Resective surgery in tuberous sclerosis complex-related epilepsy: tuberectomy and tuberectomy plus

Introduction: tuberous sclerosis complex and epilepsy

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome affecting multiple organ systems . Estimates of TSC incidence vary, generally ranging between 1:6000 and 1:13,520 live births . In the brain, the primary structural abnormalities include subependymal nodules (84.6%, 181/214), cortical tubers (73.4%, 157/214), and subependymal giant cell astrocytomas (8.4%, 18/214) . Common neurological manifestations comprise epilepsy, intellectual disabilities (56.5%, 203/359), and TSC-associated neuropsychiatric disorders (83.2%, 95/111) . Epilepsy is present in 83.5% (248/297) of individuals, with 46.2% (188/407) experiencing epileptic spasms and 52.7% (147/279) having focal seizures . Moreover, 54.1% (151/279) of TSC patients suffer from medically resistant epilepsy . In children with TSC, there is a correlation between the epilepsy-neurocognitive phenotype, with epilepsy significantly contributing to the presence of intellectual disabilities. Patients with intellectual disabilities tend to experience their first seizure attacks earlier, require more antiseizure medications (ASMs), exhibit a greater variety of seizure types, and have higher seizure frequencies .

Variations in the TSC1/TSC2 genes, leading to the disinhibition of the mammalian target of rapamycin (mTOR), are the underlying pathogenic mechanisms of TSC . The majority of patients with TSC2 gene variants are sporadic cases, whereas approximately half of the patients with TSC1 gene variants have a familial history. This is illustrated by a study documenting five generations of a large Chinese family with TSC1 gene mutations . The detection rates for TSC1 and TSC2 gene variants are 22.2% (105/473) and 67.2% (318/473), respectively, with 10.6% (50/473) of patients showing no gene mutations . The prevalence of epilepsy is significantly higher in the TSC2 group compared to the TSC1 group and those with no identified mutations . Individuals with TSC2 variants are more prone to epileptic spasms compared to those with TSC1 variants (130/301 vs 21/66) . The onset of epilepsy is earlier in individuals with TSC2 gene variants than in those with TSC1 mutations or without TSC1/TSC2 gene mutations . Moreover, patients with TSC2 mutations present with a higher number of tubers compared to those with TSC1 mutations. The clinical phenotype in children with familial TSC tends to be more severe than that observed in their parents .

Rationality and clinical basis of resective surgery in tuberous sclerosis complex-related epilepsy

TSC is a genetic disorder characterized by multiple pathological changes, leading to a debate on the effectiveness of resective surgery for TSC-related epilepsy . However, epilepsy in TSC patients is primarily associated with cortical tubers rather than subependymal nodules or subependymal giant cell astrocytomas. Notably, cortical tubers typically reach a stable phase by the age of 12 months . Long-term preoperative scalp eletroencephalograms (EEGs) reveal that approximately 90% of patients have stable epileptogenic tubers, and postoperative scalp EEGs show that more than 86% of patients do not develop new epileptogenic tubers within a 3-year follow-up period . Moreover, research indicates that not all cortical tubers are epileptogenic .

The success of postoperative seizure outcomes highlights the efficacy of resective epilepsy surgery in patients with TSC-related epilepsy . The primary goal of epilepsy surgery is seizure control rather than curing TSC . Surgical intervention is recommended for patients with medically resistant epilepsy or epilepsy linked to an epileptogenic lesion, making those with localized epileptogenic tubers and medically resistant TSC-related epilepsy ideal candidates for resective surgery.

In a nationwide multicenter study in China involving 364 patients (mean age at surgery: 10.35±7.70 years, range: 0.5–47 years, median: 8.45 years) who underwent resective surgery for medically resistant TSC-related epilepsy, the rates of postoperative seizure freedom were 71%, 60%, and 51% at 1, 4, and 10 years postsurgery, respectively . Positive prognostic factors included complete removal of epileptogenic tubers, the presence of significant tubers (defined as larger than 3 cm with a calcification nidus) on magnetic resonance imaging (MRI), and low preoperative seizure frequency for 1-year postoperative seizure freedom. For longer-term outcomes, the complete removal of epileptogenic tubers and the presence of outstanding tubers on MRI at 4 and 10 years remained positive factors . Other studies have identified late seizure onset, regional or lateral interictal EEG patterns, and temporal lobe surgery as positive predictors of postoperative seizure freedom. In contrast, ictal generalized EEG charge, a long history of preoperative seizures, and low preoperative intelligence quotient (IQ) were associated with poorer outcomes . Postoperative improvements in quality of life and intelligence quotient were observed in 43% (112/262) and 28% (67/242) of patients, respectively, particularly among those who achieved postoperative seizure freedom and had a low preoperative intelligence quotient .

Classification of epileptogenic tubers and approaches to resective surgery

Epileptogenic tubers are categorized into three distinct types, as illustrated in Fig. 11.1 :

Figure 11.1

Classification of epileptogenic tubers

. The blue line shows the boundary between the tuber and cortex.
ET-I Tubers: These tubers are situated in the middle of a cerebral sulcus, using the sulcus itself as a clear demarcation between the tuber and the adjacent peri-tuberal cortex. They are interconnected with other brain tissues via deep structures.
ET-II Tubers: The boundary of these tubers with the cortex is distinctly marked by a sulcus on one side, while the other boundary within the gyrus is less defined.
ET-III Tubers: These tubers have an indistinct boundary with the cortex, typically situated within the central region of a gyrus.

According to unpublished data, the distribution of epileptogenic tubers among patients is as follows: 17% have ET-I tubers, 59% have ET-II tubers, and 24% are characterized by ET-III tubers.

The approaches to resective surgery in the context of TSC-related epilepsy include lobectomy, tuberectomy, tuberectomy plus, and combined operations.

1.

Lobectomy: This procedure, akin to lobectomies performed for other types of epilepsy, involves the removal of an entire lobe or a part of it. Common types include anterior or total temporal lobectomy, frontal lobectomy, and occipital lobectomy. It is suitable for patients with large or multiple epileptogenic tubers located in the temporal, frontal, or occipital lobes. Lobectomy can also be combined with another lobectomy, tuberectomy, or tuberectomy plus (as shown in Fig. 11.2 ). The scope of resection in a lobectomy should encompass all epileptogenic tubers within the lobe, including those that propagate rapidly, and should extend at least to the affected gyrus. In temporal lobectomies, the hippocampal structure is generally preserved, especially in the dominant hemisphere, except when a tuber is present in the hippocampus or there is definitive evidence of hippocampal involvement in epileptogenesis (as shown in Fig. 11.3 ).

Figure 11.2

The approaches of resective surgery.

Figure 11.3

Lobectomy (panels A and B) and tuberectomy plus (panels C and D). In the first case, two epileptogenic tubers are identified in the right temporal lobe on a preoperative axial fluid attenuated inversion recovery (FLAIR) image (A). A right temporal lobectomy is subsequently performed, involving the removal of the entire temporal neocortex, tubers included, while preserving the hippocampus (B). In a separate case, epileptogenic tubers are located in the right parietal lobe, as shown on a preoperative sagittal FLAIR image (C). Here, a “tuberectomy plus” is executed, entailing the excision of the tuber along with the surrounding peri-tuberal cortex (D).
2.

Tuberectomy involves the removal of the epileptogenic tuber and the affected gyrus (see Figs. 11.3 and 11.4 ). This procedure is applicable to all patients with TSC-related epilepsy and can be combined with a lobectomy, tuberectomy plus, or another tuberectomy (refer to Fig. 11.2 ). Tuberectomy is typically conducted with the aid of intraoperative imaging navigation to ensure the precise removal of the targeted tuber (illustrated in Fig. 11.5 ). For ET-I tubers, the arachnoid and pia mater are coagulated and cut at the tuber’s surface. The tuber is then dissected and exposed along the pia mater down to the bottom of the sulcus. Tubers in noneloquent brain areas can be removed in an en-bloc or piecemeal fashion, whereas piecemeal resection is preferred in eloquent brain areas to minimize risk. En-bloc resection allows for a clear delineation of the tuber’s boundary and ensures complete removal but may increase the risk of injury to the surrounding cortex. Conversely, piecemeal resection reduces the risk of damage to the surrounding peri-tuberal cortex but may require more time to confirm the boundaries, potentially leading to incomplete removal. The resection depth should reach the gray matter at the bottom of the sulcus without excessively removing white matter to avoid damaging deep brain conduction tracts. For ET-II and ET-III tubers, resection should follow along the pia mater of the sulcus or the less defined boundary within the gyrus, ensuring the affected gyrus is completely removed beneath the pia mater. It is crucial to meticulously preserve the arterial blood supply to prevent ischemia in the surrounding cortex.

Figure 11.4

Sketch of tuberectomy and tuberectomy plus in a patient with a type-II epileptogenic tuber. The blue line indicates the boundary between the tuber and the cortex; the red line outlines the extent of resection for tuberectomy; and the light blue line delineates the resection boundaries for tuberectomy plus.

Figure 11.5

Image-guided epileptogenic tuberectomy. Preoperatively, the epileptogenic tuber was constructed on each FLAIR plane (A). During the surgery, the location of the epileptogenic tuber was displayed on cortical imaging using a navigation stick (B). After the excised epileptogenic tubers were removed (C), the complete removal of the epileptogenic nodules was verified again using the navigation stick (D).
3.

Tuberectomy plus is a procedure designed to excise the epileptogenic tuber, the affected gyrus, and the surrounding peri-tuberal cortex (as illustrated in Figs. 11.4 and 11.5 ). This approach is suitable for patients with epileptogenic tubers located away from the primary motor and sensory areas of the brain. It can be integrated with a lobectomy, tuberectomy, or another tuberectomy plus procedure (refer to Fig. 11.2 ). Tuberectomy plus can be conducted as either a one-stage or a two-stage operation. In a one-stage operation, the tuber and surrounding peri-tuberal cortex are removed en-bloc in a single procedure. This begins with the coagulation and cutting of the arachnoid and pia mater at the surface midway across the adjacent gyrus, followed by en-bloc removal of the lesion along the pia mater from the outer sulcus of the surrounding gyrus. A two-stage operation involves initially resecting the tuber itself, following the pia mater of the sulcus or the less defined boundary within the gyrus. Subsequently, the affected gyrus and the adjacent gyri are resected separately. It is crucial to meticulously preserve the arterial blood supply and the large drainage veins of the surrounding cortex to avoid ischemic damage.

Relationship between the epileptogenic zone and epileptogenic tuber

The primary distinction between tuberectomy and tuberectomy plus lies in the extent of the resection. Tuberectomy plus extends beyond the region removed in tuberectomy to include the surrounding peri-tuberal cortex, the affected gyrus, and the tuber itself. However, tuberectomy plus is not recommended for epileptogenic tubers located within the primary motor or sensory functional areas due to the risk of postoperative permanent functional deficits. This raises the question: For epileptogenic tubers situated outside these primary functional areas, should a neurosurgeon opt for tuberectomy or tuberectomy plus? The decision hinges on the relationship between the epileptogenic zone and the epileptogenic tuber.

1.

Pathological findings: The pathology of TSC tubers shares similarities with focal cortical dysplasia type-IIb, characterized by mild to severe disruption of cortical lamination, the presence of dysplastic neurons, and giant cells. Additionally, there is an overall increase in mTORC1 activity, a decrease in mTORC2 activity, enhanced axonal connectivity and growth, and hypomyelination . The surrounding peri-tuberal cortex exhibits similar histologic, immunohistochemical, and molecular features, albeit to a milder degree . While tubers may represent the most pronounced developmental anomaly in TSC, more widespread yet subtle abnormalities exist in the region . Due to the role of dysplastic neurons in spontaneous discharges, either the tuber or the surrounding peri-tuberal cortex could constitute the epileptogenic zone. Moreover, the peri-tuberal cortex may exhibit increased cortical thickness, abnormal gyration, blurring of the gray-white matter junction, and transmantle abnormalities .
2.

Neuroimage findings: The presence of cortical dysplasia features near a tuber or a hypometabolic region on interictal 18fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) images, which is larger than the tuber’s size on MRI-FLAIR images, may indicate an epileptogenic tuber . Seizure activity is often traced back to regions of pronounced FDG-PET hypometabolism surrounding tubers, with higher diffusion tensor imaging apparent diffusion coefficients noted in the subtuberal white matter . [11C]Methyl-L-tryptophan PET imaging has also been used to identify epileptogenic tissue surrounding tubers of interest . Advanced imaging techniques such as 7T-MRI, white matter suppression sequences, and gray-white matter tissue border enhancement sequences have improved the assessment of structural details in the peri-tuberal cortex of patients with TSC-related epilepsy . Diffusion tensor imaging studies have shown that the extent of diffusion abnormalities decreases with distance from the tuber, aligning with the known spread of histologic, immunohistochemical, and molecular abnormalities beyond the tuber pathology .
3.

Neurophysiology findings: Kannan et al. documented 15 electro-clinically distinct seizures across ten patients, with all seizure onsets recorded within tubers. These onsets occurred at the tuber center, sometimes involving the tuber rim or the junction between the tuber and the surrounding peri-tuberal cortex, but not within the surrounding peri-tuberal cortex itself. However, this study relied on data from extra-operative subdural electrodes and intraoperative cortical EEG, lacking EEG data from the true center of the tubers. Our stereo-EEG data indicates that approximately 40% of seizure onset zones are located at the tuber rim, 35% involve both the center and rim, 20% are in the tuber center, and 5% occur at the tuber rim and extend into the surrounding peri-tuberal cortex (unpublished data). High-frequency oscillation studies reveal that 471 (24.2%) of 1944 contacts from 144 implanted stereo-EEG electrodes detected fast ripples, including 75 (3.9%) contacts with high rates of fast ripples (frequency of fast ripples at a contact / highest frequency of fast ripples across all contacts in the same patient >0.5). Additionally, 102 (67.1%) of 152 covered tubers showed fast ripple activity. The frequency of fast ripple discharges varied significantly across tuber anatomy ( P <0.01), with 62.7% (47 of 75) of high-rate fast ripple contacts located at the tuber rim, 34.7% in the center, and 2.7% outside the tubers . Cortico-cortical evoked potential studies demonstrated a 100% occurrence rate from the rim of epileptogenic tubers to the rim of early propagating tubers, significantly higher than other observed rates. This indicates a stronger connection between the rim of epileptogenic tubers and other tubers or the surrounding peri-tuberal cortex compared to the tuber center . Thus, the tuber rim is a critical component of the epileptogenic zone, as evidenced by ictal stereo-EEG, interictal high-frequency oscillation analysis, and cortico-cortical evoked potential studies.
4.

Magnetoencephalography (MEG) findings: MEG data in TSC patients revealed a broad distribution of multilobar MEG spike sources. A significant correlation was found between the maximal resection of these scattered MEG spike sources and improved seizure outcomes, highlighting the potential role of these sources within a complex epilepsy network and as part of extensive epileptogenic zones in TSC . Koptelova et al. reported on seven patients who underwent resective surgery, noting that ictal MEG was instrumental in identifying the lobar location of the seizure onset zone in two cases and confirming the onset zone location derived from interictal data in four others.

Seizure control after tuberectomy and tuberectomy plus

Several original studies and reviews have analyzed predictors of seizure outcomes in patients with TSC-related epilepsy following various resective surgeries . While most research has focused on comparing tubectomy and lobectomy, the investigation into postoperative seizure control differences between tuberectomy and tuberectomy plus remains relatively scarce. To address this gap, a metaanalysis was conducted to assess seizure control outcomes following these two surgical interventions.

Comprehensive electronic literature searches were conducted in PUBMED, EMBASE, and COCHRANE databases from their inception until September 2022. The search terms included “Tuberous Sclerosis Complex,” “seizure/epilepsy,” “surgery,” and related MeSH terms and synonyms. The specific search strategies for each database were as follows:

PUBMED: #1 (“Tuberous Sclerosis”[Mesh Terms]) OR (tuberous sclerosis complex[Title/Abstract]) OR (TSC[Title/Abstract]) OR (tuberous sclerosis[Title/Abstract])); #2 (“seizures”[MeSH Terms]) OR (“Epilepsy”[MeSH Terms]) OR (seizure*[Title/Abstract]) OR (epilepsy [Title/Abstract]); #3 (“surgery”[Subheading] OR (“general surgery”[MeSH Terms]) OR (surg*[Title/Abstract]) OR (operation[All Fields]) OR (“Surgical Procedures, Operative”[Mesh Terms]) OR (resec*[Title/Abstract]) OR (tubectom*[All Fields]) OR (lobectom*[All Fields]) OR (lesionectom*[All Fields]) OR (lobar resection[All Fields])); #4=#1 AND #2 AND #3.
EMBASE: #1 “tuberous sclerosis complex”:ab OR “tuberous sclerosis”:ab; #2 “surgery”:ab OR “lobectomy” OR tubectomy OR “lesionectomy” OR “lobar resection”; #3 “seizure”:ab OR “epilepsy”:ab; #4=#1 AND #2 AND #3.
CONCHRANE: TSC AND surgery AND epilepsy.

Two reviewers independently conducted the screening of titles and abstracts, followed by a full-text review. They compiled a list of all citations excluded after the full-text review, providing justifications for each exclusion. Any disagreements between reviewers were resolved through discussion, based on predefined criteria (as outlined in Table 11.1 ). Ultimately, out of 1276 records screened, 23 articles were subjected to a full-text review, and three articles met the inclusion criteria. The studies included had sample sizes ranging from 29 to 163 subjects, with a total of 243 participants across all studies. Of these, 166 participants (68.3%) achieved a favorable surgical outcome, classified as Engel Class I or ILAE Type 1.

Table 11.1

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