Table A2.

Use of Corticosteroids in Pediatric Acute-Onset Neuropsychiatric Syndrome

Indications: Used to abort PANS flare. If used early in disease course, it can abort or shorten flare duration and theoretically minimize vascular and tissue inflammation/damage (Brown et al. 2017a). Introduction of corticosteroids late in the flare is less likely to result in dramatic responses and will require higher doses or more prolonged courses. If patient has longstanding untreated disease, a chronic-static, or a chronic-progressive course, a longer course of corticosteroids (oral burst+taper or weekly/monthly pulsing±adjunct immunotherapy) will be needed. More sophisticated brain imaging techniques are needed to help clinicians definitively determine presence of neuroinflammation; but in the absence of this technology, corticosteroid trials can guide the clinician in determining whether inflammation is playing a role in a brain disorder. If the child's symptoms improve in the weeks after an adequate corticosteroid trial (dosing based on disease trajectory and severity, Table 3), this suggests that inflammation may be driving the psychiatric symptoms.

Administration: Take with food, milk, or antacid to decrease GI adverse effects. Ensure adequate vitamin D levels and adequate consumption of calcium. Consider calcium and vitamin D supplementation.

Precautions: Corticosteroids should be used with caution and only in the setting wherein caregivers can manage likely escalation in psychiatric symptoms. Rapid withdrawal of steroids can cause pseudotumor cerebri and other headache syndromes. Corticosteroid-induced hypertension can cause headaches. Combination of NSAIDs and corticosteroids may lead to gastritis.

Psychiatric/behavior side effects: Temporary increase in obsessive-compulsive symptoms, tics, irritability, rage, psychosis, emotional lability, depressed or fluctuating mood, behavior regression, insomnia, life-threatening impulsivity, and behavioral outbursts can occur while the corticosteroids are in the body. Symptoms resolve rapidly in the days after a short course (i.e., 5-day oral prednisone burst) but take longer to resolve when a prolonged course is given (i.e., prednisone burst+taper) or when high-dose corticosteroids are used (i.e., oral dexamethasone pulse or IV methylprednisolone pulses described hereunder).

Physical side effects that occur with prolonged courses, frequent oral prednisone bursts, or high-dose corticosteroids: Temporary effects may include blurry vision, weight gain, Cushingoid appearance, altered glucose metabolism, dyslipidemia, and hypertension. Temporary effects resolve in the weeks to months after cessation of corticosteroids. Time to resolution of these temporary side effects is proportional to duration of time on corticosteroids and intensity of dosing (i.e., the more saturated the body, the longer it will take to normalize). Permanent effects may include cataracts, glaucoma, bone infarcts, osteopenia, type-2 diabetes, hypertension, and striae. IV methylprednisolone infusions can cause hypertension or hypotension, tachycardia or bradycardia, blurry vision, flushing, sweating, and metallic taste in mouth. Weekly or monthly corticosteroid pulses (see hereunder) are thought to have fewer physical side effects as compared with prolonged oral prednisone courses.

Monitoring: If prolonged courses, frequent bursts, or high-dose corticosteroids are used, the following should be considered: periodic ophthalmological examinations to evaluate for cataracts and glaucoma, imaging of painful limbs to evaluate for avascular necrosis of bones and/or referral to orthopedics, assessment/precautions for osteopenia, HbA1C, routine blood pressure monitoring, and periodic assessment of dyslipidemia.

Mechanisms: Potent anti-inflammatory and immunosuppressive effects through multiple mechanisms, including down regulation of cytokine gene expression in leukocytes and down regulation of leukocyte adhesion molecule gene expression in endothelial cells (thus inhibiting adhesion-dependent leukocyte migration from the vascular space into extravascular tissues).

	Purpose	Dosing
Low dose burst Oral prednisone burst	Fast acting and effective if used early in a flare and if patient has good baseline functioning. Strategy is the same as in asthma.	1–2 mg/kg·day of prednisone or prednisolonea (given once daily, or divided twice a day, maximum 60–120 mg daily) for 5 days.
Prolonged course Oral prednisone burst+taper	Can improve baseline functioning in patients with chronic-static symptoms.	1–2 mg/kg·day prednisone or prednisolone (given once daily, or divided twice daily, maximum 60–120 mg daily) for 5–10 days; then taper for 4–8 weeks. Long-standing disease requires longer tapers.
	Taper helps minimize risk of symptom recrudescence after burst completion and/or allows time for other steroid-sparing agents to take effect.	Taper strategy: decrease current dose by 10%–25% every 3–7 days such that the large step-down doses occur early in the taper, and the tail of the taper is prolonged. See the following for specific example of a taper.b
Intermediate dose pulse Oral dexamethasone pulse	This strategy is considered more aggressive than the oral prednisone burst but less aggressive than IV methylprednisolone pulse.	20 mg/m2·day divided twice daily for 3 days. If patient has response but then recrudesces (especially if patient has had long-standing disease), it will need to be repeated monthly±adjunct therapy (Table 4).c
	Intermittent pulsing may have fewer physical side effects than prolonged oral prednisone courses.	Maximum dose ranges from 9 to 16 mg/day for treatment of asthma to 30 mg/day for treatment of MS. For treatment of an acute exacerbation of MS, 30 mg/day for 1 week followed by 4–12 mg/day for 1 month.
High dose pulse Intravenous methylprednisolone pulse	Fast acting in moderate-to-severe cases to achieve an immediate, profound anti-inflammatory effect and to minimize toxicity related to long-term continuous therapy in moderate to high daily doses.	15–30 mg/kg·dose (maximum 1000 mg/dose ·24 hours). 30 mg/kg·dose is the preferred dosage for treatment of most inflammatory brain diseases.
	Intermittent pulsing to treat moderate to severe flares can quickly abort psychiatric symptoms.	For severe long-standing PANS, 3–5 daily pulses are used during induction treatment or once weekly dosing for 6 weeks to test whether disease is immuneresponsive. If there is no response to this aggressive approach or the response is not sustained, then immunomodulatory therapy is aborted.
	Repeated weekly pulsing can improve baseline of chronic-static cases with presumably fewer side effects than prolonged oral tapers.	For other inflammatory brain diseases, 3 daily pulses are used during induction treatment and then one pulse is given once monthly with adjunct therapy (typically cyclophosphamide or MMF).

^a If liquid formulation is desired, use prednisolone because it tastes better and is more readily available as compared with prednisone.

^b For example: 30 mg BID for 5–10 days; then step dose down every 3–7 days according to the following: 30 mg in AM/20 mg in PM; 30 mg in AM/10 mg in PM; 30 mg in AM only; 25 mg in AM only; 20 mg in AM; 17.5 mg in AM; 15 mg in AM; 12.5 mg in AM; 10 mg in AM; 7.5 mg in AM; then 5 mg in AM. Many patients start having recrudescence after tapering <15 mg, so further taper may have to be suspended until after another agent (e.g., IVIG) is initiated.

^c This approach was derived from a protocol used to treat opsiclonus-myoclonus syndrome, which is a presumed CNS autoimmune disease in children (Rostasy et al. 2006).

CNS, central nervous system; GI, gastrointestinal; HbA1C, hemoglobin A1C; IV, intravenous; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MS, multiple sclerosis; NSAIDs, nonsteroidal anti-inflammatory drugs; PANS, pediatric acute-onset neuropsychiatric syndrome.