Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials—impact of psychogenic non-epileptic seizures

Seizures are reported in up to 80% of low-grade gliomas (LGGs). Avila and colleagues have proposed a seizure assessment tool for brain tumor trials to quantify seizure control as a measure of antiglioma efficacy.¹ We highlight a pitfall in this assessment tool: the inability to distinguish psychogenic non-epileptic seizures (PNES) from epileptic seizures (ES).

Psychogenic non-epileptic seizures are not associated with electrical activity, but rather manifest as an involuntary behavioral response to internal and external triggers.² PNES lack a postictal state and are not characterized by a rise in prolactin levels, often distinctive for ES.² Video EEG remains the gold standard for distinguishing PNES from true ES; however, routine incorporation of video EEG into clinical care can be challenging. In patients with LGGs, the most common seizures are simple or complex partial seizures.^3,4 Evaluation of seizure control in anti-epileptic drug trials historically excludes patients with a history of pseudo-seizures or PNES.⁴ The methodology of determining how a patient meets these exclusion criteria is vague, although PNES are considered to be widely prevalent, making up about 20% of new-onset incidents.^5,6

PNES have been identified as a key neuropsychiatric issue associated with epilepsy.^2,7 A growing body of literature support 5%–10% of patients in outpatient epilepsy clinics, and 20%–40% of patients in inpatient epilepsy monitoring units have PNES; additionally, the rate of PNES and epilepsy coexistence has been reported to vary anywhere from 5% to 50%.⁷ While the rate of PNES in patients with LGG remains unknown, there is a significant correlation between patient demographics, younger age, and psychologic stressors, such as anxiety, depression, surgical procedures, and injury with LGGs and those with PNES. This coexistence may have a pathophysiologic basis with partial seizures providing ictal changes to disinhibit emotion or impulse control contributing to PNES.⁸ The coexistence of PNES and epilepsy in the LGG population is expected, and evident in our clinical practice.

With the proposed seizure assessment tool for brain tumor trials, non-epileptologists, including patients and family members, will play a significant role in determining seizure-free days between appointment visits. The inability to distinguish a PNES from a true ES presents an unresolved reporting problem. Incorrect seizure classification may lead to initiation of unnecessary anti-epileptic drugs or the incorrect conclusion of tumor treatment failure. This, in turn, may place pressure on clinicians to initiate or change the oncologic treatment approach. Since psychologic or social stressors trigger PNES, this may manifest as a subconscious coping mechanism during the patient’s treatment course. In order to ensure the efficacy of the proposed tool, it is imperative that the patient and family members have an understanding of PNES, including the psychiatric characteristics and risk factors associated with its development, as well as the incorporation of objective measures, such as video EEG.

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