The curious case of the gene, the lesion, or neither

Abstract

With increased availability of genetic testing, more patients have been identified as having causative variants. With a greater amount of diagnostic certainty, there is uncertainty in its consideration in epilepsy surgery workup. We report a case of a boy with a GRIN2B likely pathogenic variant, with medically refractory epilepsy who underwent epilepsy surgery evaluation, resulting in successful surgical resection with good outcome.

Our patient is a 15-year-old right-handed man, with seizure onset at three years of age. In the first six years of life, he had generalized tonic–clonic and myoclonic seizures that subsequently resolved. Since age seven, he has had medically refractory seizures characterized by a nonspecific aura, followed by repetition of a stereotyped phrase progressing to oral automatisms, right-sided head version, followed by right arm flexion and right-hand posturing. He was medically refractory on appropriate doses of lacosamide and lamotrigine and had previously failed nine other anti-seizure medications.

His past medical history is significant for depression, mild intellectual disability, attention difficulties, and behavioral dysregulation. His birth history was unremarkable. Family history was unremarkable. Initial EEG showed slowing and interictal discharges over the left temporal region. During EEG, a typical seizure was captured, with EEG onset of rhythmic delta over the left temporal chain (Figure 1A). MRI brain showed a lesion in the right occipitotemporal cortex, consistent with a multi nodular and vacuolating neuronal tumor (MVNT) (Figure 1B). A PET scan showed hypometabolism at the left temporal pole and medial temporal cortex. Subtraction SPECT showed increased perfusion to the left temporal pole. Whole exome sequencing identified a de novo heterozygous likely pathogenic GRIN2B variant (p. Cys946Ter).

Although the epileptogenic zone seemingly localized to the left temporal region, the epileptogenic lesion was incongruent. Intracranial electroencephalography through stereotactic electrodes was performed to clarify this inconsistency. Although the patient's genetic variant likely explained his intellectual disability and seizures, as his seizures remained stereotyped and focal, he was still considered a possible surgical candidate.

Stereotactic electrodes were implanted with seven electrodes sampling the left hemisphere, and two electrodes in the right hemisphere, as demonstrated in Figure 2. Interictal activity was most prominent from the left temporal inferior gyrus and hippocampus. Six clinical seizures were captured, all with onset from the left hippocampus. Following explantation, clinical consensus was that the epileptogenic zone involved the left hippocampus, and a left temporal lobectomy was performed, guided by electrocorticography. Surgical pathology showed no evidence of a definitive primary epileptogenic process. Following surgery, the patient was seizure-free at 11 months post surgery (Engel 1A), with improved ability to perform activities of daily living and memory.

GRIN2B encodes for the NMDA receptor subtype 2B, a class of ionotropic glutamate receptors involved in numerous cellular functions.² Patients with GRIN2B pathogenic variants express the phenotype of GRIN2B-related neurodevelopmental disorder. This is an autosomal dominant disorder characterized by mild-to-profound developmental delay/intellectual disability, muscle tone abnormalities, epilepsy, and autism spectrum disorder.³ Epilepsy occurs in 51% of individuals, with onset from birth to 9 years of age, with 50% being medically refractory.³ Seizures may be generalized or focal. Imaging shows a malformation of cortical development including polymicrogyria, irregular gyral pattern, and hypoplastic corpus callosum in a minority of individuals.⁴ No previous patients with GRIN2B have been reported to have MVNT or underwent epilepsy surgery to treat their epilepsy.³

Increased use of genetic testing has provided greater diagnostic certainty for patients with epilepsy. The hope in the future will be to leverage diagnostic knowledge to improve patient management, but this is not possible now. This case shows that even with a genetic diagnosis, epilepsy surgery remains the best treatment option for focal epilepsies. This case also demonstrates best practices in epilepsy surgery workup. A common assumption made during surgical workup is that an epileptogenic lesion is analogous to the epileptogenic zone. For our case, even though the patient had a suspected lesion known to be epileptogenic, it is incongruence with EEG studies suggested that it was not representative of the epileptogenic zone. As a result, invasive studies with stereoEEG were able to confirm this hypothesis.

In conclusion, a genetic diagnosis does not exclude a patient from being a candidate for epilepsy surgery, and an epileptogenic lesion is not always the source of a patient's seizures.

None of the authors have any conflict of interest to disclose.