Mood stabilizers like lithium, Depakote, Trileptal, and antipsychotics are not as predictably beneficial as in adults with bipolar disorder. There is some evidence that children with PANDAS share this over sensitivity to psychotropic medication.
From what has been discussed it appears that there is significant overlap in the criteria/symptoms of PANDAS or PANS and Pediatric Bipolar Disorder. One difference is that PANDAS patients have neurological symptoms e.g. tics, choreiform movements etc. that are not part of a mood disordered picture. On the other hand, tics are fairly common in childhood so the presence of motor or vocal tics in a child with pediatric bipolar disorder is not necessarily so unusual.
Unpredictable sudden mood changes, temper outbursts, intermittent flare-ups, inattention, rigidity, sensory hypersensitivity, anxiety, oppositional defiant behavior, decline in school performance, high rate of comorbidity, etc. are common in both disorders. The extensive similarities shared between the two groupings of disorders may well contribute to the diagnostic confusion.
Recognizing this commonality in the symptom picture can play a very important role in the approach to treatment. If the onset of mood disorder symptoms occurs after a youngster has been ill, this can be a potential and important clue in the diagnostic process. Of course it may be unrelated, but a careful and detailed evaluation is necessary to determine if the prior illness is relevant to the child’s problems or just a red herring. One mother described her 8-year-old daughter being quite ill with a fever for a few days and at some point soon thereafter she started exhibiting mood and behavioral changes. The child came to see me a few months later because of school refusal that was difficult to treat. Another mother described the onset of a major change in mood and behavior in her 6-year-old daughter after she had infectious mononucleosis at age 3. Both of these children had strong family histories of bipolar disorder and other psychiatric illnesses. Both children did not do well with psychiatric medications alone. Once an immunologic assessment was done, testing on both children showed evidence of previously undiagnosed infections. The addition of antibiotics to their treatment regimen made a major difference in their lives; one was able to attend school regularly for the first time in almost 2 years on antibiotics and low dose psychotropic medication. The other who had difficulty with multiple psychiatric medications, after antibiotic treatment was left with only mild mood swings and was able to be managed with psychotherapy, with minimal or no psychiatric medication for a year. In the past few months her various symptoms have increased in intensity, but which intervention will prove to be most effective at this time is uncertain.
In conclusion, it appears that there is some evidence to support the concept that there are significant overlaps between PANDAS/PANS and Pediatric Bipolar Disorder. Much more research is needed to explore these possible connections. One cannot help but wonder if the commonalities presented may contribute to the present state of confusion and heightened concern about the over diagnosis of pediatric bipolar disorder.
Resources for more information
Swedo SE, Leonard HL, Kiessling LS. Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood. Feb 1994. Pediatrics 93 (2): 323–6.
Swedo, S.E., Leonard, H.L. et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998: 155: 264-271.
Swedo, SE, Leckman JF, Rose, NR. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Feb 2012, Pediatrics & Therapeutics.
Murphy, T.K., Storch, E.A., et al: Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. The Journal of Pediatrics. (2012) Vol. 160:314-9.
Greenberg, R. Bipolar Kids: Helping Your Child Find Calm in the Mood Storm. Da Capo Press, 2007.
http://intramural.nimh.nih.gov/pdn/web.htm National Institute of Mental Health, Intramural research Program; information about studies being done and the general information about PANDAS and PANS
PANDAS Resource Network
PANS/PANDAS - Obsessive Compulsive Foundation