What are the current guidelines for prescribing leucovorin (folinic acid) for treating autism?

Guidelines for Prescribing Leucovorin for Autism Spectrum Disorder

Leucovorin (folinic acid) should be prescribed for autism spectrum disorder patients who test positive for folate receptor alpha autoantibodies (FRAAs) or soluble folate binding proteins (sFBPs) at a dosage of 2 mg/kg/day (maximum 50 mg/day). 1, 2

Patient Selection Criteria

• Testing for folate metabolism abnormalities should be performed prior to initiating treatment, specifically:

  • Folate receptor alpha autoantibodies (FRAAs) 3, 1
  • Soluble folate binding proteins (sFBPs) 4

• Patients most likely to benefit from leucovorin therapy include:

  • Those with positive FRAA test results (found in approximately 71% of ASD patients) 1
  • Those with positive sFBP test results (associated with more severe ASD symptoms) 4
  • Patients with signs of cerebral folate deficiency (CFD) 5, 1

Dosing Recommendations

• Initial dosing: 2 mg/kg/day orally (maximum 50 mg/day) 2
• Administration: Daily oral administration 1
• Duration: Long-term treatment is typically required, with ongoing monitoring of response 5

Monitoring and Assessment

• Baseline assessment should include standardized measures:

  • Social Responsiveness Scale (SRS) for core ASD symptoms 3
  • Aberrant Behavior Checklist (ABC) for disruptive behaviors 3, 4

• Follow-up evaluations should assess:

  • Improvements in verbal communication 2
  • Changes in receptive and expressive language 1, 2
  • Attention and stereotypical behaviors 1
  • Irritability (particularly in patients with high binding FRAA titers) 3

Expected Treatment Response

• Response timeline: Significant improvements may be observed over approximately 4 months of treatment 2
• Response rate: Approximately one-third of treated FRAA-positive children demonstrate moderate to substantial improvement 2
• Higher binding FRAA titers are associated with greater treatment response 3

Potential Adverse Effects

• Generally mild adverse effects may include: 1
  • Aggression (9.5%)
  • Excitement or agitation (11.7%)
  • Headache (4.9%)
  • Insomnia (8.5%)
  • Increased tantrums (6.2%)

Clinical Considerations and Caveats

• Leucovorin bypasses the folate receptor alpha by using the reduced folate carrier pathway, allowing improved folate transport to the brain 5
• The presence of FRAAs correlates with cerebrospinal fluid 5-methyltetrahydrofolate concentrations 2
• Patients with sFBPs tend to have more severe ASD symptoms and may be medically complex 4
• Treatment with leucovorin has been shown to improve both core and associated ASD symptoms in controlled clinical trials 4, 1

Important Pitfalls to Avoid

• Do not initiate treatment without appropriate testing for folate metabolism abnormalities 3, 1
• Do not expect immediate results; treatment response typically develops over several months 2
• Do not discontinue treatment prematurely; long-term therapy is usually required 5
• Do not overlook monitoring for potential adverse effects, even though they are generally mild 1