Introduction

Folate, also known as vitamin B9, is crucial for a normal functioning body. This nutrient has several beneficial roles in the body, such as:

• Cell growth 
• Cell development 
• Red blood cell production 
• DNA formation 

Folate comes from leafy greens, nuts and beans. In someone with folate deficiency, their body does not receive enough folate from these sources or supplements. As a result,  they can experience symptoms of fatigue, weakness and neurological issues.¹

This article will focus on the effect of folate deficiency in the central nervous system (CNS), where it plays a crucial role in DNA synthesis and the production of neurotransmitters. It does so through its involvement in carbon metabolism for methylation processes, which is essential for neuronal development and brain function throughout life.

In folate deficiency, cognitive health is impacted due to developmental abnormalities, such as neural tube defects. This can lead to depression, dementia and overall cognitive decline. Cerebral folate deficiency (CFD) also affects pregnant women by putting the foetus at risk of severe complications of brain and spinal cord development. Therefore, early recognition is essential for CFD.¹

While this disease is rare, it presents a high risk of recurrent seizures in patients, of which refractory seizures are a key characteristic. These seizures are resistant to antiepileptic drugs and occur due to the multiple metabolic disruptions caused by CFD in the brain. In this article, we will cover how refractory seizures are managed in CFD.¹

Clinical Features of Cerebral Folate Deficiency

CFD can begin presenting symptoms in early childhood. A child may present symptoms after a time of normal development and these symptoms manifest progressively throughout childhood.²

 In early infancy (4-6 months), children with CFD may exhibit the following:²

• Problems with sleep 
• Irritability 
• Signs of slow development 
• Poor head growth 

Years 1-2 and above show more severe symptoms, such as:²

• Losing skills 
• Severe seizures 
• Severe loss of motor skills 
• Intellectual disability becomes more obvious 
• Involuntary movements 

Children between the ages of 3-6 years can experience prominent auditory and visual impairments.² These symptoms prove to be extremely challenging to balance alongside persistent refractory seizures. 

Pathophysiology of Refractory Seizures in CFD

To understand how refractory seizures occur during CFD, it is essential to examine the physiological processes involved.

Folate is transported through the blood-brain barrier using the folate receptor alpha (FRa). There are two main causes of impairment which can lead to folate deficiency:² 

• Autoantibody production: this is the most common cause and occurs when the immune system produces antibodies, which attach to the FRa. This blocks folate from attaching to the FRa, and so folate cannot be transported across the blood-brain barrier
• Metabolic disorders: e.g. mitochondrial disease, disrupts FRa function. This is because the FRa requires energy to transport folate across the blood-brain barrier. The mitochondria are responsible for producing the energy required, as a result, any disruption in the mitochondria affects the FRa's ability to be functional
• Genetic mutations can also impact the function of the FRa protein.  FLOR1 gene mutations produce abnormal or missing FRa proteins. This disrupts the transport of folate across the blood-brain barrier. However, this is a rare cause of CFD²

The disruption of folate entry into the brain impacts several key processes within the brain and brain cells. 

Myelin production is stunted when there is a lack of folate. Myelin is an essential insulating layer, or sheath, that covers nerve cells in the brain and spinal cord, which ensures nerve transmissions are rapid and efficient. Folate is a crucial building block for forming the myelin sheath and without this layer, electrical signal transmissions across nerve cells slow down. This can lead to loss of mental and motor abilities and make an individual more susceptible to refractory seizures.³

CFD also affects the synthesis of neurotransmitters, which are chemicals that allow for communication between neurons throughout the body. Folate is used for the synthesis of BH4,  a building block for the production of neurotransmitters such as dopamine and serotonin. As a result, there are low levels of the inhibitory neurotransmitter serotonin, and the brain remains in a state of excitability, meaning that the imbalance of neurotransmitters creates an environment for seizures.³

Over time, CFD can cause brain damage that can lead to seizures. 

• Structural damage and cell loss can produce abnormal electrical signals, which make seizures more frequent and less treatable by medication
• Folate helps the body produce antioxidants, which protect cells from damage by reactive oxygen species. Therefore, CFD causes oxidative stress around the brain and disrupts DNA repair, resulting in neuronal loss in the hippocampus, causing seizures³

Diagnostic Challenges

CFD is a challenging condition to identify. This is due to its range of presentations, rarity and the procedure of diagnostic techniques used. 

CFD symptoms greatly overlap with other neurological conditions, making it difficult to isolate. The majority of symptoms are shared with autism spectrum disorder and cerebral palsy. Furthermore, these symptoms may present later on in childhood, which can lead clinicians to focus on other developmental problems. 

The diagnostic testing itself is limited.³

• Serum folate testing tests for low folate levels in the blood. However, this result is unreliable as it does not account for the folate levels in the brain, so blood tests can give a false impression of normal folate levels
• The autoantibodies blocking the FRa can be tested to identify an autoimmune cause. Although a negative result does not rule out CFD entirely, it also does not account for genetic mutations or other mechanisms
• The best diagnostic tool for CFD is invasive cerebrospinal fluid (CSF) testing. This method uses a lumbar puncture procedure to measure the folate levels in the CSF. However, this is a very invasive procedure which can be stressful for pediatric patients and their parents. It often leads to reluctance or dismissing the procedure altogether

The limited diagnosis and overlapping symptoms often lead to misdiagnosis. 

Therapeutic Challenges in Refractory Seizures

Standard seizure drugs operate by reducing the release of excitatory neurotransmitters that exacerbate epilepsy. However, the refractory seizures in CFD occur due to defects in metabolism. The standard antiseizure medications (ASMs) do not include these factors. Therefore, a more holistic approach is required  to counteract refractory seizures in CFD.⁴

The key element of CFD is the lack of folate in the brain, which disrupts the metabolic pathways for neurotransmitters and myelin production. ASMs are ineffective here as they only suppress seizure activity, but do not correct the root cause. Additionally, some ASMs can worsen folate deficiency through metabolic interference. As a result, seizures can become more difficult to control and so  this limits the value of ASMs in refractory seizures of CFD.⁴

Patients can end up spending years on ineffective medications while their neurological symptoms worsen,  due to difficulties in diagnosis. A delayed start in targeted therapies can lead to irreversible neurological damage.⁴

Folinic acid is used to treat refractory seizures in CFD by replenishing low folate levels in the CNS. It does so by using an alternate pathway, not involving the defective FRa. While this treatment works theoretically, in reality, only some patients experience partial improvements in controlling seizures. Folinic acid is even less effective if neurological damage has already occurred. To combat this, folinic acid has been combined with standard ASMs and different diets to target specific refractory seizures.⁵  

The therapeutic response is entirely dependent upon the root cause of CFD, genetic or autoimmune. Immunotherapies are used to target the underlying autoimmune or genetic cause. 

• Intravenous immunoglobulin (IVIG) can be used to neutralise FRa autoantibodies through several mechanisms. They interfere with the production and function of antibodies
• Plasma exchange involves removing the blood plasma of the patient and replacing it with a substitute. However, this is a temporary removal of defective FRa antibodies⁴

Dietary therapies are prescribed alongside primary treatments. They are especially enforced in cases of autoimmune CFD. 

• Milk-free diet - dairy products can worsen autoimmune response. Eliminating milk can increase the effectiveness of folinic acid treatment
• Ketogenic diet - this forces the body to use ketones rather than glucose for energy. As a result, mitochondrial activity is enhanced and neuronal excitability is reduced
• Omega-3 fatty acids have anti-inflammatory effects which can influence brain signalling⁴

CFD is a lifelong condition that requires constant management and monitoring of folate levels. However, due to the rarity of the condition, there is a lack of standardised protocol for management. As a result, clinicians refer to specialists and evaluate each case individually.⁴

Future Directions

A combination of new technologies is being used to enhance CFD management. These endeavour to better understand the underlying mechanisms of CFD and create a personalised, targeted approach for individual patients. 

• Genetic and autoimmune causes will be tailored to. The FLOR1 gene will be targeted in genetic cases, and antibodies in autoimmune CFD. Clinicians will use this to create detailed profiles of each case, thus more effective immunotherapies
• Researchers have found that biomarkers can be used to monitor the effectiveness of treatments. This can be used to avoid repeating invasive procedures, such as a lumbar puncture, and using blood to analyse progress instead
• Adjunctive therapies involve using nerve stimulation to counteract seizure activity when metabolic and immunotherapy are not effective
• Gene therapies can correct the mutation in the FLOR1 gene. This could be a potential cure⁴

Conclusion

Cerebral folate deficiency represents a rare but important cause of refractory seizures, often posing significant diagnostic and therapeutic challenges. Standard antiseizure medications alone are inadequate, highlighting the need for early recognition and targeted interventions such as folinic acid supplementation. Delayed diagnosis can result in irreversible neurological damage, making timely evaluation critical. Multidisciplinary management, coupled with ongoing research into tailored therapies and standardised treatment protocols, is essential to improve long-term outcomes in affected patients.