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Evidence Supporting Use of IVIG
in Moderate to Severe Cases

In moderate to severe cases, intravenous administration of immunoglobulins (IVIG) has been shown, in placebo-controlled trials, to significantly decrease (>60%) symptom severity and shorten the course of illness in PANDAS Perlmutter et al, Lancet 1999; and PANS/PANDAS (KA Williams, SE Swedo, CA Farmer, et al.Journal of the American Academy of Child & Adolescent Psychiatry 2016). IVIG currently has FDA indications for the treatment of Kawasaki disease, idiopathic thrombocytopenic purpura (ITP), and other immune-mediated diseases of childhood. 

In addition to the double-blind trials conducted at NIH, further support for the benefits of IVIG are provided by a small number of published case reports and shared clinical experiences (Kovacevic M, Grant P, Swedo SE. J Child Adolesc Psychopharmacol. 2015;25(1):65-69).  Reports from multiple clinicians confirm symptom improvements that are comparable to those demonstrated in the placebo-controlled trial Pavone P, et al. NeuroSci. 2020; 1(2):75-84.

IVIG has not shown efficacy for patients with Tourettes or with classic OCD that does not fit the PANS/PANDAS criteria (Szejko N, et al.. Front Neurol. 2020 Feb 28;11:110., Nicolson R,  et al. J Am Acad Child Adolesc Psychiatry. 2000 Oct;39(10):1313-5).

Number of Infusions

The number of IVIG treatments varies due to patient response, dosage, and other variables. Some patients have significant improvement with a single dose while others do better with multiple treatments.

In a blinded placebo controlled trial, a single course of high-dose IVIG was sufficient to produce significant and sustained improvements in symptoms and in some cases to have a complete remission of symptoms Perlmutter et al, Lancet 1999

In another trial, 1 infusion or 2 infusions sufficiently separated were needed for significant improvement (KA Williams, SE Swedo, CA Farmer, et al.Journal of the American Academy of Child & Adolescent Psychiatry 2016).

Recent open-labeled studies of multiple monthly or quarterly infusions of IVIG for PANS/PANDAS have been reported with positive benefits (Melamed, Isaac et al. Journal of child and adolescent psychopharmacology vol. 31,2 (2021): 118-128, Hajjari P, et al.. BMC Psychiatry. 2022 Aug 6;22(1):535.)

Research is ongoing as are current clinical trials.

When to Consider IVIG for Your PANS/PANDAS Patient

Since IVIG is made from pooled human donor blood products, it carries risk.  This risk must be considered as part of the “risk-benefit” analysis whenever IVIG therapy is recommended. In addition, unlike a manufactured drug, IVIG has inherent variability as it is a pooling of immunoglobulins from thousands of donors. For example, batch #1 may have IgG-specific antibodies to pathogen A, while batch #2 may have none. Whether IVIG operates by providing antibodies or by suppressing host antibodies is unknown.

For moderate to severe cases of PANS/PANDAS where the child’s symptoms are causing significant impairment in daily functioning, immunotherapy, including IVIG, should be strongly considered given the improvement seen in trials (see PANS/PANDAS treatment flowchart and JCAP treatment protocol).

Patients with immunodeficiencies should consult with their immunologists to develop the appropriate treatment protocol for the patient’s unique needs.

Setting Expectations for IVIG Treatment

Symptom relief in clinical reports had a wide range of timelines. In a minority of cases, the response of remission is as sudden and dramatic as the initial symptom onset. More often, it is a gradual process over a few weeks. Most report improvements in 3 to 4 weeks and others having a delayed response at 8 to 12 weeks after infusion. Relief tends to be step-wise, with periods of improvement interspersed with periods of continuing symptoms; at first, the child might have a good hour or two, and then the periods of remission get longer until there are good days and bad days. 

The clinical trials report an average improvement of ~60% (with some having full remission but most having residual OCD symptoms). While we seek a treatment that returns the child to baseline, it is important to set expectations.  It is likely there will be residual OCD symptoms and these are best treated with cognitive behavioral therapy and potentially low-dose SSRI.

Relapse and Remission

Many patients do  suffer relapses post IVIG although usually not at the level of anxiety or intensity seen prior to IVIG treatment. IVIG failures often occur because the patient was suffering from an infection causing an immune response either at the time of IVIG or within a few weeks of the infusion  (see antibiotic prophylaxis section).

Interviews with the patients who participated in the original IVIG trial have shown sustained improvements and are healthy. However, some have reported recurrence when infected with a pathogen, like Group A strep, but are able to inhibit a full onset of symptoms by using antibiotics.

IVIG Treatment Protocol

The dose used in the NIH trials was 2 grams/kg of child’s weight (1 gm/kg per day for 2 days). Based on calculated blood volumes, some have suggested that the dose could be reduced to 1.5gm/kg (750 mg/kg per day x 2 days). However, there is no scientific evidence that either is more beneficial. The maximum dosage of IVIG is 100 gm/day (total dose over 2 days equals 200 gm).

Administration of IVIG at the NIH Clinical Center
was done according to the following procedure:

1. Laboratory confirmation that the patient is not IgA deficient (see rare adverse effects below)

2. Insertion of indwelling intravenous catheter (topical anesthetic cream used to minimize discomfort of the needle stick)

3. Premedication with acetaminophen and diphenhydramine (30 minutes prior to start of infusion)

a. Acetaminophen 10-15 mg/kg single dose given orally 30 minutes prior to IVIG infusion
Available in 80 mg chewable tables, 100 mg/ml oral drops, 160 mg/5 ml suspension
Dose based on weight will be calculated by LIP and rounded to nearest convenient dose within 10-15 mg/kg dosing range based on formulation chosen, ordered individualized for the particular subject, not more than 650 mg total dose.Acetaminophen 10-15 mg/kg single dose given orally 30 minutes prior to IVIG infusion
b. Diphenhydramine given orally along with acetaminophen 30 minutes prior to IVIG infusion. Available in elixir 12.5 mg/5 ml, capsules 25 m. Children less than 20 kg will receive 12.5 mg. Children over 20 kg will receive 25 mg.

4.Prior to start of infusion, nursing will:

a. Obtain and record baseline vital signs
b. Verify emergency supplies on hand
c. Inform subject and family member (who will remain at bedside) of symptoms of concern (see monitoring below)

5. Monitoring guidelines:

a. Vital signs will be measured each 15 minutes from baseline until final rate escalation. Thereafter, vital signs will be measured every 15 minutes times 2, and then every 30 minutes, and more often as indicated, until end of infusion, and then at end of infusion.
b. If any of the following occur, the infusion rate should be immediately decreased by 50%: Temperature more than one degree Celsius increase from baseline, or chills, Nausea or vomiting, Pain in joints, muscles, or back, palpitations, “dizziness”, diaphoresis, itching, rash, flushing, headache

6. The following will dictate immediate cessation of infusion:

a. Fall in systolic blood pressure to less than 70 mm plus 2X age of subject, or to less than 90 mm if subject is greater than or equal to 10 years
b. Shortness of breath, dyspnea, respiratory distress
c. Urticaria, edema of eyelids, lips, or tongue
d. Chest tightness, tachycardia (heart rate more than 25% over baseline)

7. Infusion rates: Under ideal circumstances (if no symptoms as listed in #5 or #6 above occur)

a. 0.6 ml/kg/hour for first 30 minutes, then
b. 1.2 ml/kg/hour for 15 minutes, then
c. 2.4 ml/kg/hour for 15 minutes, then
d. 3.6 ml/kg/hour for 15 minutes, then
e. 4.8 ml/kg/hour thereafter until infusion complete

8. If symptoms as listed above (5) do occur, then infusion rate will be held at the rate of 50% of the highest rate previously achieved. Clinician will calculate specific rates for particular subject based on weight, and nursing orders will be individualized.

Side Effects

Mild to severe headaches (including picture comparable to aseptic meningitis where headache worsens with sitting or standing and improves when patient is lying down), nausea and vomiting, fever.

Side effects can be treated with standard palliative medications (such as acetaminophen or ibuprofen for headache or fever). If side effects are severe, anecdotal reports support the use of a single dose of steroids (prednisone) to rapidly quell the adverse events.

Rare Side Effects

  • Individuals with severe selective IgA deficiencies have a risk of immediate hypersensitivity reactions including anaphylaxis; therefore, IgA deficiency is a contraindication to IVIG administration.
  • Anaphylactic reactions have been seen rarely even in subjects without IgA deficiency who receive IVIG. These can be partially prevented by pre-treatment with diphenhydramine (Benadryl).
  • An aseptic meningitis-like illness (including CSF pleocytosis) has been reported to occur rarely after IVIG infusions. The syndrome is easily recognized, and standard therapies are effective in reducing headache and discomfort. No long-lasting sequelae have been reported.
  • There is the risk of transmission of occult infectious agents including viruses, the CJD agent, and presently unknown agents of disease.
  • IVIG can contain blood group Abs which may cause positive direct antiglobulin reactions and rare hemolysis, leading to anemia. Other adverse events have been reported rarely in the post-marketing period, including Stevens-Johnson syndrome.
  • Transmission of occult infections. Prior to the advent of testing for Hepatitis C, there were lots of IVIG that contained the virus, and patients receiving those infusions developed chronic Hepatitis C. IVIG is carefully screened for known pathogens.

Lab Side Effects

Transient elevations less than three times the upper limit of normal have been seen in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Direct Coombs (antiglobulin) tests have become positive temporarily.