Case Presentation:
The parents of your 4-year-old patient with Autism level 2 with verbal impairment comes in to ask about leucovorin and whether it will help their child speak.
Leucovorin, also known as folinic acid, is the active form of folate (vitamin B9). It is used in cancers that require specific types of chemotherapies and in certain genetic disorders that cause folate deficiency in the brain. Interest in its use in autism began when researchers found that some children with autism have autoantibodies against the folate receptor alpha (FRAAs), which can block folate transport into the central nervous system. This can lead to low cerebrospinal fluid (CSF) folate despite normal serum levels- a condition known as cerebral folate deficiency (CFD). CFD has been linked to neurological symptoms including irritability, movement abnormalities, and language impairment, which overlaps with symptoms seen in some individuals with autism.
The most commonly cited study is a randomized, double-blind, placebo-controlled study by Frye et al. (2018), which involved 48 children with autism and language impairment. Children who were FRAA positive and received leucovorin calcium at 2 mg/kg/day (max 50 mg/day) showed improvements in verbal communication over 12 weeks compared to placebo.
However, there are important caveats:
· Only children who were FRAA-positive showed significant improvement.
· FRAA testing is not easily accessible in clinical practice.
· The study was small, focused on males, and short-term. There has been no replication in large-scale trials and long-term safety remains unclear.
Leucovorin is not FDA-approved for the treatment of autism or language delay. There is ongoing discussion about its use in CFD, which can co-occur with autism but is not the same condition. There is currently no strong evidence that leucovorin can treat symptoms of autism. At this time, we do not recommend leucovorin as a universal treatment for autism. The AAP released an interim guidance: “At this time, the American Academy of Pediatrics (AAP) does not recommend the routine use of leucovorin (folinic acid) for autistic children.” The foundation of care remains behavioral and developmental therapies including ABA, speech therapy, and occupational therapy, which have demonstrated effectiveness and minimal risk.
We also do not recommend routine folate receptor autoantibody testing; this test is not validated, reliable, or covered by insurance. Additionally, we do not recommend testing for cerebral folate deficiency unless a child displays the symptoms typical for this disorder. Testing for cerebral folate deficiency is invasive, consisting of a lumbar puncture.
If your patients or their caregivers ask about leucovorin, a risk-benefit discussion may be helpful. One option could be enrolling in a research study. Otherwise, the cost of the medication would not be covered by insurance and would have to be paid out of pocket by families. Here are some points to consider in such discussions:
Potential Benefits:
· Some evidence of improved verbal communication only in FRAA-positive autism.
· Generally tolerated in short-term use.
Potential Risks:
· Long-term safety and effectiveness are not well studied.
· May cause hyperactivity or irritability, which may require discontinuation.
· No large trials to support use in the general autistic population.
· No guidelines on starting doses or titration schedules.
If You Decide to Prescribe After Shared Decision-Making
· Start low, go slow.
· Some studies have used 0.5–2 mg/kg/day (max 50 mg/day).
· Monitor closely for side effects and discontinue if symptoms worsen.
Back to our Case Presentation:
Prior to considering leucovorin, it will be important to review therapies and supports already in place, including autism intervention, speech therapy, and school-based services. It would also be important to review parents’ expectations about their child’s ability to communicate verbally and ensure their child has access to Augmentative and Alternative Communication devices.
Please call the SmartCare Behavioral Health Consultation Services at 858-880-6405 if you have a specific case you would like to discuss.
With Contributions by Dr. Hohui Eileen Wang (UCSF) and Dr. Will Connor (RCHSD)
References:
INSAR Public Statement – International Society for Autism Research
https://myemail.constantcontact.com/Cal-MAP-Clinical-Pearl–Leucovorin-and-Autism—Know-the-facts.html?soid=1136358974476&aid=fOmagiWxNiM
https://www.aap.org/en/patient-care/autism/use-of-leucovorin-in-autistic-pediatric-patients/?srsltid=AfmBOoqsvlDZJN1WxYZe7mrSlN-5YWGiD5-EcA_RKS27uTMZA3Sc3w-V
https://www.aap.org/en/pages/podcast/interim-guidance-on-leucovorin-25th-anniversary-of-pedialnk/?utm_source=MagnetMail&utm_medium=email&utm_term=MKG%5FPodcast%20Promotion&utm_campaign=POD%2DEpisodes%20269%2D270
AUTHOR:
Charmi Patel Rao MD, DFAACAP
Medical Director, Vista Hill Foundation
Voluntary Assistant Clinical Professor, UCSD Department of Psychia