Challenge Case Report: New Onset Seizures

Diagnosis and Differential Diagnosis

Mr L presented with a seizure semiology of left-sided focal paresthesias and clonic activity localizing to the right frontal lobe, as evidenced by a small fluid-attenuated inversion recovery (FLAIR)-MRI hyperintense, nonenhancing mass within the right superior frontal gyrus. He underwent tissue sampling that revealed the classic histopathologic pattern of round nuclei and perinuclear halos, colloquially referred to as a “fried-egg appearance.” Molecular testing also revealed the pathognomonic 1p/19q co-deletion with an isocitrate dehydrogenase (IDH) gene mutation.

Oligodendrogliomas are lower-grade infiltrative glial neoplasms typically affecting the subcortical white matter and adjacent cortex and occurring most often in the frontal and temporal lobes. Oligodendrogliomas are hyperintense on T2 MRI, hypointense on T1 MRI, and less likely to demonstrate gadolinium contrast enhancement. Oligodendrogliomas are sometimes associated with calcifications, which are suggestive, but not diagnostic. The primary differential for oligodendrogliomas is IDH-mutant astrocytoma, which often share similar geographic brain locations and radiographic characteristics. The T2-FLAIR mismatch sign is a specific radiographic pattern associated with IDH-mutant astrocytoma, described as homogenous T2 hyperintensity with corresponding central hypointensity on FLAIR.¹

High-grade gliomas are another possible etiology for new-onset seizures in older adults. Like oligodendroglioma, high-grade gliomas are typically hyperintense on T2 and hypointense on T1 imaging, although high-grade gliomas are more likely to demonstrate enhancement following contrast infusion. In glioblastoma, the enhancement pattern is often circumferential, or “ring-enhancing” caused by central necrosis. Early high-grade gliomas may not demonstrate any contrast enhancement, highlighting the need for early tissue sampling to confirm a diagnosis. Cerebritis, an early stage in the pathogenesis of brain abscess, can present with similar imaging findings. Although a brain abscess appears as a ring-enhancing fibrotic capsule around central necrosis, cerebritis presents with a poorly demarcated lesion with localized edema, without significant necrosis or fibrosis. Cerebritis often causes seizures and is more likely in the setting of infectious symptoms (eg, fever and malaise).

Glioneuronal tumors, characterized by both neuronal and glial differentiation, are rare tumors that tend to be cortically based, well circumscribed, and associated with seizures. They also tend to have both cystic and enhancing solid components. These tumors tend to be diagnosed in children and young adults. Neurodevelopmental lesions (NDL) are lesions that occur due to errors in either neuronal proliferation, migration, or cortical organization. They are strongly associated with seizures and can sometimes present on imaging as focal cortical dysplasia. Because NDLs are congenital lesions, these also tend to be diagnosed in children and young adults.

Overall, based on the patient’s age, focal seizure, lack of infectious symptoms, and T2/FLAIR hyperintensity without enhancement on MRI, this presentation is most suggestive of lower grade glioma, more specifically an oligodendroglioma based on the histologic and molecular findings.

Histopathology and Molecular Markers

Based on the revised 4th edition World Health Organization (WHO) classification of central nervous system (CNS) tumors, classification of glial tumors is dependent on an integrated molecular and morphologic approach rather than primarily histopathologic findings. In this update, astrocytoma and oligodendroglioma are grouped under the common tumor subtype “diffuse glioma,” because they share a mutation in IDH1 or IDH2. The presence of an IDH mutation with a 1p/19q codeletion is diagnostic for oligodendroglioma, whereas an IDH mutation with loss of ATP-dependent helicase (ATRX) and mutation in the tumor protein p53 (TP53) gene defines astrocytoma.^2,3 Alternatively, diffuse gliomas may be IDH wildtype, and these are shown to have a poor prognosis compared to tumors with IDH1 and IDH2 mutations.⁴ Mr L’s tumor was positive for IDH R132H, the most common IDH1 mutation, and also had a 1p/19q codeletion.

Further, Mr L’s tumor was negative for neuronal nuclei protein (NeuN) immunoreactivity. NeuN is a reliable marker of postmitotic neurons, and absence of reactivity suggests that the neoplasm is glial in origin, without neuronal components.⁵ Mr L was also positive for a telomerase reverse transcriptase (TERT) promoter mutation. This mutation, which results in increased telomerase activity, has unclear prognostic value, and is seen in both low-grade and high-grade gliomas.⁶

On histopathology, oligodendrogliomas are characterized by cells with round and uniform nuclei and perinuclear halos. Oligodendrogliomas will often show secondary structuring, such as clustering of tumor cells around the cell bodies of preexisting neurons (satellitosis).⁷ Histologic criteria for a high-grade glioma includes mitotic activity and nuclear atypia.⁸ Mr L’s tumor showed cells with round nuclei and perinuclear halos, without mitotic activity. Mr L’s molecular and morphologic findings confirmed the diagnosis of oligodendroglioma.

Treatment

The goals of oligodendroglioma treatment are to prolong overall survival, delay malignant transformation, and maintain a good quality of life by minimizing treatment-related sequelae. Treatment consists of upfront maximal safe surgical resection, with an addition of adjuvant radiation and chemotherapy for higher risk tumors.

Early surgical resection and maximal extent of surgical resection are associated with improved outcomes.^9,10 For higher risk tumors, in which total resection is not possible or if the patient is more than age 40, adjuvant treatment with radiation and chemotherapy is recommended. Lower risk tumors, in which gross total resection is possible and patients are less than age 40, can potentially be observed closely with serial imaging. There have been significant advancements in the molecular characterization of brain tumors, and it is possible that currently undetermined molecular subtypes may ultimately classify tumors currently considered low risk as higher risk tumors that could benefit from earlier adjuvant treatment.

Typically, adjuvant therapy for oligodendroglioma consists of radiation followed by chemotherapy. Mature data from a large, randomized phase 3 study has demonstrated a nearly twofold increase in survival (13.3 years vs 7.8 years) in patients with high-risk low-grade gliomas who received radiation therapy followed chemotherapy (procarbazine, lomustine, and vincristine [PCV]) compared with radiotherapy alone.¹¹ In many centers, PCV chemotherapy is replaced with single agent temozolomide because of its more favorable and predictable side effect profile. Head-to-head prospective comparison of these two chemotherapy regimens is pending and will be answered by the ongoing phase 3 CODEL trial.^a

Recurrence

Mr L received radiation followed by temozolomide and is currently doing well without any recurrence of tumor or seizures. As there is no known curative treatment for infiltrating gliomas, there will likely be tumor progression at some point. There is no standard management regimen or consensus for treatment of recurrent oligodendrogliomas.

Treatment options can include repeat surgery, rechallenge with the original chemotherapy agent or an alternative agent(s), or potentially repeat irradiation if significant time has elapsed from initial exposure, especially if the recurrence is within the initial radiation field. There are IDH inhibitors in clinical trials for glioma and other malignancies with no mature data to draw any meaningful conclusions, currently.