SEEG Radiofrequency Thermocoagulation and Memory: For Now,Avoid the Trap of Overpromising and Underdelivering

Abstract

Neuropsychological Outcomes After Stereo-EEG Radiofrequency Thermocoagulation

Cockle E, Malpas CB, Coleman H, McIlroy A, Laing J, Kwan P, Hunn M, Gutman M, Harb C, Meade C, D'Souza WJ, Halliday AJ, Bulluss K, Vogrin SJ, Alpitsis R, O'Brien TJ, Rayner G, Neal A. Neurology. 2024;103(11):e209815. doi:10.1212/WNL.0000000000209815. Epub 2024 Nov 18. PMID: 39556777.

Background and objectives: Stereo-EEG-guided radiofrequency thermocoagulation (RFTHC) has been proposed as relatively safe from a cognitive perspective; however, there is a lack of evidence based on neuropsychological assessments supporting this. This study is the first prospective evaluation of neuropsychological outcomes associated with stereo-EEG-guided RFTHC in patients with focal drug-resistant epilepsy. Methods: This cohort study involved prospective recruitment of consecutive patients undergoing stereo-EEG from 2 Australian centers. A comprehensive neuropsychological assessment was administered before implantation and 3 months after RFTHC (M = 104.51 days, SD = 29.25). Outcomes across cognitive domains were assessed at a group level with repeated measures t tests. Factorial repeated measures analyses of variance compared memory and language outcomes according to whether dominant mesial temporal lobe (mTL) structures were coagulated. Reliable change indices (RCIs) were computed to explore psychometrically reliable changes at an individual level. Results: The sample comprised 39 patients who underwent stereo-EEG (M = 37.08 ± 9.67 years, range = 17-56 years, 54% female). Nineteen (49%) had a language dominant epileptogenic zone (EZ), 16 (41%) a non-dominant EZ, and 4 (10%) a bilateral EZ. All patients underwent RFTHC with a mean of 11.87 (SD = 6.82, range = 2-29) coagulation sites. Ten patients (26%) had RFTHC within the dominant mTL. At a group level, RFTHC was not associated with a significant decline on any neuropsychological measures (all comparisons p > 0.05). Subgroup analyses revealed a decline in delayed verbal recall after RFTHC of dominant mTL structures (F(1,37) = 4.46, p = 0.04, ηp² = 0.11, 95% CI [0–0.30]; medium to large effect), although it did not remain statistically significant after correction for false discovery rate. No statistically significant group differences were observed on visual memory or language measures post-RFTHC (all comparisons p > 0.05). RCI revealed that after RFTHC within the dominant mTL, 20% of patients experienced a decline in verbal memory and 10% in visual memory. By contrast, 7% declined in verbal memory and 10% in visual memory post-RFTHC outside the dominant mTL. Discussion: While these findings support the current view that RFTHC is cognitively benign for most cases, the results raise the question of a verbal memory decline after coagulation of the dominant mTL. Individualized neuropsychological counseling before stereo-EEG is essential to avoid unanticipated deficits.

Commentary

Every decision is a trade-off, especially when considering therapeutic options. Deciding surgical therapy for patients with drug-resistant epilepsy (DRE) is a high-stakes situation. Epilepsy surgery's potential impact, including seizure freedom and risk for neurological deficits, inherent uncertainty, and irreversibility, makes it one of the most nuanced, individualized, and crucial decision-making exercises in medicine. Ideally, we aim to tilt the cost-benefit scale lopsided in the latter's favor and make it as close as possible to a win-win situation. However, the latter is a unicorn in epilepsy surgery, especially when the epileptogenic zone involves a dominant temporal lobe.

The aim of providing the best chance of seizure freedom with minimal memory deficit in mesial temporal lobe epilepsy (MTLE) has been the proverbial necessity that has mothered several inventions. One of the earliest and foremost alternatives to the standard anterior temporal lobectomy (ATL) was the selective amygdalohippocampectomy (SAH). Performed as early as the 1950s, Yasargil and Wieser popularized the transsylvian SAH in the 1980s.^1,2 However, meta-analysis studies show that SAH provides 8% lower Engel Class I seizure outcome than ATL, and its benefit in better cognitive outcomes remains debatable.^3,4 Laser interstitial thermal therapy (LITT) is another innovation with hopes similar to SAH's, especially in MTLE. Unsurprisingly, with its ablation of around 70% of the hippocampus and amygdala, 10% to 15% fewer patients achieve seizure freedom with LITT than ATL.^5,6 One may consider the trade-off of reduced seizure freedom worth it if the memory deficit were avoided. In contrast to around 40% of dominant ATL experiencing verbal decline, around 10% of patients undergoing mesial temporal lobe (mTL) LITT have verbal decline, which rises to 15% in the dominant hemisphere. ⁷ While it may seem substantially lower memory decline risk at a group level, the 1 in 6 chance can be a scary proposition at an individual patient level.

One could be excused for imagining the possibility of altogether avoiding cognitive deficit and potentially salvaging some seizure freedom or making a substantial improvement if we could develop tools to create even smaller, “mini” lesions in the mTL. Can we then turn surgical therapy for MTLE into a win-win deal? Presto, stereo-EEG-guided radiofrequency thermocoagulation (SEEG-RFTHC). It is a technique of coagulating, like the egg white coagulates on boiling rather than ablating. The latter, derived from the Latin ablat, means “taken away,” that is, liquification or vaporization of the brain tissue. Described by Guenot et al in 2004, it uses SEEG contacts as dipoles to create heat by passing radiofrequency current. With its ability to produce brain lesions ranging from 35 to 105 mm³, it has been proposed as a palliative procedure if resective surgery is not possible, given that only 10% to 20% of patients become seizure-free.^8,9 Performed at the conclusion of a diagnostic SEEG monitoring, it has been used as a “proof of concept” for the putative epileptogenic zone before a more definitive, more extensive resection. Another proposed but poorly investigated benefit of RFTHC is its lack of impact on cognition. That is the knowledge gap that the study by Cockle et al attempts to fill. ¹⁰

The authors use a modest sample size of 39 prospectively enrolled patients who underwent, on average, around 3 months of pre- and post-RFTHC neuropsychological testing at two Australian centers. One-fifth of the patients were seizure-free at the 12-month follow-up, and 60% were subsequently considered for surgical resection. Overall, no significant declines were noted in any neuropsychological measures after RFTHC. Half of the study cohort had an epileptogenic zone in the dominant hemisphere. Among the study cohort, 10 patients underwent RFTHC in the dominant mTL, targeting lesions in the hippocampus, amygdala, or parahippocampal gyrus using orthogonal trajectories. Compared to the rest of the cohort, which included 6 patients with RFTHC in the non-dominant mTL, the dominant sub-group showed verbal memory decline in a higher proportion of patients. After correction for multiple comparisons, this difference was not statistically significant, secondary to a small sample size. More importantly, the difference in the proportion of patients with verbal memory deficit based on reliable change indices is substantial [20% (n = 2) in dominant mTL versus 7% (n = 2) in the rest], and the average sub-group score for delayed recall changed from normal to borderline in the dominant mTL group.

The difference in verbal memory outcomes is despite the dominant mTL group undergoing significantly fewer SEEG electrode implantations. With an increasing number of patients undergoing SEEG, a quick detour is warranted to determine whether SEEG implantation, the smallest iatrogenic lesion, can cause cognitive deficits by itself. While we do not have a definitive answer yet, a study by Busch et al found that patients undergoing SEEG before dominant ATL had comparable cognitive outcomes to those who did not require invasive monitoring. ¹¹ Recalling that RFTHC was performed after SEEG in Cockle et al's study helps contextualize their findings. SEEG was performed because more than two-thirds of the study cohort was non-lesional. Consequently, most patients had normal hippocampi on MRI, except for two in each subgroup with hippocampal sclerosis. Therefore, RFTHC was performed chiefly in non-lesional dominant MTLE, which, extrapolating from ATL literature, is associated with a higher memory decline risk. Of note, because the study only included 4 patients with non-lesional, non-dominant MTLE, the absence of a significant visual memory deficit in this sub-group should not be taken as evidence of the absence of such a deficit.

Despite being hamstrung by a small sample size, especially of the dominant mTL sub-group, the study by Cockle et al provides some important lessons. There has been a steady increase in non-lesional DRE patients undergoing SEEG without subsequently receiving resection. ¹² RFTHC may offer a low morbidity intervention in such cases, especially given that cognitive outcomes remain overall stable. However, we need to be careful wielding this double-edged sword. The promise of a substantial seizure improvement from a theragnostic procedure (diagnostic SEEG followed by a therapeutic RFTHC) may help PWE overcome clinical inertia and, hence, improve epilepsy surgery's abysmal utilization. ¹³ But we need to be wary of overpromising and underdelivering in cases like the dominant mTL subgroup, where only 1 patient was seizure-free at 12 months, but 2 had significant verbal memory decline. That word of caution is the most crucial kernel of knowledge from the Cockle et al study. It enriches the landscape of RFTHC literature by underscoring that no amount of therapeutic tissue damage is too small in some dominant MTLE patients to avoid verbal memory deficits. Additionally, it informs that a subsequent more extensive resection in such cases is fraught with further verbal memory decline. It is critical to reemphasize that the sample size in the Cockle et al study did not allow a meaningful way to identify such patients. Nonetheless, their study cautions us against assuring patients that small lesions from RFTHR are cognitively risk-free, particularly in dominant MTLE.