One of the most important—and often polarizing—questions in the treatment of chronic vector-borne infections is this:
Why do some patients continue to experience anxiety, OCD, depression, cognitive dysfunction, executive dysfunction, sensory sensitivities, mood instability, and other neuropsychiatric symptoms long after treatment begins?
Some clinicians argue these symptoms are primarily driven by ongoing infection and the inflammatory response generated by the immune system's efforts to control it.
Others believe the infection serves as a trigger, setting off autoimmune processes that continue to affect brain function long after the initial infectious insult.
In my experience, the answer is rarely one or the other.
For many patients, both processes appear to be occurring simultaneously.
Active infection can continue to drive inflammation and immune activation while, at the same time, triggering secondary autoimmune mechanisms that create their own symptoms and require their own treatment approach.
A newly published study, Folate Receptor Alpha Autoantibodies in Vector-Borne Diseases: Implications for Neuropsychiatric Symptoms and Cerebral Folate Deficiency, by Lindsey Wells, Richard I. Frye, Joseph Burrascano, and colleagues, provides evidence for one such autoimmune mechanism. The study examined the prevalence of folate receptor alpha autoantibodies (FRAAs) in patients with Borrelia, Bartonella, and Babesia infections and raises important questions about the role of infection-triggered autoimmunity in persistent neuropsychiatric symptoms. Readers can access the full study here: https://www.mdpi.com/2079-9721/14/6/202.
Most importantly, the study identifies a potentially treatable autoimmune mechanism that may contribute to neuropsychiatric symptoms in a substantial subset of patients with vector-borne infections.
One Example of Infection-Triggered Autoimmunity
The study investigated folate receptor alpha autoantibodies (FRAAs), antibodies directed against the receptor responsible for transporting folate across the blood-brain barrier.
When these antibodies develop, folate transport into the brain can become impaired despite normal blood folate levels. The result is a condition known as cerebral folate deficiency (CFD).
This is important because folate plays a critical role in:
- Neurotransmitter production
- Dopamine and serotonin synthesis
- Methylation
- Mitochondrial function
- Neurodevelopment
- Neuroimmune regulation
When folate delivery to the brain becomes impaired, patients can develop a wide range of neurological and psychiatric symptoms.
In this sense, cerebral folate deficiency represents one example of an infection-triggered autoimmune encephalopathy—a condition in which infection initiates an immune response that subsequently interferes with normal brain function. While there are undoubtedly multiple mechanisms through which vector-borne infections affect the brain, this study highlights one pathway that is measurable, biologically plausible, and potentially treatable.
What the Researchers Found
The investigators evaluated 68 patients with confirmed vector-borne infections and tested them for folate receptor alpha autoantibodies.
The results were striking:
- 61.8% of patients were positive for FRAAs.
- FRAA-positive patients were approximately three times more likely to carry a diagnosis of PANS/PANDAS.
- A subset of patients tested positive for soluble folate receptor (sFR), a marker that may further impair folate transport.
- Among patients with detectable sFR, 87.5% had evidence of Borrelia infection.
The study cannot prove that Borrelia, Bartonella, or Babesia directly cause folate receptor autoimmunity. However, it does suggest that autoimmune disruption of folate transport may be far more common in patients with vector-borne infections than previously recognized.
Why This Matters Clinically
The significance of this study is not simply that another laboratory marker was identified.
The significance is that it provides evidence for one specific autoimmune mechanism that may contribute to persistent neuropsychiatric symptoms in patients with vector-borne infections.
For years, clinicians have observed patients whose symptoms could not always be fully explained by active infection alone. At the same time, many patients clearly improve as infectious burden is reduced and inflammation decreases.
This has fueled an ongoing debate within the vector-borne disease community:
Are persistent symptoms driven by ongoing infection and inflammation, or by autoimmune processes triggered by infection?
This study suggests that the answer may be more complicated than either side of the debate often acknowledges.
In many patients, infection and autoimmunity may coexist.
Infection may continue to drive inflammation and immune activation while simultaneously triggering downstream autoimmune processes that create their own symptoms and require their own treatment strategies.
FRAA-associated cerebral folate deficiency may be one example of that phenomenon.
A Potential Therapeutic Opportunity
One reason these findings are especially important is that cerebral folate deficiency is potentially treatable.
Folinic acid (leucovorin) bypasses some of the transport limitations created by folate receptor autoantibodies and has demonstrated benefit in other FRAA-associated conditions, including autism spectrum disorder, treatment-resistant depression, schizophrenia, and PANS/PANDAS.
Importantly, addressing cerebral folate deficiency does not replace treatment of the underlying infections.
Rather, it may provide an opportunity to address one of the downstream consequences of infection-triggered immune dysfunction while continuing to treat the infectious drivers themselves.
In my own clinical experience, folinic acid can sometimes provide a meaningful shortcut to improving neuropsychiatric symptoms while the longer process of treating Borrelia, Bartonella, and Babesia continues.
For some patients, the results can be profound. Improvements in cognitive function, emotional regulation, executive functioning, anxiety, OCD symptoms, and overall quality of life can occur more rapidly than would be expected from antimicrobial treatment alone.
At the same time, folinic acid is not universally beneficial.
Some patients experience little improvement.
Others develop increased agitation, irritability, hyperactivity, or sleep disruption that requires dose adjustment or discontinuation.
Like many interventions in complex chronic illness, response is highly individualized.
Nevertheless, the remarkably high prevalence of FRAAs identified in this study strengthens the case for considering a trial of folinic acid in patients with Borrelia, Bartonella, or Babesia infections who are struggling with cognitive, behavioral, emotional, or psychiatric symptoms—particularly when progress has plateaued despite ongoing antimicrobial treatment.
The Bigger Picture
The most important contribution of this study may be that it moves the conversation beyond the false dichotomy of infection versus autoimmunity.
For many patients, the reality is likely both.
Infection can trigger inflammation.
Inflammation can trigger autoimmunity.
Autoimmunity can create new mechanisms of dysfunction that persist alongside the infection itself.
Importantly, identifying FRAA-associated cerebral folate deficiency does not necessarily answer the question of whether infection persists. Rather, it identifies one potentially modifiable consequence of infection-triggered immune dysfunction that may be contributing to symptom burden regardless of where a patient falls on the ongoing infection-versus-autoimmunity spectrum.
For clinicians treating patients with vector-borne infections, the question may not be whether symptoms are caused by infection or autoimmunity, but rather which combination of infectious, inflammatory, and autoimmune mechanisms is contributing to a particular patient's presentation.
This study provides evidence for one specific example of that process—and one that may offer a practical therapeutic opportunity for patients struggling with persistent neuropsychiatric symptoms associated with Borrelia, Bartonella, and Babesia infections.