Bitemporal Lobe Epilepsy: Evolving Diagnostic and Treatment Paradigms

Abstract

Bilateral temporal lobe epilepsy (BTLE) represents a challenging subset of drug-resistant epilepsy, accounting for 20-35% of temporal lobe epilepsy cases. Characterized by independent seizure onset from both temporal lobes, BTLE complicates diagnosis and treatment due to the difficulty in precisely localizing seizure onset zones (SOZs) and its profound cognitive and quality-of-life impact. Memory impairment and frequent seizures significantly burden patients, necessitating advanced diagnostic and therapeutic strategies. Traditional scalp EEG often reveals bilateral ictal patterns but lacks specificity to confirm independent seizure foci. Stereoelectroencephalography remains the gold standard for accurate SOZ localization in BTLE, supported by comprehensive semiological and neuropsychological assessments. Understanding the structural and functional connectivity of the temporal lobes is essential for tailored management. Surgical resection is generally discouraged in BTLE owing to modest seizure control and high risk of cognitive decline. However, unilateral resection may benefit selected patients with pronounced seizure laterality (≥80%), though data remain inconsistent. Neuromodulation therapies, including vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation (RNS), have emerged as promising alternatives, demonstrating responder rates around 70%. Notably, RNS offers unique advantages by enabling long-term monitoring to refine seizure laterality and potentially guide future surgical decisions. Despite these advances, access to neuromodulation remains limited in many settings. BTLE continues to pose diagnostic and therapeutic challenges, emphasizing the need for ongoing research to optimize individualized approaches and improve patient outcomes.

Keywords

temporal bitemporal memory neuromodulation ultra-long recordings connectivity resource-limited settings semiology

Introduction

Bilateral temporal lobe epilepsy (BTLE) is a form of drug-resistant epilepsy that requires treatment options beyond anti-seizure medications (ASMs). BTLE occurs when epileptic activity emerges independently from both temporal lobes, accounting for approximately 20% to 35% of all temporal lobe epilepsy (TLE) cases.¹ BTLE presents significant challenges in diagnosis and treatment selection due to the complexity of seizure localization and its impact on cognition and quality of life. Patients with BTLE often experience frequent seizures, memory impairment, and poor overall quality of life.

We present a case of a 31-year-old woman with a history of seronegative autoimmune encephalitis diagnosed in 2017, treated with methylprednisolone, plasmapheresis, cyclophosphamide, and rituximab. This patient presented with two seizure types. Type 1 seizures were characterized by diffuse paresthesias in her hands and feet, accompanied by a sensation of déjà vu, with preserved awareness, lasting 2 to 3 minutes, with an approximate frequency of 10 events per month. Type 2 seizures consisted of behavioral arrest, right ocular supraversion, predominantly right-sided manual automatisms, flexion of the upper extremities, and extension of the right arm, lasting 2 to 3 minutes, with an approximate frequency of 20 events per month.

Scalp EEG demonstrated bilateral and independent temporal epileptiform activity with right-sided predominance. Video-EEG monitoring recorded three focal-onset seizures with impaired awareness and bilateral tonic–clonic motor components, with right temporal onset. Brain MRI revealed hippocampal asymmetry due to reduced volume of the right CA1 and subiculum, within normal limits for age and sex. Brain PET showed a moderate bilateral reduction in radiotracer uptake in the inferior and superior parietal cortices, temporal neocortex, insula, and dorsolateral occipital cortex. Neuropsychological evaluation documented cortical dysfunction with bilateral temporal, frontal, and parietal predominance.

Given this clinical scenario, a multidisciplinary team decided to proceed with neuromodulation using vagus nerve stimulation (VNS). At 6 months post-implantation, the patient achieved an 80% reduction in seizure frequency, with improvement in quality of life according to the QOLIE-31 scale, from fair to good.

As illustrated by the case presented here, bitemporal epilepsy represents a particularly complex diagnostic and therapeutic challenge; consequently, a comprehensive and systematic evaluation of all available clinical, electrophysiological, and imaging data is essential to guide optimal therapeutic decision-making.

Connectivity

Understanding how temporal lobe connectivity shapes seizure onset, propagation, and recovery is central to improving diagnosis, prognostication, and treatment strategies in BTLE. The temporal lobes are embedded in a dense architecture of intra- and interhemispheric pathways that facilitate rapid propagation of ictal and interictal activity, often within seconds, which can blur apparent lateralization on routine presurgical evaluations. Appreciating this connectivity is essential for understanding why a substantial proportion of patients with apparently unilateral TLE show bilateral interictal discharges and why unilateral surgery sometimes fails despite a seemingly well-defined seizure onset zone (SOZ). Within each temporal lobe, longitudinal anatomical and functional gradients organize mesial and lateral structures into partially segregated, yet tightly coupled, subcircuits. Developmental and neuroanatomical work suggests that the anterior temporal pole and amygdala are preferentially engaged in emotion and autobiographical memory, whereas posterior hippocampal and parahippocampal regions are more involved in contextual and spatial processing, with distinct dominant frequency bands (delta–theta anteriorly, alpha–beta–gamma posteriorly) that support these functions.^2,3 This anterior–posterior axis is supported by longitudinal pathways such as the subiculum and entorhinal cortex, which integrate information along the hippocampal long axis.⁴ Disruption of these intratemporal networks in TLE affects both seizure dynamics and higher cognitive functions, including autobiographical memory and spatial navigation.

Interhemispheric connectivity further complicates the picture in BTLE. The anterior commissure provides direct connections between amygdalae and temporal poles, the tapetum interconnects parahippocampal regions, and the commissural fibers of the fornix link both hippocampi. Tractography and structural imaging studies in TLE consistently demonstrate reduced fractional anisotropy and other markers of microstructural damage in these pathways, including the uncinate fasciculus, fornix, and cingulum.⁵ These abnormalities are not restricted to the ipsilateral temporal lobe but often extend contralaterally and into extratemporal hubs, supporting the concept of a bilateral limbic network prone to hypersynchrony. In BTLE, preserved or abnormally organized interhemispheric pathways likely facilitate rapid cross-temporal propagation, contributing to the near-synchronous ictal onsets often seen on short-duration recordings.

Functional connectivity and effective connectivity studies reinforce this network view. Resting-state fMRI and graph theoretical analyses have shown that TLE is associated with reduced integration and abnormal hubness of temporal lobe nodes within the broader connectome, with patterns of interhemispheric imbalance that correlate with cognitive impairment and surgical outcome. Patients with BTLE or with unilateral TLE and poor post-operative seizure control often exhibit connectivity profiles that differ from those of good outcome unilateral cases, including greater interhemispheric synchrony and less segregation between temporal lobes.⁶ These findings suggest that what is labeled “bitemporal” at the scalp level can reflect both true bilateral epileptogenesis and a unilateral driver embedded in an excessively efficient bilateral network.

In addition, invasive approaches, such as cortico-cortical evoked potentials (CCEPs) as well as chronic electrocorticography, have shown that temporal lobe connectivity is both structurally constrained and dynamically modulated,⁷ and that these patterns may critically influence whether seizures appear unilateral, bilateral, or rapidly generalizing.

In addition, structural and functional connectome-based models using graph theory metrics have been able to predict post-surgical seizure outcomes with high positive predictive value in unilateral TLE.^8–10 Patients with more normalized temporal integration and preserved network architecture tend to have better outcomes after temporal resection, whereas those with widespread network disruption, including contralateral temporal and extratemporal changes, are at higher risk for persistent seizures. Extending these predictive models explicitly to BTLE cohorts could clarify which patients harbor a dominant, surgically targetable network and which are better served by neuromodulation or other palliative approaches.

Semiology

Careful analysis of temporal lobe seizure semiology can provide valuable information for both lateralization and localization of the SOZ, while accounting for age differences. Studies have shown that seizure semiology differs according to age. In adults, there is a higher incidence of motor manifestations, including motor automatisms, clonic or tonic components, and focal to bilateral tonic–clonic seizures.¹¹ This likely reflects the involvement of a more complex cortical–subcortical network than that present in the developing brain. In contrast, young infants may develop generalized seizures, such as epileptic spasms, even when focal lesions are confined to the temporal regions.

Temporal lobe seizure semiology can be challenging to distinguish from that of frontal lobe seizures. In a multivariate logistic regression analysis of video-recorded seizures,¹² the most discriminative features were fencing posturing for frontal lobe seizures and postictal confusion for temporal lobe seizures. However, analysis of multiple seizures is often required for accurate differentiation.

In TLE, unilateral dystonic posturing is the most reliable lateralizing sign, indicating a contralateral focus in approximately 96% of patients with mesial temporal epilepsy.¹³ Other lateralizing features have variable reliability, such as: postictal aphasia (dominant hemisphere), normal ictal speech (nondominant hemisphere), postictal nose wiping (usually ipsilateral focus) and head and eye deviation (usually contralateral).

In general, mesial TLE often presents with an epigastric aura (associated with anterior insular activation), fear (amygdala involvement), and oromotor automatisms (linked to the temporal pole, hippocampal tail, and amygdala). Loss of awareness tends to occur later in the course of the seizure. In contrast, lateral or neocortical TLE may present with auditory auras—simple (primary auditory cortex) or complex (superior temporal gyrus). Loss of awareness typically occurs earlier, and secondary generalization is more common than in MTLE.¹⁴

Patients with BTLE may present a diagnostic challenge. However, several findings suggest bilateral temporal seizure onset zones. Different seizure semiologies—or seizures with clinical features that localize to different hemispheres—raise suspicion for bitemporal epilepsy. A higher frequency of ictal motor phenomena and a longer period of postictal unresponsiveness have been described in patients with BTLE.^15,16 Patients with clinical features suggesting bitemporal onset require careful assessment of neuroimaging and EEG findings to refine the diagnosis.

Beyond Seizures

One of the most commonly reported symptoms beyond seizures is memory dysfunction. Patients with mesial temporal epilepsy show significant deficits in both verbal and visual episodic memory, affecting immediate learning and delayed recall of both memory types.^17,18 Patients with selective hippocampal lesions (such as hippocampal sclerosis) may retain previously acquired semantic memory and can acquire some degree of new semantic memory, thanks to the perirhinal and parahippocampal cortices, which play a critical role in semantic learning and consolidation (acontextual). In contrast, patients with extensive medial temporal lobe lesions (as occurs in viral or autoimmune encephalitis) show severe impairment in retrieving established semantic memory and an absence of new semantic learning.^19–23

In patients with bilateral mesial temporal epilepsy, there is an apparent discrepancy between severe anterograde amnesia and the capacity to acquire some new semantic memory. This is explained by the hierarchical organization of the medial temporal lobe system, where the hippocampus is critical for episodic (contextual) memory, while the perihippocampal cortices (perirhinal, entorhinal, parahippocampal) can support the acquisition of semantic (acontextual) knowledge relatively independently.²¹ Bilateral mesial temporal lesions typically produce severe anterograde amnesia (inability to form new memories) and variable retrograde amnesia (loss of previously formed memories), with the temporal extent depending on the magnitude and precise location of damage within the medial temporal lobe and related structures.^19,20,24

Permanent global amnesia after TLE surgery is a rare complication (less than 1%) that occurs mainly in patients with preoperative bilateral dysfunction of mesial temporal structures. Thorough preoperative evaluation and careful candidate selection are essential to minimize this devastating risk.²⁵

Global amnesia can be mitigated through specific preventive strategies:

Comprehensive presurgical evaluation: Incorporating volumetric MRI, FDG-PET, detailed neuropsychological assessment, and, in selected cases, Wada testing or functional MRI (fMRI) to identify patients with bilateral dysfunction.^25,26

Careful candidate selection: Patients demonstrating clear evidence of significant bilateral dysfunction are generally not considered candidates for standard resective surgery.^25,26

Alternative surgical techniques: For high-risk patients who remain potential candidates, more conservative approaches—such as multiple hippocampal transections (MHT), which has shown better memory preservation in high-risk cases such as language-dominant mesio-temporal lobe epilepsies at risk for memory decline—may be considered.^25,26

More selective resections: Resective or ablative (LITT) selective amygdalohippocampectomy, as opposed to anterior temporal lobectomy, may reduce the risk of cognitive decline; however, evidence remains mixed regarding its effectiveness in specifically preventing global amnesia in patients with bilateral dysfunction.²⁷

Electrophysiology

Current practice relies almost exclusively on patient self-reported seizure logs. Multiple studies have shown that these are unreliable and miss many seizures.²⁸ Furthermore, presurgical evaluation may not provide sufficient information for localization or lateralization of seizure onset. This is often due to the limited time of the video EEG recordings. The average length of stay in the epilepsy monitoring unit for presurgical evaluation is only 7 days.²⁹

Several alternatives are emerging to provide ultra-long recordings, trying to minimize some of the limitations of the video EEG. Reduced channel wearable “peel and stick” scalp EEG sensors have been cleared by the FDA for use up to 30 days.³⁰ Sub-scalp EEG (ssEEG) systems in development can provide unilateral or bilateral coverage and one such device was authorized by the FDA in 2025. These systems can record for months or even years. These systems involve a wearable companion that uploads data to the cloud and typically allow access to the raw EEG data. Some already use automated seizure detection algorithms.³¹ In the UMPIRE clinical trial, bilateral ultralong ssEEG showed relevant findings not possible with unilateral recordings in 6 of 26 (23%) individuals with epilepsy (including a couple of unexpected bitemporal lobe epilepsy).³²

Intracranial ultra-long EEG monitoring using the responsive neurostimulation (RNS) System, FDA-approved in 2013, has provided important insights into bitemporal lobe epilepsy. It continuously records electrocorticographic (ECoG) activity and stores eight epochs of ECoG data as well as counts of interictal and ictal epileptiform activity. In bitemporal lobe epilepsy, the average time to record bilateral temporal lobe seizures was 41.6 days (range: 0-376),³³ with poor correlation between phase one data and RNS chronic data. Intracranial ECoG in patients with bitemporal lobe epilepsy has shown that up to 16% of these patients could potentially benefit from temporal lobectomy. Some had unilateral seizure onset or more than 90% of seizures from one side on chronic recordings, and 15 out of 25 such patients undergoing lobectomy became seizure free.³⁴

Ultra-long EEG data, primarily from intracranial RNS data, has been used to uncover the presence of circadian, multidien or circannual cycles for seizures and interictal epileptiform activity. There seems to be a preferential multidien phase of occurrence of electrographic seizures during the upslope of increased interictal epileptiform activity.³⁵ Furthermore, this technology can help with distinguishing epileptic from nonepileptic events, more accurate seizure counts, and assessing seizure laterality, which is not specific for bitemporal lobe epilepsy. Leveraging this information can potentially help in the future with seizure prediction and forecasting.

Management

In BTLE the benefit of anterior temporal lobectomy (ATL) remains uncertain, with heterogeneous and often modest seizure-freedom rates across series.^36,37 Early iEEG studies suggested that a laterality index ≥80% could clinically justify unilateral ATL, but results have been contradictive.³⁸ Alternative strategies such as selective amygdalohippocampectomy, MHT, laser interstitial thermal therapy, and radiofrequency ablation remain options for selected patients.

As a result of the limited improvements after resective surgery, neuromodulation has become a central therapeutic strategy for BTLE. VNS, RNS, and deep brain stimulation (DBS) represent the three evidence-supported approaches used in this population, each aiming to modulate pathological temporal networks without requiring resection.³⁹ Although fundamentally palliative, these modalities have demonstrated clinically meaningful reductions in seizure burden and, in selected patients, have facilitated more definitive interventions.^40,41

Evidence for VNS in BTLE remains limited but increasingly consistent. The largest VNS series for BTLE reported on 17 with a median seizure reduction from 9.5 to 2 seizures per month, with 70.5% achieving ≥50% reduction and sustained benefit over a median 36-month follow-up.⁴⁰ Importantly, the authors found comparable responder rates between scalp-EEG–defined and iEEG-confirmed BTLE.

RNS represents the most quantitatively informative modality for BTLE due to its chronic ambulatory electrocorticography (ECoG). Studies demonstrated that seizure laterality ratios obtained from inpatient scalp EEG correlated poorly with long-term RNS recordings underscoring the difficulty of accurately characterizing BTLE in short monitoring windows.⁴² Furthermore, approximately 5 to 8 months of chronic RNS are needed for reliable laterality estimation, with direct implications for surgical decision-making.⁷ Hirsch et al further extended this evidence by showing that, among 25 patients initially treated with bilateral mesial temporal RNS who subsequently underwent resection informed by chronic RNS data, median seizure reduction after surgery was 100%, including seizure freedom in 71%.³⁷ Crucially, most patients continued RNS after resection, suggesting an additive therapeutic effect in BTLE.

While direct DBS data specific to BTLE are sparse, broader thalamic DBS literature indicates robust long-term benefits in focal epilepsies with temporal involvement. Median seizure reductions of 56% to 75% over 2 to 7 years, particularly in cases with prominent mesial temporal network participation, have been reported.⁴³ The anterior thalamic nucleus, deeply interconnected with both hippocampi, represents a biologically plausible target for bilateral network modulation. Meta-analytic data further corroborate comparable long-term efficacy trajectories for VNS, RNS and DBS, with these therapies showing progressive improvement over years and increasing proportions of seizure-free patients, unlike earlier VNS cohorts.³⁹

Epilepsy Surgery in Resource-Limited Settings

Epilepsy surgery is one of the most effective treatments for drug-resistant epilepsy, yet access remains profoundly unequal, especially in low- and middle-income countries (LMICs) where over 60% of patients lack adequate care.^44,45 Managing bitemporal epilepsy exemplifies these challenges, as it requires advanced neuroimaging, prolonged video-EEG, functional mapping and, ultimately, intracranial EEG, resources often unavailable in such settings.³⁶ In Latin America and the Caribbean, around 6.3 million people live with active epilepsy (nearly 10% of the global burden), but fewer than 1% of those with drug-resistant forms reach surgical evaluation.⁴⁴ Although outcomes in well-structured LMIC centers can match those in high-income countries, systemic barriers, limited specialists, scarce diagnostic technology, and fragmented care, continue to restrict access.

In the specific context of bitemporal epilepsy, these limitations have direct consequences. While bilateral involvement has traditionally been viewed as a contraindication for resection, recent series demonstrate that careful identification of lateralized or asymmetric dysfunction, through integration of clinical semiology, structural MRI, and extended video-EEG, can yield meaningful surgical benefit.^36,46 Even in resource-limited environments, tiered evaluation algorithms can be applied to stratify surgical candidacy: beginning with noninvasive tools (neuroimaging, EEG, neuropsychology), followed by selective invasive monitoring only when indispensable.⁴⁷ Low-cost adjuncts, including radiofrequency thermocoagulation and simplified intracranial electrode arrangements can be used.⁴⁸ Furthermore, palliative neuromodulation (VNS, DBS and if available RNS), expand therapeutic options where standard resections are not feasible.³⁴

Emerging technologies such as artificial intelligence (AI) provide additional potential to facilitate access to epilepsy surgery by automating lesion detection, lateralization, and prognostic modeling, thus reducing dependence on scarce expert interpretation and, perhaps, the need of invasive monitoring.⁴⁹ In LMICs, the strategic integration of AI with tele-epilepsy networks, regional surgical referral systems, and targeted training initiatives may significantly enhance access to effective treatment, even for complex cases like bitemporal epilepsy.⁵⁰ Expanding surgical capacity in these contexts is not only clinically justified but constitutes an imperative in global epilepsy care.

Conclusion

Bitemporal lobe epilepsy is a relatively prevalent clinical entity that poses substantial diagnostic challenges, particularly in establishing bilateral temporal seizure onset. Therapeutic management is likewise complex, as seizure freedom is achieved in only a minority of patients. Accordingly, a comprehensive evaluation and careful, patient-centered discussion are essential. Moreover, well-designed prospective studies are required to systematically assess outcomes across different therapeutic strategies.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Ana Suller Marti

Naiara García Losarcos

Dragos Sabau

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