Endoscopic corpus callosotomy for drug-resistant epilepsy due to cerebral folate transporter deficiency: illustrative case

Abstract

BACKGROUND

Cerebral folate transporter deficiency (FOLR1-related CFTD, MIM #613068) is a rare, autosomal recessive neurological disease characterized by markedly deficient CSF folate levels arising from impaired transport of folate across the blood-brain barrier. Current research highlights the role of folinic acid in treatment for patients with CFTD. To date, there has been minimal published evidence on seizure management for CFTD patients whose conditions are refractory to folinic acid treatment, and there are no standardized approaches for guiding care in this subset.

OBSERVATIONS

The authors report a successful clinical outcome after corpus callosotomy in a patient with drug-resistant epilepsy (DRE) secondary to folinic acid–refractory CFTD.

LESSONS

This case represents the first documented surgical treatment for DRE in this patient population. Intracranial epilepsy surgery might play an important role for managing DRE in this patient population in the future.

https://thejns.org/doi/10.3171/CASE25793

Cerebral folate transporter deficiency (FOLR1-related CFTD, MIM #613068) is a rare,¹ autosomal recessive disease characterized by markedly deficient CSF folate levels from impaired transport of folate across the blood-brain barrier.² It presents as ataxia, cerebellar atrophy, global delay, cerebral hypomyelination, and/or epilepsy within the first 3 years of life and can lead to severe neurological regression if left untreated.^3,4 Seizures in CFTD are often a prominent and early feature of the disease course and are believed to arise from a folate-dependent metabolic imbalance in the production of inhibitory neurotransmitters.^3,5 Current literature highlights the role of high-dose folinic acid for treating patients with CFTD and suggests that antiseizure medications (ASMs) offer little to no efficacy for seizure control in this population.^1,3,6 To date, there is minimal published research on seizure management for CFTD patients whose conditions are refractory to folinic acid treatment.

Corpus callosotomy (CC) is a neurosurgical technique for drug-resistant epilepsy (DRE) whereby the corpus callosum is mechanically or thermally severed to disrupt interhemispheric communication and interrupt seizure propagation. The most typical indication for CC includes generalized DRE in the absence of a resective seizure focus and is most effective at reducing drop seizure burden.⁷ We report the case of an 8-year-old female with DRE secondary to CFTD who experienced near–seizure freedom 3 months after undergoing CC. This case shows the potential for cranial epilepsy surgery as a treatment option in CFTD patients who do not respond to folinic acid.

Illustrative Case

A 4-year-old girl presented to our genetics clinic with symptoms of regression, global developmental delay, and uncontrollable seizures. She was reported to be developing normally until the age of 2 years, when she began experiencing up to 50 daily episodes of full-body shaking, flexion, sudden atony, startling at loud noises, and staring spells with drooling. Prior to presentation, she was able to babble words, but by age 2 years had progressively lost her ability to speak, nonverbally communicate, and independently ambulate. After a year of failed medication treatment for her epilepsy including topiramate, levetiracetam, and vigabatrin, she underwent vagus nerve stimulator implantation surgery and electrical dosing optimization at another hospital at 3.5 years of age, with no clinical improvement.

The patient underwent genetic testing via a sponsored epilepsy gene panel, which detected compound heterozygous variants of uncertain significance in FOLR1, c.415T>C (p.Cys139Arg); c.726G>A (p.Trp242*), raising suspicion for CFTD. Lumbar puncture revealed a CSF 5-methyltetrahydrofolate level of less than 10 nmol/L and a normal plasma folate level of 4.9, confirming the diagnosis.

The patient began daily enteral folinic acid (2.2 mg/kg/day) and cannabidiol for seizure control and began additional weekly intravenous (IV) folinic acid infusions (5 mg/kg/day) 1 week after starting enteral therapy.^3,4,8 After 1 month of folinic acid therapy, her seizure burden was dramatically reduced from 50 episodes to 2 episodes daily. After 4 months of IV folinic acid therapy, repeat laboratory tests revealed a persistently low CSF 5-methyltetrahydrofolate level of 31 nmol/L, prompting an increase in her enteral and IV infusions to 6 and 10 mg/kg/day, respectively. After 6 months of folinic acid therapy, the patient continued having about 5–6 seizures a day and demonstrated improved communicative ability (previously was saying “no” consistently nonverbally), more frequent wheelchair ambulation, and increased socialization prior to folinic therapy.

Thirteen months after initiating folinic acid treatment, her mother reported an increase in seizure burden to about 15 atonic drop seizures daily. Figure 1 demonstrates an electroencephalogram with continuous multifocal and diffuse epileptiform discharges, absence of a posterior dominant rhythm, and several brief events correlated with abrupt head/truncal flexion, consistent with generalized atonic seizures. Figure 2 demonstrates brain MRI with diffuse cerebral and cerebellar volume loss, hypomyelination and high T2/FLAIR signal in the thalami, findings consistent with CFTD^3,8,9 and signaling progression of her disease.

FIG. 1.

Electroencephalogram showing drop seizure as well as multifocal and diffuse interictal epileptiform discharges (sensitivity 15 μV/mm).

FIG. 2.

Axial T2-weighted (A), axial FLAIR (B), and coronal T2-weighted (C) MR images demonstrating cerebral volume loss, hypomyelination, high T2/FLAIR signal in the thalami and cerebellar volume loss.

After 4 years of high-dose folinic acid, a ketogenic diet, and multiple trials of ASMs (vigabatrin, fenfluramine, brivaracetam, and clobazam), the patient continued experiencing multiple daily generalized tonic-clonic seizures and weekly drop seizures, meeting criteria for DRE. Multidisciplinary epilepsy surgery conference discussion of her case determined her metabolic condition to be refractory to multimodal medical management and her seizure disorder to be progressive and the reason for her regression. Generalized seizures with multifocal bilateral electrographic involvement made her a candidate for CC or thalamic neuromodulation as opposed to seizure focus resection or ablation. After shared decision-making discussions about the options of CC or thalamic neuromodulation of the centromedian nucleus,¹⁰ the family opted for CC. The biggest motivation of the family and care team was identified as the atonic seizure type, being the most frequent and the most burdensome over all other seizure types.^11–13 Complete callosotomy was recommended during the multidisciplinary conference to maximize surgical disconnection to reduce the atonic seizures, taking into account that the patient was almost nonverbal and used a wheelchair at baseline. Per our multidisciplinary team's preoperative workflow, the patient’s family met with the epilepsy and neurosurgery teams, as well as with the anesthesiology, neuropsychology, social work, and physical medicine and rehabilitation teams to anticipate, optimize, and support possible needs along the patient’s perioperative journey.

The patient underwent an endoscope-assisted CC, which is the technique of choice in our group for complete callosotomy, although it is recognized that there are multiple viable approaches to achieve the goals of this surgery. Microscope, endoscope, and stereotactic navigation were utilized for the midline interhemispheric approach, dissecting on the right side of the falx cerebri to visualize the corpus callosum and perform a complete callosotomy via microneurosurgical technique. The anatomy was as expected from her preoperative imaging. The surgery was uneventful with no blood transfusion and no need for an intensive care unit stay postoperatively. As anticipated, the patient was transferred to inpatient rehabilitation for continued postoperative therapies. She experienced mild disconnection symptoms that showed rapid recovery starting within 2 days, and her mood and behavior were noted by her family to be more alert and happy, with notably improved response to hearing her own name.

At the 3-month follow-up, the family reported no drop seizures since surgery and a subjective improvement in socialization. The patient had convulsive seizures every single night prior to surgery, and in the months since surgery, she has had only one. Her family noted that she was doing things postoperatively that she never did before surgery: reaching for objects, engaging in play, and laughing with delight. She remained on her previous multimodal regimen of enteral and IV folinic acid, brivaracetam, clobazam, vigabatrin, fenfluramine, ketogenic diet, and vagus nerve stimulation.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

The CFTD literature describing the efficacy of folinic acid for any symptom of CFTD specifically¹⁴ is anecdotal level 4 data without systematic reviews, randomized controlled trials, or meta-analyses. Prior case reports described high-dose oral or IV folinic acid therapy as an effective treatment for CFTD,^6,9,15–19 resulting in moderate to significant clinical and radiological improvement if started early in the disease course.^3,15,17 They also indicated low efficacy of ASMs as a stand-alone therapy,^3,7,8,17,19 suggesting that epilepsy in CFTD is likely mediated by a folate-dependent reduction in the intracerebral production of inhibitory neurotransmitters.² Additional treatment modalities for patients with CFTD who do not respond to folinic acid remain undescribed.

Observations

To our knowledge, this case represents the first documented intracranial surgery to treat DRE in a patient with CFTD. Our patient’s initial near–seizure freedom (Engel class 1C) at 3 months demonstrates a promising role for CC in this rare disease. While CC was pursued to specifically address the patient’s atonic drop seizures, the patient’s family reported that the frequency of all seizure types was significantly reduced, suggesting a broad therapeutic network effect. Given this study’s short follow-up period, the patient’s outcomes might not be generalizable to the broader medically refractory CFTD population. The durability of outcomes will need to be examined and will require longer-term follow-up.

Lessons

We report a successful initial reduction in seizures and improvement in neurological function following CC for a patient with DRE secondary to folinic acid–refractory CFTD. This case signals promise for the role of well-selected, safe application of intracranial surgery options for prompt and adequate seizure control in patients with metabolic disorders such as folinic acid–refractory CFTD. More systematic research is needed to assess the efficacy of all medical and surgical therapies for CFTD.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Lam, Balaguer Townsend. Acquisition of data: Lam, Bieber, Widjaja. Analysis and interpretation of data: Lam, Balaguer Townsend, Raskin, Baker, Widjaja. Drafting the article: Balaguer Townsend, Gopalka, Raskin. Critically revising the article: all authors. Reviewed submitted version of manuscript: Lam, Gopalka, Raskin, Widjaja. Approved the final version of the manuscript on behalf of all authors: Lam. Administrative/technical/material support: Lam, Balaguer Townsend. Study supervision: Lam, Balaguer Townsend.

Correspondence

Sandi K. Lam: Ann & Robert H. Lurie Children’s Hospital of Chicago, IL. slam@luriechildrens.org.