The forum introduction: Insular cortex epilepsy (ICE) was first proposed by scholars such as GUILLAUME and MAZARS. Due to the insula being hidden deep within the lateral fissure and covered by the frontal, temporal, and parietal lobes, its complex anatomical structure and dense surface vascular barrier make surgeries related to the insula quite challenging. Additionally, the insula has fiber connections with the limbic system, amygdala, basal ganglia, and all brain lobes except the occipital lobe. The complex fiber connections lead to diverse symptomatology and discharge patterns of ICE, and the interictal and ictal EEG characteristics of ICE lack distinctive features, making it difficult to differentiate from other types of epilepsy. As a result, early understanding of ICE has been inadequate, often neglecting considerations of the insula when it comes to surgical resection of the epileptogenic focus or implantation of intracranial electrodes.
1. Cortical Function and Anatomical Localization of the Insula
Research has confirmed that the insula is involved in various functions including visceral sensation and movement, somatic sensation, pain, language function, and hearing. Electrical stimulation functional mapping has become the gold standard for studying brain function, and SEEG-based cortical electrical stimulation can more accurately understand the functional characteristics and distribution of the insula. In PENFIELD’s research, stimulation of the insular cortex elicited visceral movement and sensation, taste, and somatic sensation responses.
Recent studies have shown that the symptoms related to the insula elicited by cortical electrical stimulation include somatic sensation, pain, auditory, pharyngeal symptoms, speech disorders, autonomic symptoms, and other unclassifiable symptoms. Somatic sensation is the most commonly elicited symptom, including superficial sensation and deep sensation or non-painful sensory abnormalities. The most common superficial sensations are numbness and hyperesthesia, along with thermal sensations or cold sensations. Deep sensations mainly include crawling sensations, sensations of water flowing, or kinesthetic sensations, primarily localized to the tectum and posterior central gyrus of the insula. Previous studies on the insula’s pain perception using cortical electrical stimulation have yielded varying results; for example, Wang Haixiang et al. reported that pain perception includes pinprick pain, blunt pain, or unspecified headaches, with a more dispersed distribution primarily localized to the posterior central gyrus of the insula.
The auditory responses include primary auditory hallucinations and auditory misperceptions. Auditory hallucinations manifest as “buzzing,” “whistling,” “croaking,” and sounds of animals or flowing water. Auditory misperceptions manifest as sounds becoming unclear or sounds changing from soft to loud, primarily localized to the temporal cover and the long gyrus of the insula. Laryngeal symptoms are considered specific symptoms of ICE, which can manifest as discomfort in the throat, swallowing, tightness, and choking sensations, primarily localized around the central sulcus and the posterior central gyrus of the insula.
Speech disorders mainly manifest as speech slurring or pauses in speech, primarily involving the Broca’s area of the frontal cover and anterior central cover. Autonomic symptoms primarily manifest as nausea, gastrointestinal discomfort, and palpitations, mainly seen in the extreme insula. Other unclassifiable symptoms include feelings of interruption in thought, loss of control over the head, and feelings of organ disappearance (mouth), localized to the central cover; the feeling of “becoming two people, out-of-body sensations” is localized to the tectum and temporal cover.
2. Symptomatology of ICE
Due to the unique anatomy of the insula and the complexity of its cortical functions, the symptomatology of ICE also has certain characteristics. Comprehensive data from various research centers and case reports indicate that the symptomatology related to ICE includes:
1. Consciousness state: During the onset of seizures, ICE patients do not completely lose consciousness and can communicate with the surrounding environment, which can help differentiate it from temporal lobe epilepsy, where the onset of seizures generally involves consciousness disturbances.
2. Somatic sensation symptoms: Abnormal sensations are the most common, which can manifest as tingling, warmth, electrical sensations, or pulsating sensations, and may be localized to the face, shoulders, or widely distributed across one side of the body, primarily seen in the tectum and posterior central gyrus of the insula. Some studies suggest that when abnormal sensations are accompanied by early olfactory, gustatory, visceral, or auditory symptoms, involve a larger skin area, and are bilateral or coexist with throat tightness, the likelihood of epilepsy originating from the insula is significant.
3. Visceral sensation and visceral movement symptoms: Visceral sensations are common early clinical manifestations of ICE, which can occur in the throat, abdomen, esophagus, and chest, manifesting as tightness or choking sensations in the throat, gas sensations in the abdomen (rising or not rising), abdominal pain, nausea, and chest tightness, which may be accompanied by throat-grabbing actions; visceral movement symptoms mainly occur in the pharyngeal region, manifesting as hiccups, retching, or vomiting, localized to the anterior insula.
4. Somatic movement symptoms: These primarily manifest as excessive movements and involuntary movements, with visceral, somatic sensation, gustatory, and auditory symptoms preceding the onset, respectively localized to the anterior and posterior insula.
5. Language symptoms: ICE patients may experience speech cessation while conscious during seizures, primarily related to the short gyrus of the insula.
6. Special sensory symptoms: Special sensory symptoms related to ICE include taste, hearing, and vestibular sensations. Taste often manifests as discomfort in the mouth, localized to the upper part of the insula; auditory symptoms may include simple sounds or complex sentences, as the discharges spread to the transverse gyrus of the temporal lobe; vestibular sensations mainly include symptoms of spinning, floating, and falling.
7. Autonomic nervous system symptoms: ICE patients may experience changes in heart rate, either too fast or too slow, or symptoms such as pallor, flushing, and piloerection, primarily related to the right insula.
8. Emotional responses: Emotional responses in ICE patients are primarily related to the anterior insula. Research by LANDTBLOM et al. suggests that the right insula is associated with negative emotions, sympathetic activation, and energy consumption, while the left anterior insula is associated with positive emotions, parasympathetic activation, and energy storage. Diagnosing ICE should emphasize understanding and analyzing its symptomatology. When a patient is clearly conscious early on and has sensory premonitions, if visceral movement and visceral sensation are the main manifestations, followed by somatic movement, the possibility of ICE should be considered.
3. Differential Diagnosis of ICE
The complex fiber connections between the insula and adjacent brain tissues lead to diverse symptomatology and discharge patterns of ICE. ICE can exist independently or coexist with other types of epilepsy. Epilepsy originating from the insula is not limited to the insula but can rapidly spread to other brain areas, and other types of epilepsy originating from different brain regions can also quickly spread to the insula through complex fiber connections, resulting in diverse symptomatology in ICE. This often confuses the diagnosis with temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and parietal lobe epilepsy (PLE). Depending on the different pathways of spread, ICE can present with various early manifestations such as somatic sensations, visceral, olfactory, gustatory, or vestibular symptoms, and may also exhibit changes in consciousness, muscle tone disorders, complex movements, or even autonomic nervous system functions, making the clinical features of ICE often misleading.
In a study using SEEG to record 21 cases of refractory temporal lobe epilepsy, it was found that in 81 recorded clinical seizures, the discharges involved the insula, with the most common area being the ipsilateral hippocampus. Another study also found that in the included TLE patients, the discharge during seizures spread to the insula, and different electrophysiological patterns were observed during the spread, primarily depending on the role of the hippocampus or temporal pole in the onset of seizures.
From an anatomical perspective, the insula has the closest fiber connections with the temporal lobe. From a symptomatological perspective, the clinical manifestations of ICE patients are diverse, and although the symptomatology is similar to focal epilepsy, it is difficult to differentiate from TLE, FLE, and PLE. However, when early consciousness is clear, and interaction with the outside world is possible, and symptoms such as throat tightness and drooling occur, ICE should be highly suspected. Some studies suggest that the spread of discharges to the insular cortex occurs early and frequently during the onset of TLE, following two constant patterns of preferential spread from the amygdala and hippocampus to the cingulate gyrus and orbitofrontal cortex.
Additionally, in a study on temporal plus epilepsy (TPE), the insula’s role in its diagnosis and treatment cannot be ignored, as the insula participates in its complex epileptogenic network, indicating tight connections between the temporal lobe and adjacent structures such as the insula with the superior frontal cover, orbitofrontal cortex, and the junction of the temporal, parietal, and occipital lobes. Therefore, a comprehensive assessment of the anatomical, electrical, and clinical characteristics of epilepsy patients, combined with other auxiliary examinations, will help in diagnosing ICE.
4. Epilepsy Networks Related to ICE
The abnormal discharges in epilepsy affect brain regions far beyond the range of local epileptogenic foci, involving corresponding functional and structural brain areas, leading to a re-evaluation of the nature of epilepsy and suggesting that epilepsy is a network disease of the brain. In epilepsy network research, the epileptogenic network is defined as the brain regions involved in the generation and propagation of epileptic discharges, and the concept of the epileptogenic network can better describe the complexity of dynamic evolution during seizures and more accurately depict the abnormal distribution of epileptogenicity in brain tissue.
Due to the complexity of the functions and epileptogenic networks involving the insula, which have not only structural connections but also functional connections with other brain lobes, the insula often serves as a “node” in the conduction network. The types of seizures and discharge patterns in ICE often exhibit diversity. Research indicates that the characteristics during interictal periods involve changes in functional connectivity due to abnormal electrical activity generated by the epileptogenic network (interictal spikes), while ictal symptomatology results from the abnormal activation or disruption of normal brain functional network mechanisms.
There are three types of epileptogenic networks involving the insula: 1) Temporal lobe – perisylvian – insular network, which is defined by the lateral fissure and involves different brain regions surrounding the insula, including the frontal, parietal, and temporal covers; 2) Temporal lobe – limbic system – insular network, primarily including the medial structures of the temporal lobe and/or the temporal pole; 3) Medial temporal and orbitofrontal – insular network, including the medial insula and orbitofrontal parts. Although these research findings reveal the anatomical and functional network connections of the insula, they do not elucidate the conduction patterns of discharges during the onset and spread of ICE and the related network connections.
In ISNARD’s application of SEEG to record signals from the insula, three conduction patterns of insular discharges were discovered: 1) conduction from the anterior insula to the temporal cover of the insula; 2) conduction from the posterior insula to the medial hippocampal structures; 3) conduction from the posterior insula to the anterior insula, then to the temporal cover. The conduction time of these discharges ranged from 0.2s to 15s. This indicates that the insula is closely connected to the temporal lobe both structurally and functionally, and reveals the different conduction patterns of discharges, laying the foundation for the diversity of ICE symptomatology.
Mei Shanshan et al. proposed two conduction modes of electrical activity in the insula: 1) conduction from lateral to medial, from the lateral cortical surface of the insula to its deep structures or from the temporal cover of the insula to its cortical surface; 2) conduction from medial to lateral, from the cortical surface of the insula to the top cover or temporal cover of the insula. Furthermore, some researchers have studied the insula in relation to cognitive and emotional functions, proposing three networks associated with cognitive and emotional functions: the salient network, executive network, and default network, suggesting that the anterior insula is fundamental for detecting salient external events, capable of influencing cognitive functions, and serves as a hub for switching between different networks.
From the perspective of the concept of the epileptogenic network, the fiber bundles related to the insula serve as the basis for the symptomatology of ICE and related epilepsy networks, providing reliable evidence for understanding ICE’s symptomatology, conducting precise preoperative assessments, and differentiating it from focal epilepsy.
5. Application of SEEG and Associated Electrophysiological Indicators in ICE
SEEG, as a new technology, has advantages such as minimal trauma, accurate localization, coverage of deep structures, fewer complications, and prolonged monitoring time. The application of SEEG can clarify the epileptogenic zones, study the relationship between the epileptogenic zones and functional areas, and evaluate the feasibility of surgical treatment, becoming a key technology for precise preoperative assessment in epilepsy surgery.
The role of SEEG and cortical electrical stimulation has been widely proven to be crucial in defining the symptomatology of ICE through an “anatomical-electrical-clinical” approach. SEEG can facilitate the collection of intracranial EEG signals and select appropriate stimulation intensities for functional localization and studies on the initiation network and early spread network. In a study using SEEG for children with ICE, the results indicated that SEEG is a safe and reliable preoperative examination method for this population, with 7 out of 8 patients included in the study achieving Engel I-level outcomes.
Electrophysiological indicators based on SEEG are crucial for understanding ICE and its epileptogenic networks, further guiding surgical interventions for ICE. High-frequency oscillations (HFO), direct current shifts (DC shift), and epileptogenic index (EI) are considered to play significant roles in localizing the epileptogenic zones. HFO is regarded as a characteristic electrophysiological marker of the epileptogenic zone. EI is a quantitative analysis method based on the spectral and temporal characteristics of intracranial EEG signals, aimed at providing quantitative information on the behavior of brain structures during seizures (from onset to end) and objectively quantifying and defining the neural network during seizures.
EI assesses the epileptogenicity of each structure and can classify seizures based on the onset zone, enabling the quantification of EEG signals and their application in brain network studies. Additionally, when high-frequency electrical activity originating from the onset rapidly involves multiple brain regions covered by electrodes, the quantitative analysis of EI provides evidence for determining the onset zone and early spread network and helps quantitatively evaluate the strength of epileptogenicity in the recorded brain regions, analyzing the spatiotemporal evolution of the epileptogenic network. Therefore, this indicator can be used in studies of ICE networks.
In summary, due to the insula’s significant role in the epileptogenic system, there is an increasing understanding and research on the insula and ICE. There is a certain understanding of the anatomy, function, and related epileptogenic networks of the insula. In the context of modern neurosurgery, we hope to combine SEEG-based EEG post-processing technology and imaging post-processing technology to study the initiation network and early spread network related to the insula. This will not only assist in accurately locating the seizure onset zone to improve surgical efficacy and benefit patients but also help us understand the abnormal brain networks of epilepsy as a heterogeneous brain disease.
Source: Shen Yunjuan, He Wenbin, Zhang Xinding. Advances in Research on Insular Cortex Epilepsy and Its Epileptic Networks [J]. Chinese Journal of Neurology and Mental Disorders, 2019, 45(11): 697-700.
