Challenge Case Report: New-Onset Seizures and Brain Lesions in First Trimester

Treatment and Outcome

LB was transferred to our hospital and subsequently underwent a right frontal craniotomy for biopsy and debulking of the larger lesion. Surgical pathology showed an anaplastic astrocytoma with mutations in isocitrate dehydrogenase (IDH1) (World Health Organization [WHO] grade III). In addition to the mutation in IDH1, mutations were also noted in tumor protein 53 (TP53) and alpha thalassemia X-linked mental retardation (ATRX) genes. The methylguanine methyltransferase (MGMT) promoter was unmethylated. On arrival at our institution, LB’s antiseizure medication (ASM) was switched to levetiracetam 750 mg twice daily, and 1 mg of folic acid was added to her regimen. Following the change in ASM, LB had no further seizures. Further surgical intervention was postponed until after her delivery when she underwent an awake left parietal craniotomy for resection of the smaller lesion. Surgical pathology from this lesion was consistent with diffuse astrocytoma (WHO grade II), IDH1 mutated. As with the initial tumor sample, mutations in TP53 and ATRX were detected and MGMT promoter methylation was present. LB has since been evaluated in neuro-oncology, epilepsy, and neurosurgery clinics, and continues treatment of her brain tumor and brain tumor-related epilepsy (BTRE).

Discussion

Classification of Gliomas

The incidence of primary brain tumors in the US is estimated to be 23.4 per 100,000 people. Gliomas are one of the most common primary brain tumor groups, with an incidence of 7.1 per 100,000.^2,3 Differentiation of glioma types is based on histologic and molecular features, with a growing importance of molecular characteristics.⁴ This has been codified in the WHO 2016 classification system⁵ with additional clarifications published since the 2016 revision in the cIMPACT-NOW series of manuscripts.^6-9 Of particular importance is the mutational status of the IDH genes (both IDH1 and IDH2), which are used to classify infiltrating gliomas into glioblastoma and other related astrocytomas without IDH mutation, infiltrating astrocytomas with IDH mutation, oligodendrogliomas, and infiltrating astrocytomas with histone mutations (most frequently H3 K27M).¹⁰

BTRE

Depending on the tumor type, up to 80% of individuals with brain tumor may have seizures as a result of their tumor, and a large proportion of brain tumors come to medical attention because of a seizure.^11-14 Seizures secondary to brain tumor often have focal onset because they occur as a consequence of a focal lesion. LB’s focal clonic seizures involving her left face and upper extremity are semiologically consistent with the right frontal lesion seen on imaging. According to the American Academy of Neurology (AAN) Practice Parameter, seizure recurrence risk is increased if a significant abnormality is found on brain imaging.¹⁵ Brain MRI is warranted after a first seizure, and a study found 29% of all adults who presented with a first seizure had epileptogenic lesions on MRIs. Furthermore, of those with a normal CT who also had an MRI, 12% had an epileptogenic lesion on MRI.

Of all tumor types, glioneuronal tumors—including gangliogliomas and dysembryoplastic neuroepithelial tumors—have the highest incidence of associated seizures.¹¹ Among gliomas, lower-grade gliomas carry the greatest risk of associated seizures occurring in 70% to 90% of cases. With glioblastoma, seizure incidence is approximately 30% to 60%.¹⁶ The wide incidence ranges reflect, in part, differing methodologies across studies and the difficulty of accurately capturing this data.

The overall approach to surgery for lower-grade tumors is distinct from that for higher-grade tumors. For glioneuronal tumors and low-grade gliomas, a primary goal of surgery is seizure freedom, and as such, an epilepsy evaluation including a presurgical evaluation in an epilepsy monitoring unit should be considered. Additional diagnostic tools that should be considered for surgical planning include positron emission tomography (PET), single-photon emission CT (SPECT), magnetic EEG (MEG), functional MRI (fMRI), and intraoperative or extraoperative electrocorticography. For those with epilepsy in the context of higher-grade tumors, the surgical goal is maximal resection and the role of electrocorticography is debated.

The pathophysiology of BTRE is incompletely understood; however, low-grade gliomas with an IDH mutation have been shown to be particularly epileptogenic.^17,18 IDH is a key enzyme in the Krebs cycle that normally leads to the production of alpha-ketoglutarate. When IDH is mutated, the oncometabolite 2-hydroxyglutarate (2HG), which directly stimulates the N-methyl d aspartate receptor (NMDAR), is produced, and this in turn, likely helps propagate epileptogenic activity.¹⁹ Mathematic modeling has shown that when mutated IDH is present, 2HG concentration is elevated over a wide swathe of the brain, placing a substantial amount of cortex at risk for seizures.²⁰ This putative pathophysiologic mechanism for BTRE explains the higher incidence of seizures in lower-grade gliomas that are predominantly IDH mutated.

Beyond gliomas with IDH mutations, there are alterations in the peritumoral environment of brain tumors in general that likely contribute to the epileptogenic behavior of brain tumors, including decreased inhibitory neurotransmission that is likely accentuated by glutamate neurotransmission.²¹

Risk factors for BTRE other than IDH mutations include tumor type (ie, lower grade with an increased incidence of seizures), superficial cortical location, and regional tumor location (ie, frontal or temporal lobe location with a higher incidence of seizures).¹¹ Because metabolic activity in some tumor types correlates with epileptogenesis, the frequency of seizures is actively being considered as a potential clinical trial endpoint in gauging efficacy in therapeutic trials for some glioma subtypes.²²

Medical management of seizures in BTRE presents a challenge in that seizures are often refractory to medical management, and a significant portion still experience seizures after surgical resection.¹⁶ In addition, the interactions between ASMs and chemotherapeutic agents must be considered. Strong CYP3A4 coenzyme inducing ASMs, such as phenytoin, carbamazepine, and phenobarbital, may lower serum chemotherapy concentrations, and therefore are often avoided in this population.

Brain Tumors in Pregnancy

Although a relatively small proportion of those with brain tumors, pregnant patients require special consideration in regard to the prognosis and treatment of brain tumors and BTRE. It has been hypothesized, but not definitively demonstrated, that pregnancy may negatively affect outcomes in high-grade glioma.²³ Pregnancy presents an increased risk for surgical complications, confounding the treatment plans for pregnant patients.

Furthermore, ASM choice is limited by pregnancy, as some ASMs are associated with major congenital malformations (MCMs) in addition to worsened cognitive outcomes in children exposed to those ASMs in utero. The prevalence of MCMs depends on the ASM, with valproic acid having the highest prevalence of MCM (6.7%-10.3%) and lamotrigine and levetiracetam having the lowest prevalence of MCM (1.9%-2.9% and 0.7%-2.8% respectively).^24,25 Reported MCMs are similar to those seen in the general population, including neural tube defects, cardiac defects, cleft palate, hypospadias, and polydactyly.^24,25 Valproic acid, in particular, has been associated with cognitive outcomes for children exposed in utero, including worsened verbal and memory abilities compared to other ASMs, and worsened nonverbal and executive functions compared with lamotrigine.¹

Although LB was in week 10 of pregnancy and neural tube formation was therefore complete, exposure to an ASM could still place her fetus at risk for other MCMs and poor cognitive outcomes. When choosing an ASM, given the low risk of MCMs with lamotrigine and levetiracetam, these agents are most commonly prescribed to pregnant individuals and those of childbearing potential. Presumably, this is why LB was initially treated with lamotrigine.

However, ASM clearance increases during pregnancy, with varying degrees of ASM serum concentration reductions dependent on the ASM.²⁵ Lamotrigine clearance significantly increases during pregnancy, likely related to estrogen-driven enhanced glucuronidation during pregnancy,²⁵ increasing the already prolonged titration period of 8 to 12 weeks to 16 weeks or longer in a pregnant person.

Considering the potential risks to a mother and her fetus with ongoing seizures, initiation of an ASM for which a therapeutic dose may be achieved relatively quickly is preferred. Levetiracetam has been shown to be relatively safe in pregnancy and can provide immediate efficacy because it does not require titration.²⁶ Levetiracetam is a better option for women who present with a first seizure during pregnancy or women of childbearing age with BTRE. Of note, folic acid supplementation should be used in conjunction with all ASMs to minimize the risk of neural tube defects.²⁵

Recent preclinical work has demonstrated that folate can facilitate a switch of glioma cells to a more dedifferentiated “stem-like” population.²⁷ As such, cessation of folate supplementation after week 5 of pregnancy following neural tube formation in pregnant patients with brain tumors may be a consideration. Whereas this work is preclinical, it reinforces that we should move with careful consideration in our recommendations of supplementation in individuals with brain tumors.