Members of our Clinical and Scientific Advisory Board have graciously answered some of the most frequently asked questions.
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Laboratory tests guide treatment and help differentiate between PANS and PANDAS, however, there are no lab tests that determine whether or not an individual has PANS. PANS is strictly a clinical diagnosis.
Clinicians often order the following tests:
- Throat culture or culture of peri-anal region
- ANA titer
- ASO titer
- Anti-DNase B titer
- Lyme Western Blot in Lyme endemic areas
- Comprehensive Metabolic Panel
- Quantitative immunoglobulins (IGG, IGA, IGE, IGM)
Negative titers or negative strep culture do not rule out PANS, while positive lab values do not rule PANS or PANDAS in. Presence of strep simply distinguishes between PANS and PANDAS.
Individuals with PANS and PANDAS often have relapsing and remitting symptoms. Some are symptom free for months or years or may even have only one PANS/PANDAS episode. There is currently no cure for PANS and no treatment that helps all patients.
The first onset of symptoms often occurs between the ages of three and twelve. Diagnosis of PANS is not limited to a specific age range.
It is important to realize that criteria in both PANS and PANDAS was established primarily so that scientists could more quickly elicit answers by focusing on a relatively homogenous and well-defined group.
Yes. Autism and PANS/PANDAS are not mutually exclusive.
References from the literature for further reading:
Brown KD, Farmer C, Freeman GM Jr, Spartz EJ, Farhadian B, Thienemann M, Frankovich J. Effect of Early and Prophylactic Nonsteroidal Anti-Inflammatory Drugs on Flare Duration in Pediatric Acute-Onset Neuropsychiatric Syndrome: An Observational Study of Patients Followed by an Academic Community-Based Pediatric Acute-Onset Neuropsychiatric Syndrome Clinic. J Child Adolesc Psychopharmacol. 2017 Sep;27(7):619-628. doi: 10.1089/cap.2016.0193.
Risks and dosing recommendations for each type of NSAID are listed in Appendix A1 here:
Frankovich J, Swedo S, Murphy T, Dale R C, Agalliu D, Williams K, Daines M, Hornig M, Chugani H, Sanger T, Muscal E, Pasternack M, Cooperstock, et al. Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II—Use of Immunomodulatory Therapies. Journal of Child and Adolescent Psychopharmacology, Vol. 27, No. 7, 574-593. September 2017. doi: 10.1089/cap.2016.0148
For those with renal impact concerns or stomach sensitivities, celecoxib is typically used. However, some patients report that it is not as effective for pain and behavioral issues as other NSAIDS.
Reference from the literature for further reading:
Spartz E, Freeman GM, Brown K, Farhadian B, Thienemann M, Frankovich J. Course of Neuropsychiatric Symptoms after Introduction or Removal of Non-Steroidal Anti-Inflammatory Drugs: A Pediatric Observational Study. Journal of Child and Adolescent Psychopharmacology, Vol. 27, No. 7, July 2017, online ahead of print. PMID: 28696783. DOI: 10.1089/cap.2016.0179
In cases of relapse, the precipitating infection should be identified and treated first. Sometimes, particularly in harder to identify infections, a physical exam including the skin, perianal region, sinuses, and oral cavity should be performed. Patients who may either be embarrassed by or unaware of skin abscess or infection in the perianal regions may not volunteer that information without further questioning and exam.
Once the infection is treated, if the patient is still symptomatic and has not returned to a reasonable baseline, a course of steroid treatment may be considered if it is still early in the duration of the flare. NSAIDS may also be considered in lieu of steroids, depending on the severity of the flare.
After treating the infection and administering steroids, and the patient is improved but has ongoing residual anxiety, supportive therapy or psychiatric intervention may be beneficial for rehabilitation. If improvement is not realized from steroids, consideration to whether infection was fully treated or whether other treatments are needed should be considered as part of next steps.
Invariably, psychiatric symptoms may be worse while on the steroids so this should be considered in the risk/benefit analysis.
If the patient has had a positive response following a prednisone burst, but then symptoms re-escalate, consider giving another prednisone burst or an extended course. However, the risk/benefit ratio should be discussed (i.e. risk of weight gain, cataracts, worsening psychiatric symptoms, etc).
Psychiatric medications often have less risks than steroids. While on steroids, the patient may have life-threatening impulsivity, psychosis, etc. making steroids a poor option in older kids and teenagers.
References from the literature for further reading:
Brown K, Farmer C, Farhadian B, Hernandez J, Thienemann M, Frankovich J. Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic. J Child Adolesc Psychopharmacol. 2017 Sep;27(7):629-639. doi: 10.1089/cap.2016.0139.
The dosing of IVIg used by most clinicians ranges from 1g/kg to 2g/kg, with some capping the total dose at 70g. The most effective dose for PANS has not been determined yet through randomized clinical trials, so rheumatology protocols are typically used. Most IVIg protocols recommend dosing monthly for 1 – 12 months. In patients who clearly improve, but have breakthroughs at 3 weeks post-infusion, some centers have moved patients to an every 3 week regimen (temporarily).
If a new-onset case or relapse is treated rapidly, then often only 1 or 2 doses are needed. But if a child has a more long standing flare, then monthly IVIg may be needed: and in this case, the goal is to see a stair-step improvement. If, after 2-3 doses, only a transient improvement is observed, the patient will likely need additional therapies or IVIg may not be a good choice for that patient. If there is a stair-step improvement with each IVIg, then the goal would be to slowly space the infusions farther apart.
Some patients have significant improvement after IVIg while others do not. Identifying other diagnoses or symptoms, like arthritis or other autoimmune diseases can inform additional immunomodulation to be used in combination with IVIg or alone.
The decision to treat a patient with IVIg is often a judgment call on the part of the clinician, based on experience with that individual patient, the severity of their symptoms, and their response to prior treatments. For moderate to severe cases, a clinician may determine the best course of action is to proceed with IVIg. Although, typically steroids or NSAIDS are trialed before moving on to IVIg. If a patient has had prior relapses that did not respond to steroids or NSAIDS, but did respond to IVIg, then rapidly progressing to IVIg with a new relapse may be in the best interest of that patient.
Patients who are suspected to have unresolved infections or immunodeficiency may also benefit from IVIg more readily than other patients. Patients with a more classical PANDAS presentation may respond well to IVIg.
Clinicians have reported mixed responses to weekly subcutaneous Ig (SCig). For patients with frequent infections (and subsequent PANS flares), and meet criteria for an immune deficiency, such as IgG deficiency or CVID, it may be worth considering due to less significant side effects and less downtime overall and the ability to administer it at home. However, we do not think that the SCig will help resolve a major relapse, rather it is more about controlling infections and post-infectious responses. Some patients on SCig report worse PANS symptoms and/or more troubles with fatigue. While others report an improved trajectory, less relapses (and hence better recovery from the last relapse). Other patients have reported improvement in fatigue. Monthly high dose IVIg will have more anti-inflammatory/immunomodulatory effects then SCig and is the preferred administration for patients who are in a major relapse.
How long after you have IVIg should you wait to do the serologies if you forgot to have them done before?
Antibodies from IVIg will linger 3-9 months after a dose of IVIg. Thus titers for common infections (EBV, strep, HSV, parvo, HHV6, etc) will likely be positive and reflect what is in IVIg. However, overtime, these antibodies should be decreasing in titer. So if an antibody increases as time passes from the last IVIg, then this represents the patient’s endogenous production of that antibody.
Some autoantibodies are very common in the baseline population including thyroid antibodies, GAD antibodies, antibodies to nuclear proteins (i.e. the “ANA”). Thus, these will almost always be positive after IVIg.
If a patient gets aseptic meningitis from the IVIG, what can be done to avoid this with future infusions?
- Adjust infusion rate, and/or reduce the total dose and/or space the IVIg over more hours (often extending it over 2-5 days depending on the case).
- Increase hydration: Ask the patient to pre-hydrate and drink adequate low-sugar fluids during the infusion (targets should be established based on weight). In patients who tend to not be good at oral hydration, add in normal saline boluses pre- and post-infusion and sometimes mid-way through.
- NSAIDs can be started during the infusion and continued for 5 days after the infusion.
- If NSAIDs are not sufficient, then they can be REPLACED by corticosteroids (but not used concurrently). Different formulations can be used and may have differential tolerability/efficacy (e.g. IV vs. PO and methylprednisolone vs. dexamethasone vs. prednisone).
- Some clinicians have also found that adding furosemide at a low-dose decreases the severity of headaches for those patients who experience them as a side effect of IVIg. It is typically dosed at 0.25-0.5 mg/kg/dose with the first dose halfway through the total IVIg dose and a second dose at the end. For example, for an infusion given over 24 hours, one dose is given at hour 12 and the second dose is given at the end or hour 24. If the infusion is over two separate days, one dose would be given at the end of day one and the second dose given at the end of day two.
If a patient experiences improvement after a given number of rounds of IVIg, what steps should be considered next?
Usually, if there is a stair-step pattern, where the patient gets better after the infusion and then they begin to regress before the next infusion, but the net is positive, increasing the time between infusions may considered with the goal to eventually taper off IVIg (when the pre IVIg regression is minimal or gone)..
If a patient experiences bad side effects from the infusions, but still experiences a regression right before their next IVIg, then the spacing between infusions may be increased to see if the regression is limited.
Patients who are immune deficient and don’t want to be on SCig supplementation, but need IgG, may receive IVIg every 3-4 months as a high dose infusion to keep IgG above a minimum threshold (determined by the immunologist). In terms of what is used for immune modulation in lieu of IVIg, it depends on the other symptoms the child has. In those with arthritis, methotrexate, leflunomide, abatacept , or adalimumab are sometimes used by rheumatology.
The Stanford PANS clinic looks for arthritis very carefully, because ~ 30% of their cohort have been diagnosed with arthritis. If arthritis is found, treating it may help PANS symptoms. If no arthritis is identified, it is difficult to justify more aggressive immunomodulatory medications. Sometimes patients do well on maintenance NSAIDS, and the addition of sulfasalazine (mild immunomodulator) may help if they have symptoms adjacent to inflammatory bowel disease (IBD). They try to identify symptom/family history similarities to guide treatment when patients don’t meet a specific diagnosis.
If a patient has resolution of most of their PANS symptoms after they are treated, but continues to have difficulty with their emotional development or is not quite to baseline, would further treatment be useful?
This is an issue that can be challenging to parse out. Most, although not all, inflammatory brain disorders will cause brain injury, which can require a lot of rehabilitation, similar to a stroke. In addition, patients may have had underlying tendencies toward anxiety/OCD/depression and benefit tremendously from appropriate psychiatric therapies.
On the other hand, there may be ongoing inflammation in patients who do not get to baseline after treating infections and modulating the immune system. Keep in mind that many psychiatric therapies have anti-inflammatory effects so using standard of care for the residual symptoms (anxiety, OCD, etc) is still the recommended path.
If the patient has ongoing psychiatric symptoms without the typical response to psychiatric interventions, then another look at infections and systemic inflammation should be pursued (using standard of care). Be aware that, based on statistics, if one orders broad infection and autoantibody screening, 1 in 10 tests will be falsely positive since this is how the sensitivity of 90% is set for most tests. So choose further testing judiciously so as to not put the patient on a path of over-medicalization and overuse of antibiotics.
Keep an open mind to identify any emerging comorbid arthritis, autoimmune or inflammatory disease through the child’s life course, especially teenage girls since they are more likely to develop autoimmune diseases in general.
Some ways that ongoing inflammation may be seen include enteritis and arthritis. Even if a patient does not report pain or GI troubles, either because their communication is lacking or because their body symptoms are overshadowed by their mental anguish, further questioning and sometimes further non-invasive investigations (if risks outweigh benefits) are warranted. For example, they may be stiff and achy in the morning or after long car rides and not realize that it is not normal. This has been observed in teenagers by some clinicians, who did not realize they had arthritis because it developed slowly over time. Asking the parents to observe the patient getting out of bed (or the car) and taking their first steps can be helpful. Many of our patients have “dry arthritis” meaning that the arthritis is difficult to see on a physical exam. In this case, ultrasound of the joints can detect the “dry” arthritis by showing synovitis or capsulitis. Unfortunately, ultrasound is a limited resource for children and not widely available. MRI of joints can also be helpful but more challenging for kids with anxiety and other psychiatric symptoms.
In addition, untreated IBD could contribute to ongoing inflammation. A patient may deny GI symptoms, but when shown pictures of different types of stool, it may be clear that they have constipation, diarrhea, or both. Stool testing would then be indicated and the results of that may warrant endoscopy. It is important to note that the kind of arthritis the Stanford PANS research has most often identified has significant overlap with the arthritis associated with IBD.
Lastly, treating folic acid receptor antibodies can be very beneficial to some patients.
Once a flare has passed and the patient is mostly symptom free for a year or more, what supportive immunologic steps should then be taken?
It is typically advised to not irritate the immune system unnecessarily. In many rheumatological diseases, if a patient goes into remission, the approach is to maintain remission with immune calming medications for 1-2 years in order to prevent relapse. However, this has not been established for PANS.
Some patients with PANS can still experience relapses after being in remission for multiple years, which is hard. To prevent relapses, patients should be up-to-date on vaccines to prevent serious infections which can cause flares. Vaccines should be spaced and given in the summer when possible. Multiple vaccines on the same day, or illnesses in combination with vaccines, can be problematic.
The most important thing for patients is to be aware of their symptoms so they can seek help quickly, which is where psychotherapy can be very useful. Intervening before a relapse becomes entrenched can allow for less aggressive interventions and earlier, more robust recoveries. Psychotherapy can help address symptoms during flares but also help increase insight into symptoms to allow for earlier recognition of future flares.
Some clinicians report that they have a subset of patients who appear to experience symptoms of mast cell activation. However, Mast Cell Activation Syndrome is difficult to diagnose and generally requires endoscopic biopsies and time-sensitive urine and blood testing. In this situation, patients will have excessive histamine response to some trigger, so urine histamine will be elevated when they are very symptomatic. These patients can respond positively to layered antihistamine treatment. Whether mast cell activation is part of the immune dysregulation in some PANS patients or due to a different mechanism is not currently known.