CCPR: Dr. Greenberg, thanks for returning to CCPR. You gave great information in our March issue on Tourette’s disorder, and we know you also treat kids with PANDAS/PANS. How many kids have you seen with PANDAS/PANS?

Dr. Greenberg: I devote one day a week to patients with PANDAS/PANS, and I see one to two new cases a week. I’ve probably seen 50–60 cases so far. I would say of that number, probably a third clearly fit into the PANDAS/PANS profile, while a third have some evidence for PANDAS/PANS but not quite enough to clearly distinguish them from a more typical OCD or Tourette’s case. The final third is unlikely to be PANDAS/PANS for various reasons, including having non-acute onset and a course more consistent with other typical psychiatric disorders.

 

CCPR: How do you make the PANS diagnosis?

Dr. Greenberg: For either PANS and/or PANDAS, we are looking for an individual with acute-onset symptoms, meaning going from either no premorbid symptoms or minimal symptoms to severe exacerbation or onset of OCD and/or tics, and/or severe eating restriction in a period of days. This should be accompanied by what we call the ancillary symptoms (see Diagnostic Criteria for PANDAS and PANS on page 5). A PANS diagnosis requires at least 2 out of 7 ancillary symptoms, but these children typically have at least 4 or 5. Additionally, the patient should be pre-pubertal. That designation was originally developed for PANDAS, as post-streptococcal reactions are rare in those over age 12 (https://www.nimh.nih.gov/labs-at-nimh/research-areas/clinics-and-labs/pdnb/web.shtml), but it seems to also apply to the general PANS population as well. I’ve yet to see a new-onset case in a post-pubertal child. So basically, what we are really looking for is a child with acute onset or severe exacerbation of OCD/tics with these ancillary symptoms. It’s also helpful in terms of making the diagnosis if the parents can pinpoint when symptoms began. Oftentimes parents can tell us the exact date—I’ll hear something like, “Everything changed May 2nd.” One day their child woke up or came home from school with these new, severe symptoms that the parents had never seen before.

 

CCPR: About how common is PANS?

Dr. Greenberg: In a study that was just published, researchers found that of patients referred to their specialty OCD clinic, about 5% met criteria for PANS and/or PANDAS (Jaspers-Fayer F et al, J Child Adolesc Psychopharmacol 2017;27(4):332–341). To translate this to an estimate of prevalence, the prevalence of OCD in children is about 2%–3%, and if we assume 5% of these kids have PANDAS/PANS, we’re talking around 0.1%–0.2% of the general population. So we believe it’s rare, maybe about 2 per 1,000. But, as we learn more, this estimate may adjust, especially since it doesn’t include sudden-onset tic and/or restricted eating cases.

 

CCPR: Let’s say a parent brings an 8-year-old into my office with new onset of OCD symptoms. I’ve been hearing about PANDAS, and while it’s rare, I don’t want to miss the diagnosis. How should I go about doing the evaluation to make sure that I can at least check off that box that I’ve ruled out PANDAS?

Dr. Greenberg: PANDAS is a diagnosis of exclusion. I begin as I would with any evaluation, asking what symptoms the child is experiencing and when they started. I will often hear something like, “You know, it was crazy: One day he had absolutely nothing—he wasn’t even an anxious kid—and then the next day he couldn’t stop washing his hands.” Once I hear those types of symptoms, I’ll ask, “Was it associated with anything? Do you remember anything about the time of onset?” I keep the questions open-ended because I don’t want to “lead the witness” toward a particular diagnosis. In a case of someone with PANDAS/PANS, I might hear, “He happened to be really sick a few weeks before (or during the onset of) these symptoms. When I took him to the doctor, we got a strep culture, and it was positive.” Since there aren’t any official, foolproof diagnostic tests or markers, I always want to make sure I understand the biopsychosocial context in which the patient and family are presenting. After my open-ended questions, I’ll ask specifically about trauma, recent changes in the family or at school, and so on, since all of these can also lead to the acute onset of symptoms in children.

 

CCPR: What about ancillary symptoms?

Dr. Greenberg: I would frame these by asking, “Were the OCD symptoms associated with any other behavioral or other changes in your child?” I’ll also ask about some key symptoms that a few studies have identified as being more common in PANDAS/PANS than typical OCD. These include increased urinary frequency or enuresis, clumsiness, other autoimmune illness, and the absence of the “symmetry” OCD category (including symmetry, counting, and checking).

 

CCPR: The symptoms of PANS are often described as “relapsing/remitting.” How is that different from typical OCD or tics?

Dr. Greenberg: In PANDAS/PANS, we see abrupt episodes with the child typically returning to baseline, with either very limited or no symptoms between episodes. In ordinary OCD, there’s often more of a waxing/waning course where symptoms get better and worse more gradually rather than starting and stopping in a matter of hours/days. If the child receives antibiotics after an abrupt symptom onset and then returns to baseline within a week or two, then I’m suspicious that this is more consistent with the PANDAS/PANS picture. However, if I hear something from the parents such as, “He’s always been a little bit anxious, and then something happened in school where he might have been bullied, and then he came home and started lining things up more—and then a week or two later, the symptoms got much worse, and now he just can’t stop counting things,” then that sounds like a more typical course of OCD, even if the child might have been sick around this time.

 

CCPR: Interesting. Anything else regarding symptoms?

Dr. Greenberg: There is one other thing that I think could be really helpful. Separation anxiety is huge in these kids, but it can be a sign of OCD. And oftentimes we might miss the PANDAS/PANS diagnosis because parents don’t know to say “OCD.” They will say, “Yeah, he won’t leave my side.” But when you get more into it, it’s really that before the parent leaves, the kid will have to do a ritual or will have to say goodbye a certain number of times or something like that in order to “prevent something bad from happening.” So even though we are calling it separation anxiety, it is probably more akin to OCD, and I have seen that as a presenting symptom in a number of kids.

 

CCPR: So if at some point you are fairly confident that this is PANDAS/PANS, how do you proceed?

Dr. Greenberg: If it’s a textbook case with a strep infection in a kid with no premorbid conditions and an acute symptom onset 4–6 weeks later, I will say, “Yes, this sounds very consistent with PANDAS.” If it’s more in the middle, I will say, “Let me explain the symptoms that I think are consistent with PANS and the symptoms that I think are not consistent with PANS. I don’t think we should make an official diagnosis right now, but we will continue to be vigilant and will likely learn more over time.” I’ll also explain that, in general, we don’t typically treat children with PANS that differently from kids with the same symptoms without PANS, and I’ll note that the diagnosis is less important than getting a handle on the symptoms. In the cases that are very consistent with PANDAS/PANS, I will speak about lab tests, anti-inflammatories, antibiotics, and likely collaborating with specialists in infectious disease or immunology. If the diagnosis is more equivocal, I will suggest considering those lab tests and speak about anti-inflammatories, but likely not discuss antibiotics.

 

CCPR: Let’s talk about treatment. How successful are antibiotics?

Dr. Greenberg: Antibiotics are often used in PANDAS/PANS, and they often do appear to work, but a caveat is that we don’t really know why or how they work—which of course is a consequence of not fully understanding what causes PANDAS/PANS in the first place. We think it might be a post-infectious autoimmune disease. If it is, then if a child has an infection that is actively leading to antibodies, which in turn are causing psychiatric symptoms, then it makes sense to use antibiotics to knock out the infection. Or if a child has had at least 2 bad flares subsequent to infection, it makes sense to have the child take prophylactic antibiotics that will ideally prevent infections from leading to flares. But sometimes we see kids at a later point, when there no longer is any obvious infection, and we still see them improve with antibiotics. It may be that the antibiotic has nonspecific anti-inflammatory components, or it may have some ability to modulate neurotransmitters. It’s possible that the antibiotics are helping the psychiatric symptoms regardless of whether there’s a PANS component. Perhaps the antibiotics might work for kids with typical OCD; we simply don’t know.

 

CCPR: Have there been any clinical trials of antibiotics for typical OCD?

Dr. Greenberg: No, there haven’t, but it would be really helpful to have those studies. Depending on the findings, it could certainly complicate our understanding of PANDAS/PANS-related OCD and typical OCD. There’s also a lot of research now into the connection between the immune system and psychiatry, and so we might discover even more connections regarding OCD and the immune system outside of PANDAS/PANS. It’s an exciting time for an exciting field. However, we do know that for patients with a clear PANDAS picture, antibiotics can work very well and bring these kids back to baseline, often with near-complete resolution of symptoms.

 

CCPR: So in a nutshell, which children should get antibiotics, and how long of an antibiotics course should they receive?

Dr. Greenberg: There’s no clear-cut answer because there are no published guidelines for treatment, though we expect some to be published this summer by a group of experts. Nonetheless, generally, for kids with diagnosed PANDAS who recently had an infection and are having neuropsychiatric symptoms, we commonly recommend a one-month course of antibiotics. It is more complicated in PANS, when there isn’t a known-associated infection. We will often still give at least one initial course of antibiotics for those who meet clear PANS criteria, but after that it may be more individualized. If a patient with PANDAS has a history of having had at least 2 exacerbations of psychiatric symptoms associated with strep infections, then we consider prophylactic antibiotics. There has been at least one study that shows prophylactic antibiotics can prevent or decrease both strep infections and flares of psychiatric symptoms (Snider LA et al, Biol Psychiatry 2005;57(7):788–792). However, there has also been at least one negative study as well (Garvey MA et al, Biol Psychiatry 1999;45(12):1564e1571).

 

CCPR: By prophylactic antibiotics, how long of a course are we talking about?

Dr. Greenberg: It should be individualized based on severity of symptoms, and on what the infectious disease specialist (who also prescribes it) recommends. That said, it is typically for a year or two after symptoms have remitted, and the antibiotics are sometimes suspended during the summer months, when strep exposures are less common. While there may be a few individuals with very severe symptoms on prophylactic antibiotics until age 18, that is not the norm.

 

CCPR: Which specific antibiotics are used?

Dr. Greenberg: There is limited research into this, but the three that are most often used are cephalexin (Keflex), amoxicillin/clavulanic acid (Augmentin), and azithromycin (Zithromax). They each have pros and cons. Cephalexin tends to be the most well tolerated with the least side effects, and it is the least likely to cause C. difficile infection. Amoxicillin/clavulanic acid is thought to potentially have strong neuro-modulating properties, which might theoretically be part of why it’s helpful—in addition to its antibacterial properties. Azithromycin is good because it targets both strep and mycoplasma (which is also commonly associated with PANS), but it is associated with QTc prolongation. And given that we might be using psychotropics, which also are associated with QTc prolongation, there’s a bit of an increased risk there.

 

CCPR: What’s your approach to treating the psychiatric component of PANDAS/PANS?

Dr. Greenberg: If the picture is very consistent with PANDAS/PANS, then we may try antibiotics and/or anti-inflammatories alone first and see if the symptoms resolve without other meds. But if there continue to be residual symptoms, I will often start with an alpha agonist if those symptoms are more in the tic/ADHD/irritability cluster. But if it’s a very clear-cut anxiety and/or OCD case, I will start an SSRI, such as sertraline (Zoloft), fluoxetine (Prozac), or escitalopram (Lexapro).

 

CCPR: What doses do you use?

Dr. Greenberg: I start very low because I have found that younger kids (and again, these patients are often 7 to 9) tend to be more prone to activation symptoms with SSRIs. For sertraline, for example, I might start as low as 6.25 mg for a few days, then increase to 12.5 mg, then to 25 mg. I’ve seen it floating around the Internet that one shouldn’t use SSRIs in children with PANS, but we have no hard evidence or studies on that. Many PANS patients have improved significantly with SSRIs. Sometimes the symptoms are quite severe, and it’s not so much OCD symptoms as severe rage episodes that are problematic. Parents will say that their children’s pupils appear dilated and that they’re in this fight/flight animal-like mode: clawing, screaming, hitting, growling—for up to an hour or two nightly. In those cases, I might temporarily give an atypical like Risperdal for the short term to help cool things down. Or, depending on what’s going on, if these are children who have never had a trial of antibiotics, I might give them a short course.

 

CCPR: So there’s no problem combining the psychiatric medications with the antibiotics?

Dr. Greenberg: No, there’s no reason to think that we can’t combine both and that they might be acting in different ways, as long as you are following QTc and other interaction effects. And I always add—or talk to parents about adding—cognitive behavior therapy (CBT).

 

CCPR: I’ve also heard that anti-inflammatories are used in PANDAS.

Dr. Greenberg: Yes, and regardless of whether the symptoms are clear-cut PANDAS/PANS, or if they’re more in that middle ground, people with PANDAS/PANS have anecdotally (but very strongly anecdotally) seen tremendous benefit from anti-inflammatories (NSAIDs). Often if a kid does have some symptoms consistent with PANDAS/PANS or even is having an OCD-type flare, I’ll try either child Advil (pediatric dosing) or Naprosyn (5–10 mg/kg bid) for 2–4 weeks before thinking about antibiotics. It’s one of those strategies that sounds odd, and I didn’t believe it until I saw it, but parents consistently report that the NSAIDs help, and that’s why we wonder if, in addition to an autoimmune component, this might be an inflammatory-related condition to some degree. And because NSAIDs are a relatively benign treatment, we will tell parents to use them almost like they would use a rescue inhaler—a 2-week course when needed. Again, though, given that there are known adverse effects of NSAIDs over time on the gut and kidneys, we advise parents to use them in short-term courses, and not in perpetuity.

 

CCPR: Any final thoughts?

Dr. Greenberg: I want to emphasize that I think it’s really important to stick to the guidelines and specific criteria when diagnosing a patient with PANDAS or PANS. Although many of the treatments we use are the same in children with typical OCD (psychotropics, CBT), the additional ones, including antibiotics, steroids at times, and so on, are not without their own risks, so we should be very discerning before suggesting those treatments.

 

 

Diagnostic Criteria for PANDAS and PANS

 

Although neither PANDAS nor PANS are in DSM-5, the following diagnostic criteria have been published and widely accepted by the medical community.

Pediatric Autoimmune Neuropsychiatric Syndrome Associated With Streptococcal Infection (PANDAS) (Swedo SE et al, Am J Psychiatry 1998;155:264–271)

I. Abrupt-onset OCD and/or tic disorder

II. Prepubertal onset

III. Acute onset + episodic course (relapsing/remitting, not waxing and waning)

IV. Association with neurological abnormalities (choreiform* movements, hyperactivity, handwriting changes)

V. Temporal relationship between symptom exacerbations and Group A hemolytic streptococcal (GAS) infection

* Editor’s note: Choreiform is different from the “chorea” that can accompany rheumatic fever; “choreiform” is thought to look akin to “piano-playing movements.”

 

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

(Chang K et al, J Child Adolesc Psychopharmacol 2015;25(1):3–13. doi:10.1089/cap.2014.0084)

I. Abrupt, dramatic onset or recurrence of OCD or restricted eating

II. Comorbid neuropsychiatric symptoms (at least 2), acute onset, severe

• A. New onset/severe escalation in anxiety (commonly severe separation anxiety)


• B. Sensory amplification to light, sounds, or smells, or motor abnormalities (deterioration in handwriting, choreiform movements, motoric hyper­activity, tics, etc)


• C. Behavioral (developmental) regression


• D. Deterioration in school performance


• E. Mood disorder: emotional lability, depression, irritability, rage*


• F. Urinary symptoms (urinary frequency, secondary enuresis)


• G. Severe sleep disturbances

III. Symptoms are not better explained by a known disorder (Sydenham’s chorea, SLE, Tourette’s disorder, etc)

* Editor’s note: You might want to also ask about rage attacks, a symptom often described by parents: no tantrums pre-illness, going to “severe animalistic rage for at least an hour with screaming, hitting, spitting, growling”—oftentimes with thoughts of calling the police.