The role of neurosurgery in the management of tuberous sclerosis complex–associated epilepsy: a systematic review

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  • 1 Southern Illinois University School of Medicine, Springfield, Illinois;
  • | 2 Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
  • | 3 Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
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OBJECTIVE

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem neurocutaneous disorder associated with cortical tubers, brain lesions seen in nearly all patients with TSC, which are frequently epileptogenic. Seizures are often the earliest clinical manifestation of TSC, leading to epilepsy in over 70% of patients. Medical management with antiepileptic drugs constitutes early therapy, but over 50% develop medically refractory epilepsy, necessitating surgical evaluation and treatment. The objective of this study was to summarize the literature and report seizure outcomes following surgical treatment for TSC-associated epilepsy.

METHODS

A systematic literature review was performed in accordance with the PRISMA guidelines. The PubMed and Embase databases were searched for journal articles reporting seizure outcomes following epilepsy surgery in TSC patients. Included studies were placed into one of two groups based on the surgical technique used. Excellent and worthwhile seizure reductions were defined for each group as outcomes and extracted from each study.

RESULTS

A total of 46 studies were included. Forty of these studies reported seizure outcomes following any combination of resection, disconnection, and ablation on a collective 1157 patients. Excellent and worthwhile seizure reductions were achieved in 59% (683/1157) and 85% (450/528) of patients, respectively. Six of these studies reported seizure outcomes following treatment with neuromodulation. Excellent and worthwhile seizure reductions were achieved in 34% (24/70) and 76% (53/70) of patients, respectively.

CONCLUSIONS

Surgery effectively controls seizures in select patients with TSC-associated epilepsy, but outcomes vary. Further understanding of TSC-associated epilepsy, improving localization strategies, and emerging surgical techniques represent promising avenues for improving surgical outcomes.

ABBREVIATIONS

CCT = corpus callosotomy; DTI = diffusion tensor imaging; DWI = diffusion-weighted imaging; EEG = electroencephalography; fMRI = functional MRI; HFO = high-frequency oscillation; IED = interictal epileptiform discharge; iEEG = intracranial EEG; MEG = magnetoencephalography; RNS = responsive neurostimulation; ROBINS-I = Risk of Bias in Non-randomised Studies—of Interventions; sEEG = stereo-EEG; SISCOM = subtraction ictal SPECT coregistered to MRI; TSC = tuberous sclerosis complex; VNS = vagus nerve stimulation.

OBJECTIVE

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem neurocutaneous disorder associated with cortical tubers, brain lesions seen in nearly all patients with TSC, which are frequently epileptogenic. Seizures are often the earliest clinical manifestation of TSC, leading to epilepsy in over 70% of patients. Medical management with antiepileptic drugs constitutes early therapy, but over 50% develop medically refractory epilepsy, necessitating surgical evaluation and treatment. The objective of this study was to summarize the literature and report seizure outcomes following surgical treatment for TSC-associated epilepsy.

METHODS

A systematic literature review was performed in accordance with the PRISMA guidelines. The PubMed and Embase databases were searched for journal articles reporting seizure outcomes following epilepsy surgery in TSC patients. Included studies were placed into one of two groups based on the surgical technique used. Excellent and worthwhile seizure reductions were defined for each group as outcomes and extracted from each study.

RESULTS

A total of 46 studies were included. Forty of these studies reported seizure outcomes following any combination of resection, disconnection, and ablation on a collective 1157 patients. Excellent and worthwhile seizure reductions were achieved in 59% (683/1157) and 85% (450/528) of patients, respectively. Six of these studies reported seizure outcomes following treatment with neuromodulation. Excellent and worthwhile seizure reductions were achieved in 34% (24/70) and 76% (53/70) of patients, respectively.

CONCLUSIONS

Surgery effectively controls seizures in select patients with TSC-associated epilepsy, but outcomes vary. Further understanding of TSC-associated epilepsy, improving localization strategies, and emerging surgical techniques represent promising avenues for improving surgical outcomes.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with a birth incidence of approximately 1 per 6000 to 10,000.1 Arising from inactivating mutations in the tumor suppressor genes TSC1 (hamartin) and TSC2 (tuberin), TSC is characterized by widespread hamartomas in multiple organ systems.2 In the CNS, characteristic lesions include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas.3 Other prominent neurological manifestations include epilepsy and TSC-associated neuropsychiatric disorders.2,3 Epilepsy may be the most prevalent and challenging to manage, occurring in over 70% of patients with TSC and often requiring neurosurgical intervention.2

The lesion associated with epilepsy in TSC is the cortical tuber: aggregates of large abnormal cells lacking normal cortical lamination, present in 80%–90% of TSC patients, and found anywhere in the parenchyma.2,3 These lesions and the perituberal cortex are potential epileptogenic foci,47 but cortex without clear structural lesions can be epileptogenic as well.5,8 Although it is thought that most seizures in TSC-associated epilepsy have a focal onset,9 both focal and generalized seizure semiologies can occur.2,6,1013

Earlier onset of seizures is associated with more severe developmental impairment and epilepsy.14 Thus, management is focused on preventing or controlling seizures as soon as possible to maximize quality of life and potentially improve neurodevelopment.14 Medical management with antiepileptic drugs constitutes preventative, first-line, and second-line therapies.14 However, over 50% of TSC patients develop epilepsy refractory to antiepileptic drugs,6 necessitating alternative treatment options. Alternative nonsurgical treatment options include a ketogenic diet, everolimus, and cannabidiol treatment, but surgery should always be considered for TSC patients with medically refractory epilepsy.14 With emerging and constantly evolving traditional surgical techniques, surgery is being offered to more TSC patients to treat epilepsy. To evaluate the effectiveness of surgery for TSC-associated epilepsy, we performed a systematic review of all literature from 2000 to 2022 reporting seizure outcomes following epilepsy surgery in TSC patients. We also discuss the current landscape regarding the role of neurosurgery in the management of TSC-associated epilepsy.

Methods

Search Strategy and Selection Criteria

A systematic review was performed according to the PRISMA guidelines. The PubMed and Embase databases were searched for journal articles from January 1, 2000, to January 24, 2022, using appropriate combinations of the following keywords and phrases: tuberous sclerosis, surgery, epilepsy, epileptogenic, tubers, ablation, stimulation, and neurostimulation. To be considered for inclusion, articles had to report seizure outcomes and exact follow-up times for ≥ 5 TSC patients treated with resection, disconnection, ablation, or neuromodulation. Additionally, included studies must have had a study period that did not completely overlap with another study utilizing similar surgical techniques (i.e., had to include unique patients), as well as have been original retrospective or prospective investigations. Animal studies, non–English-language articles, and review articles without unique patients were excluded.

Data Extraction and Outcomes

Articles meeting the inclusion criteria were divided into two groups: those including data on any combination of resection, disconnection, and ablation (group 1, mechanical interventions) and those including data on neuromodulation (group 2, electrical interventions). From studies in both groups, the number of surgically treated TSC patients, age of seizure onset, age at surgery or time of study, follow-up time, and number of patients with excellent and worthwhile seizure reduction were extracted. For group 1, excellent seizure reduction was defined as Engel class I, Engel classes IA and IB,15 ILAE (International League Against Epilepsy) classes 1 and 2,16 100% seizure reduction, or an explicit statement of seizure freedom. Worthwhile seizure reduction was defined as Engel classes I–III, Engel classes IA–IIIB,15 ILAE classes 1–4,16 ≥ 50% seizure reduction, or an explicit statement of worthwhile seizure reduction. Additionally, localization modalities and surgical strategies utilized in these studies were extracted. For group 2, excellent seizure reduction was defined as McHugh class I, McHugh classes IA and IB,17 or ≥ 80% seizure reduction. Worthwhile seizure reduction was defined as McHugh classes I and II, McHugh classes IA–IIB,17 or ≥ 50% seizure reduction. The type of neuromodulation treatment utilized in these studies was also extracted. Across all studies in each group, excellent and worthwhile seizure reduction data were combined to estimate overall seizure outcomes. For studies with multiple follow-up times, the latest follow-up time that included the total number of patients in that study was used when combining seizure outcomes. Risk of bias was assessed using the ROBINS-I (Risk of Bias in Non-randomised Studies—of Interventions) tool for nonrandomized studies.18

Results

The PubMed and Embase searches returned 1063 records (Fig. 1). Of these, 296 duplicates, 1 book chapter, and 1 retracted article were removed, leaving 765 journal articles. After title and abstract screening, the full text of 252 articles were screened and 46 articles were included. Articles were often excluded due to irrelevant focus, absence of seizure outcomes and/or follow-up times for only TSC patients, a study period completely overlapping with another study, reporting < 5 patients, or a combination of the four.

FIG. 1.
FIG. 1.

PRISMA search flow diagram.

Of the 46 included studies, 40 (87%) were put in group 1 (Table 1). Across all these studies, a collective 683 (59%) of 1157 patients had excellent seizure reduction following treatment with any combination of resection, disconnection, and ablation. Moreover, across these studies reporting enough outcome information, a collective 450 (85%) of 528 patients had worthwhile seizure reduction. The remaining 6 studies (13%) were put in group 2 (Table 2). Across all these studies, 24 (34%) and 53 (76%) of 70 patients had excellent and worthwhile seizure reductions, respectively, following treatment with neuromodulation. For each group, the relationship between seizure outcome and follow-up time is summarized in Fig. 2.

TABLE 1.

List of included studies using any combination of resective, disconnective, and ablative surgery (group 1, mechanical interventions)

Authors & YearInstitution (study period)No. of Pts w/ Op & FUAge at Sz Onset, yrs*Age at Time of Op/Study, yrs*Localization ModalitySurgical StrategyFU, yrs*No. of Pts w/ Excellent Sz Reduction (%)No. of Pts w/ Worthwhile Sz Reduction (%)
Koh et al., 200019Miami Children’s Hospital (—)124.0 (0.3–10.7)CT, MRI, scalp EEG, SPECT, iEEGFR2.7 (0.5–6.8)9 (75)10 (83)
Asano et al., 200020Wayne State University (—)75.6 (0.6–16.2)MRI, scalp EEG, FDG-PET, AMT-PET, iEEGFR, L1.4 (0.3–2.3)5 (71)7 (100)
Karenfort et al., 200221Epilepsy Centre Bethel (1996–2001)81.3 (0–6)10.0 (0.5–34.3)CT, MRI, scalp EEG, FDG-PET, iEEGFR, L, HO1.6 (0.5–4.3)2 (25)8 (100)
Mackay et al., 200322The Hospital for Sick Children (1990–2000)60.7 (0–3.5)6.3 (1.8–12.8)MRI, scalp EEG, MEG, SPECT, FDG-PET, iEEGL, adjunctive MST5.1 (3.2–7.8)2 (33)
Jarrar et al., 200423Mayo Clinic Rochester (1986–2002)222.6 (0–25)12.5 (1–54)MRI, scalp EEG, SPECT, iEEGFR, L, CCT113 (59)
Lachhwani et al., 200524Cleveland Clinic (1981–2003)17Median 0.8 (0–11)Median 12 (0.2–31)MRI, scalp EEG, iEEGLMedian 2.1 (0.5–15)11 (65)
Kagawa et al., 200525Children’s Hospital of Michigan (November 1996–March 2003)170.6 (0–3.5)4.7 (0.3–12.3)MRI, scalp EEG, FDG-PET, AMT-PET, iEEGFR, L, HE1.9 (0.4–4.8)12 (71)14 (82)
Asano et al., 200526Children’s Hospital of Michigan (May 2001–October 2004)80.3 (0–0.8)3.3 (0.4–7)MRI, scalp EEG, FDG-PET, iEEGFR, L2.3 (0.3–3.8)6 (75)8 (100)
Weiner et al., 200627New York University (—)254.4 (0.6–16.6)CT, MRI, scalp EEG, MEG, SPECT, PET, iEEGFR, L0.5, 2.3 (0.5–6.2)21 (84), 17 (68)23 (92), 25 (100)
Madhavan et al., 2007286 centers: 1 France, 2 Canada, 3 US (1977–2003)701.1 ± 1.70.8 ± 0.9CT, MRI, scalp EEG, SPECT, PET, iEEGFR, L, CCT, HE5.2 ± 8.037 (53)58 (83)
Teutonico et al., 2008293 centers: 2 Italy, 1 US (1992–2007)110.5 ± 0.60.6 ± 0.8CT, MRI, scalp EEG, MEG, SPECT, MRS, iEEGFR, FR+Median 5 (0.6–14)3 (27)9 (82)
Sugiyama et al., 200930The Hospital for Sick Children (2006–2009)80.6 (0.1–1.1)7.6 (2.2–18.1)MRI, scalp EEG, MEG/SAMFR, L, CCT1.1 (0.1–2.8)5 (63)
Moshel et al., 201031New York University (2000–2008)150.3 (0.1–0.6)3.7 (1–7)MRI, scalp EEG, MEG, SPECT, PET, iEEGFR3.3 (0.3–7.5)9 (60)14 (93)
Hemb et al., 201032University of California, Los Angeles (January 1986–December 2008)24212 (50)
van der Heide et al., 201033University Medical Centre, Utrecht (1998–2008)6Median 1.6 (0.2–12)12.9 (2–29)MRI, scalp EEG, MEG, Wada test, iEEGFR, LMedian 4.2 (2.8–7)3 (50)4 (67)
Aboian et al., 201134Mayo Clinic Rochester (1998–2008)60.5 (0–0.7)5.4 (0.7–13)MRI, scalp EEG, SPECT/SISCOMFR, L4.4 (2–9.5)3 (50)4 (67)
Ochi et al., 201135The Hospital for Sick Children (June 2003–December 2008)131.0 (0.1–6)5.8 (1.1–17)MRI, scalp EEG, iEEGFR, L2.7 (1.2–5.8)8 (62)11 (85)
Kassiri et al., 201136University of Alberta (1987–2006)10MRI, scalp EEGFR, L2 (1–6)9 (90)10 (100)
Mohamed et al., 201237The Royal Children’s Hospital (January 1997–June 2011)45MRI, scalp EEG, iEEGFRMedian 3.724 (53)
Krsek et al., 201338Miami Children’s Hospital (1996–2010)332.6 (0–5)5.2 (0.1–17.6)MRI, scalp EEG, SPECT, FDG-PET, fMRI, iEEGFR, FR+, L218 (55)27 (82)
Kargiotis et al., 201439University Hospital and Faculty of Medicine of Geneva (—)110.6 (0.1–1)11.9 (1–32)MRI, scalp EEG, SPECT/SISCOM, FDG-PETFR, L2.2 (1–7)7 (64)9 (82)
Arya et al., 201540Cincinnati Children’s Hospital (January 2007–December 2012)370.7 ± 1.26.2 ± 6.0MRI, scalp EEG, MEG, SPECT/SISCOM, FDG-PET, iEEGFR+, L, FHE5.7 ± 3.721 (57)32 (86)
Fallah et al., 2015106 centers: 3 Canada, 3 US (January 2005–December 2013)74Median 0.4 (IQR 0.2–0.8)Median 4.1 (IQR 2.1–8)MRI, scalp EEG, MEG, SPECT, FDG-PET, iEEGFR, L, HE1, 248 (65), 37 (50)
Lewis et al., 201541Miami Children’s Hospital (May 2011–March 2014)53.2 (0.1–11)12.1 (5.9–15.9)MRI, scalp EEG, SPECT, PET, DTI, fMRILA1.1 (0.8–1.9)2 (40)4 (80)
Kannan et al., 20167The Royal Children’s Hospital (January 1997–June 2015)100.5 (0–2)Median 3.8 (2.4–13.3)MRI, scalp EEG, iEEGFR2.9 (0.8–4.6)3 (30)10 (100)
Iwasaki et al., 201642Tohoku University (2008–2013)50.3 (0–0.4)7.2 (1–17)MRI, scalp EEG, MEG, SPECT, FDG-PETComplete CCT2.2 (1.3–3.5)02 (40)
Tovar-Spinoza et al., 201843SUNY Upstate Golisano Children’s Hospital (February 2013–November 2015)76.6 (2–17)MRI, scalp EEG, SPECT, PET, DTILA1.6 (0.3–4.1)3 (43)7 (100)
Koptelova et al., 2018442 centers: 1 Finland, 1 Russia (1995–2017)71.4 (0.1–2.5)2.2 (4–16.8)MRI, scalp EEG, MEG, SPECT/SISCOM, iEEGFR, L, LD, PQD2.5 (1–4)4 (57)6 (86)
Fohlen et al., 201845Rothschild Foundation Hospital (January 2006–January 2016)150.2 (0–1.0)2.1 (0.4–5.5)CT, MRI, scalp EEG, iEEGFR, L, adjuvant LD4.7 (1.9–7.2)9 (60)14 (93)
Okanishi et al., 201946Seirei Hauarymamatsu General Hospital (November 2014–December 2018)70.3 (0.2–0.5)6.6 (2.1–21.5)MRI, scalp EEG, SPECT, FDG-PETFR, complete CCT, PQD2.3 (0.8–3.5)2 (29)5 (71)
Neal et al., 202054 centers in France (2004–2018)155.3 (0–23)15.5 (3.7–37.1)MRI, scalp EEG, MEG, FDG-PET, AMT-PET, iEEGFR, L, LD4.8 (1.0–7.3)9 (60)12 (80)
Grayson et al., 2020479 centers in US (—)19Median 0.2 (0–0.9)Median 1.4 (0.3–1.8)iEEGFR, FR+, L1.9 (1–4)10 (53)
Liu et al., 2020626 centers in China (January 2000–December 2017)36435.710.4 (0.5–47)CT, MRI, scalp EEG, FDG-PET, DWI, iEEGFR, FR+, L, adjuvant anterior CCT1 (n = 364), 4 (n = 196), 10 (n = 71)258 (71), 118 (60), 36 (51)
Stomberg et al., 202148Epilepsy Centre Bethel (2001–2015)33Median 0.4 (IQR 0.2–0.8)Median 2.6 (IQR 1.6–6.2)MRI, scalp EEG, DTI, fMRI, Wada test, iEEGFR, L, FHEMedian 2 (n = 33), 8 (n = 13) (2.6–10.8)13 (39), 10 (77)
Vannicola et al., 2021497 centers in Italy (September 1997–February 2019)35Median 0.4 (0–16)Median 6.0 (IQR 3–13)MRI, scalp EEG, DWI, iEEGFR, FR+, L, FHEMedian 7.2 (IQR 2–9.8)18 (51)27 (77)
Hulshof et al., 2021502 centers: 1 Czech Republic, 1 the Netherlands (2003–2015)281.0 (0–6.6)Median 9.3 (1–47)MRI, iEEGFR, L, HO5.2 (2–14)15 (54)25 (89)
Huang et al., 202151Sanbo Brain Hospital (April 2004–June 2019)81Median 4 (IQR 1–11)Median 19 (IQR 7.9–26)CT, MRI, scalp EEG, FDG-PET, DWI, iEEGFR, FR+, L, adjuvant anterior CCTMedian 7 (IQR 4–11)36 (44)67 (83)
Wang et al., 2021522 centers in China (January 2016–December 2018)171.3 (0.2–5.9)6.1 (2.9–12.6)MRI, scalp EEG, PET, iEEGFR, L2.0 (1–3.7)12 (71)
Luo et al., 202253Children’s Hospital of Fudan University (May 2018–January 2021)9Median 0.7 (0–3.4)Median 4.2 (3.4–16.6)MRI, scalp EEG, FDG-PET, iEEGRFAMedian 1.3 (0.5–3.3)7 (78)9 (100)
Mouthaan et al., 2022543 centers in the Netherlands (—)157.2 (1–26)MRI, scalp EEG, MEG, SPECT, DTI, fMRI, Wada test, iEEGFR, FR+, L, LD1.6 (0.3–6.1)9 (60)12 (80)

AMT-PET = α-methyltryptophan PET; FHE = functional HE; FR = focal resection (e.g., tuberectomy, lesionectomy); FR+ = FR plus perilesional corticectomy; FU = follow-up; HE = hemispherectomy; HO = hemispherotomy; L = lobectomy; LA = laser ablation; LD = lobe disconnection; MRF = 3D MR fingerprinting; MRS = MR spectroscopy; MST = multiple subpial transections; PQD = posterior quadrant disconnection; pt = patient; RFA = radiofrequency ablation; SAM = synthetic aperture magnetometry; Sz = seizure; — = missing data.

Mean values are presented as mean (range) or mean ± SD. Median values are presented as median (range) unless otherwise indicated.

TABLE 2.

List of included studies using neuromodulation (group 2, electrical interventions)

Authors & YearInstitution (inclusion period)No. of Pts w/ Op & FUAge at Sz Onset, yrs*Age at Implantation Op, yrs*Stimulation TypeFU, yrs*No. of Pts w/ Excellent Sz Reduction (%)No. of Pts w/ Worthwhile Sz Reduction (%)
Parain et al., 2001555 centers: 4 France, 1 US (—)10Median 1 (0–6)Median 14.5 (5–20)VNSMedian 1.6 (0.5–3.5)6 (60)9 (100)
Major & Thiele, 200856Massachusetts General Hospital (—)161 (0–7)15 (2–44)VNS4 (0.5–8.6)3 (19)8 (50)
Elliott et al., 2009572 centers in US (1999–2008)111.6 (0.1–14)16.2 (2–44)VNS4.2 (1–9.6)4 (36)10 (91)
Zamponi et al., 201058Ospedali Riuniti (2000–2008)1113.3 (2–33)14.4 (2–35)VNS11 (9)9 (82)
McDermott et al., 2021595 centers in US (November 2016–October 2019)5Median 8 (0–14)Median 35 (23–41)RNSMedian 1 (n = 4), 1.4 (n = 5) (0.8–2.8)0, 4 (80)3 (75), 5 (100)
Tong et al., 202260Sanbo Brain Hospital (2008–2020)173.7 (0.3–11)11.4 (0.9–30)VNS4.1 (0.5–10)6 (35)12 (71)

Values are presented as mean (range) unless otherwise indicated. Median values are presented as median (range) unless otherwise indicated.

FIG. 2.
FIG. 2.

Seizure outcomes versus mean or median follow-up time. Each point is a seizure outcome and follow-up time pair. Point size is scaled by the sample size of each study within each group (larger point represents larger sample). Proportion of patients with excellent (A) and worthwhile (B) seizure reductions in group 1. Proportion of patients with excellent (C) and worthwhile (D) seizure reductions in group 2.

Discussion

The goal of surgical intervention for TSC-associated epilepsy is to maximize quality of life and minimize neurodevelopmental impairment by minimizing seizures.14 This is done by interrupting epileptogenic networks through mechanical or electrical means. Resection of epileptogenic foci is a traditional and commonly performed treatment that effectively controls seizures in select TSC patients with medically refractory epilepsy.5,9,14 Three systematic reviews, the most recent being published in 2013,11 found that approximately 55%–60% of TSC patients treated with resection achieved seizure freedom.1113 Similarly, our systematic review found that 59% of TSC patients had excellent seizure reduction following any combination of resection, disconnection, and ablation. We also found that these treatments yielded worthwhile seizure reduction in 85% of patients. Furthermore, we found that neuromodulation, an alternative surgical option for TSC-associated epilepsy, yielded excellent and worthwhile seizure reduction in 34% and 76% of patients, respectively. Although these studies and findings repeatedly demonstrated the utility of surgery in TSC-associated epilepsy, these results are intrinsically biased, as not every patient is offered surgery.9 Moreover, a notable proportion of patients did not have worthwhile benefit from surgery, highlighting room for optimization to improve outcomes. Indeed, advancements in localization and in the understanding of TSC-associated epilepsy have allowed for the development and utilization of more optimal surgical strategies, resulting in better seizure outcomes in more patients who previously would not have been considered surgical candidates.

Resection

Generally, good surgical candidates have epileptogenic foci identified with concordant test results that are amenable to resection. It is well established that in patients with a single primary epileptogenic tuber producing focal seizures, resection results in excellent seizure control.4,9 However, this is often not the case, as TSC patients commonly have multiple potentially epileptogenic regions that can result in generalized seizures and epileptiform discharges.5,6 It is thought that in the setting of multiple apparent epileptogenic foci, a primary focus drives the complex epileptogenic network.9 Indeed, the presence of multiple lesions should not preclude preoperative evaluation since resection can be successful for these patients,5,6,9,10,14 but they represent a challenge to surgical management unique to TSC. Any given tuber can be epileptogenic concurrently and contribute to multifocal epilepsy, be located on either side of the brain, and involve eloquent cortex.4,31,61 Moreover, epileptogenic foci can shift from one tuber to another over time and be in normal-appearing cortex without a corresponding tuber.5,8 Different regions of the brain can become epileptogenic over time,8,61 and previously silent tubers may present as epileptogenic foci following resection of the primary focus.4 Thus, a thorough multidisciplinary preoperative evaluation is critical to localize epileptogenic foci and improve outcomes of resection (Fig. 3).

FIG. 3.
FIG. 3.

Summary of localization and surgical strategies used to treat TSC-associated epilepsy.

Noninvasive Localization

Confident localization is achieved with concordant results from different modalities. MRI and CT are noninvasive imaging techniques central to preoperative evaluation. There are three types of tubers that vary in appearance on MRI: type A, type B, and type C.5 Tubers are often hypodense on CT unless they contain calcifications, which are seen in over 50% of patients.62 Several radiographic findings can be suggestive of an epileptogenic focus in TSC, such as a large and/or calcified tuber,6,10 perituberal focal cortical dysplasia–like dysplastic tissue,62 and a type C tuber.5,7 However, type C tubers identified on 1.5-T or 3-T MRI have an estimated sensitivity of 85% and positive predictive value of 15% for identifying primary epileptogenic tubers, limiting the utility of this finding.5 High-resolution 7-T MRI can identify subtle tubers, tuber details, and brain abnormalities extending beyond tuber borders that 1.5-T and 3-T MRI cannot.63,64 Thus, more regular use of 7-T MRI may improve identification of epileptogenic foci in TSC.

Scalp electroencephalography (EEG) with simultaneous video monitoring is a cornerstone of preoperative evaluation and is used to detect focal ictal or interictal abnormalities that correlate with seizure semiology and radiographic lesions. However, the modality is limited by the generalized semiologies and multifocal and diffuse EEG abnormalities seen in TSC.6,8 Additional noninvasive modalities and techniques that are potentially useful for localization in TSC-associated epilepsy include magnetoencephalography (MEG),44 SPECT,19 subtraction ictal SPECT coregistered to MRI (SISCOM),34,40 FDG-PET,20,25 α-[11C]methyl-l-tryptophan PET,20,25 diffusion-weighted imaging (DWI),65 diffusion tensor imaging (DTI),66 neurite orientation dispersion and density imaging,67 functional MRI (fMRI),68 electric source imaging,54 and synthetic aperture magnetometry.30 Of these additional modalities, MEG, SPECT/SISCOM, FDG-PET, and DWI were the most commonly used in the largest outcome-focused studies, although usage varied considerably between centers (Table 1).6,10,28,40,49,51

Invasive Monitoring and Surgical Approaches

The development and utilization of these additional modalities have expanded the armamentarium for localizing epileptogenic foci noninvasively. When noninvasive test results are concordant, a single-stage resection of the identified focus can be performed. However, even when using multiple modalities, noninvasive evaluation is often inconclusive, necessitating invasive monitoring.5,7,9 Intracranial EEG (iEEG), recorded from either subdural electrode grids/strips (electrocorticography) or depth electrodes placed minimally invasively with stereotactic navigation (stereo-EEG [sEEG]), improves the identification of epileptogenic foci via precision monitoring and provides precise neurophysiological data that can be analyzed to further understand TSC-associated epilepsy. Additionally, intracranial electrodes allow for more precise functional mapping, which is critical for working around eloquent cortex.31 Typical for epilepsy of any etiology, a two-stage surgical approach—where intracranial electrodes are first implanted for extraoperative mapping and localization, followed by resection of epileptogenic foci4—has been utilized for TSC patients and is especially successful for those with a single primary epileptogenic focus.4,7,9,28,31 For apparent multifocal TSC-associated epilepsy, a multistage approach has been utilized, in which intracranial electrodes are first implanted, followed by resection of the primary epileptogenic focus and replacement of intracranial electrodes, and ending with resection of any additional epileptogenic foci unmasked by resection of the primary focus and removal of intracranial electrodes.4,9,27,28,31

Analyzing iEEG recordings can reveal biomarkers of epileptogenicity. High-frequency oscillations (HFOs), consisting of ripples and fast ripples, are thought to be associated with epileptogenicity.52,69,70 One study of 17 TSC patients observed high occurrences of interictal fast ripples in 67.1% of recorded tubers.52 Moreover, 3 studies of a collective 39 TSC patients observed that resecting cortex producing interictal and ictal HFOs was correlated with good seizure control.52,69,70 However, 1 study found that interictal fast ripples localized the epileptogenic tuber in only 1 of 10 patients and observed them in tubers not involved in seizure onset.7 This, as well as the difficulty of distinguishing between physiological and pathologic HFOs, limits the clinical utility of this biomarker.7,70 Periodic and continuous interictal epileptiform discharges (IEDs) are additional biomarkers of epileptogenicity. Several studies of iEEG recordings found an association between IEDs and the ictal onset zone, suggesting that locating these discharges can help identify epileptogenic foci.5,7,37 This finding has partly motivated the development of an alternative single-stage approach for TSC-associated epilepsy, in which intraoperative iEEG is used to guide resection of identified epileptogenic tubers.7 Although successfully practiced, 1 study of sEEG estimated a sensitivity of 100% and a positive predictive value of 53% for continuous IEDs identifying epileptogenic tubers, cautioning against overreliance on this biomarker for guiding resection.5

Regarding the extent of resection, several approaches ranging from tuber center resection to anatomical hemispherectomy have been reported with varying degrees of success.6,7,1013,28,37,51,61 However, no consensus on the optimal amount of resection exists.6 One study of sEEG observed strong epileptogenicity in nontuber regions with or without concurrent primary epileptogenic tuber in some TSC patients.5 Another study more frequently observed interictal fast ripples at the tuber rim and immediately adjacent cortex.52 These findings, as well as radiographic evidence of focal cortical dysplasia–like dysplastic tissue within the perituberal cortex,62 suggest that conservative resection may not adequately control seizures in some patients. Indeed, several studies have reported better seizure control when resecting beyond the margins of the tuber.6,9,10 One large multicenter study of 74 TSC patients found that resection beyond the tuber margins was associated with better seizure control than tuberectomy alone.10 Another multicenter study of 364 TSC patients, the largest to date, found that tuberectomy plus perituberal corticectomy and lobectomy resulted in better seizure control than tuberectomy alone, as well as lobectomy providing no additional seizure control over tuberectomy plus perituberal corticectomy.6

However, evidence from iEEG recordings shows that in many epileptogenic foci, the epileptiform discharges arise from the tuber center and propagate to the tuber rim, perituberal cortex, and other epileptogenic tubers.5,7,37 In contrast to the findings of another report,52 several studies observed a higher occurrence of ictal and interictal fast ripples in the tuber than in the perituberal cortex.37,71 One of these studies also observed higher IED amplitudes and a greater proportion of neurons being modulated during times of IEDs in the tuber than in the perituberal cortex.71 In another study of TSC patients with a single primary tuber, the greatest epileptogenicity occurred in the tuber center and decreased toward the tuber rim.5 These findings support the claim that the seizures arise in the tubers, not the perituberal cortex, and a gradient of epileptogenicity exists, with the epileptogenicity being greatest in the tuber and decreasing outward.5,7,71 Furthermore, a subset of TSC patients may sufficiently benefit from tuberectomy alone. Indeed, several studies have reported on performing tuberectomies while sparing the surrounding tissue, achieving seizure freedom in 35%–60% of patients.6,7,37 Another study reported resecting the tuber center only in 4 patients with epileptogenic tubers in the sensorimotor cortex, eliminating the associated focal motor seizures in all 4 patients.61 In the setting of high tuber load and tubers in eloquent cortex or deep white matter, these more conservative approaches are useful to avoid contiguous resection of tissue and iatrogenic neurological deficit,37,61 as the tubers themselves have no neurological function.31

Early Resection

Early surgery is thought to significantly increase the probability of seizure freedom.14 To potentially normalize development, several small studies have recently investigated early resection in exclusively younger children for early seizure control.45,47 In a study of 15 TSC patients younger than 6 years treated with resection, 9 became seizure free, of whom none were on the autism spectrum and 4 regained a normal developmental trajectory.45 Another study of 19 TSC patients younger than 2 years reported that 10 became seizure free and experienced gains in some, but not all, developmental domains following resective surgery.47 Although promising, both studies recommended that a larger study be conducted to fully evaluate the impact of early epilepsy surgery on development in TSC patients.45,47

Positive Predictors of Seizure Freedom Following Resection

Various positive predictors of postoperative seizure control have been reported, such as a lack of (or mild) preoperative cognitive impairment,12,13 the absence of generalized seizure semiologies,12,13,49 unilateral and focal interictal and ictal epileptiform discharges,11,12,49 the presence of a large and/or calcified tuber,6,10 total resection of all epileptogenic foci,6,51 and resection beyond the tuber margins.6,10,11 From the largest studies that identified positive predictors following multivariable regression analysis,6,10,28,38,40,49,51 predictors reflecting absolute identification and complete removal of epileptogenic tissue were repeatedly reported (Table 3).

TABLE 3.

Independent positive predictors of seizure freedom following resection identified using multivariable regression from studies with ≥ 30 patients

Authors & YearNo. of PtsIndependent Positive Predictors of Sz Freedom
Liu et al., 20206364

Total resection of epileptogenic tubers (HR 11.7, 95% CI 3.5–39.6)

Presence of outstanding tuber (HR 2.1, 95% CI 1.2–3.8)

Monthly Sz vs daily Sz (HR 3.4, 95% CI 1.4–7.9)

Fallah et al., 20151074Lobectomies or greater (compared w/ tuberectomy alone) (HR 2.9, 95% CI 1.2–7.2)
Arya et al., 20154037No positive predictors identified
Madhavan et al., 20072870No positive predictors identified
Huang et al., 20215181En bloc resection of epileptogenic zone (HR 4.9, 95% CI 1.1–23.2)
Krsek et al., 20133833

Complete removal of epileptogenic tissue detected by both MRI & iEEG (p = 0.018)

Presence of regional scalp interictal EEG patterns (p = 0.02)

Colocalized interictal & ictal epileptiform activity on EEG (p = 0.009)

Vannicola et al., 20214935Fewer tubers (p = 0.023) Lower postop neurological severity score (OR 2.5, 95% CI 1.1–5.7)

Ablation Procedures

Ablative surgery is an emerging, minimally invasive alternative to resection that utilizes heat to destroy tissue. This precise surgery can be advantageous when targeting deep-seated lesions. Two ablative techniques, MR-guided laser interstitial thermal therapy (MRgLITT) and radiofrequency thermocoagulation (RFTC), have been used to treat TSC-associated epilepsy.41,43,53 MRgLITT uses thermal imaging from MRI to guide ablation from thermal energy delivered via stereotactically placed catheters.41 Two included studies used this technique in a collective 12 TSC patients, reporting excellent and worthwhile seizure outcomes in 5 (42%) and 11 (92%) patients, respectively, at a mean follow-up > 1 year.41,43 RFTC utilizes radio waves to generate heat and ablate tissue. One study used this technique with sEEG to treat 9 TSC patients, reporting excellent and worthwhile seizure outcomes in 7 and 9 patients, respectively, at a median follow-up of 1.3 years.53

Disconnection Procedures

Disconnection procedures are traditional alternatives to resection that mechanically interrupt neural connections without removing tissue. They have been utilized as a palliative treatment for refractory epilepsy, especially in the absence of lesions or presence of bilateral lesions,46 and as an adjunct to resection in TSC patients.6,13,46,51 Corpus callosotomy (CCT) is one such procedure and is performed on either the anterior two-thirds or the entire corpus callosum.72 A complete CCT is more effective at relieving seizures but is associated with a higher rate of disconnection syndromes unless performed in younger children.72 One study of 7 TSC patients reported marked reduction in epileptic and tonic spasms in 5 (Engel class I or II), of whom 3 patients were spasm free (Engel class I), following palliative complete CCT at a median follow-up of 2 years.46 In a multicenter study of 364 TSC patients treated with resection, 43 patients with Lennox-Gastaut syndrome, a low intelligence quotient, and severe behavioral and/or emotional problems received adjuvant anterior CCT, resulting in seizure freedom in 59%, 48%, and 36% at the 1-, 4-, and 10-year follow-ups, respectively.6 Other less commonly performed disconnection procedures utilized in TSC include lobar disconnections,44,54 posterior quadrant disconnection,44 and functional hemispherectomy.25,40

Neuromodulation

Neuromodulation is a treatment modality that involves altering neural signaling to relieve symptoms, usually by electrically stimulating specific structures via an implanted electrode connected to a pulse generator. Vagus nerve stimulation (VNS) is an established treatment option for refractory epilepsy and the most studied neuromodulation treatment in TSC.58 For TSC patients, VNS is suggested as a palliative treatment option for those with refractory epilepsy who are not candidates for resection.14 Of a collective 65 TSC patients treated with VNS over 5 separate studies, 74% had at least a 50% reduction in seizures, and 31% had at least an 80% reduction in seizures.5558,60 Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) bilaterally has been shown to reduce the frequency of medically refractory partial and secondarily generalized seizures in adults.73 In one study, the authors performed bilateral ANT DBS in a 22-year-old TSC patient with refractory nonlocalizing epilepsy and found that it reduced seizure frequency by 90% at the 15-month follow-up.74 Responsive neurostimulation (RNS) is a more recent neurostimulation technique, in which an implanted electrode directly stimulates the epileptogenic focus on detection of epileptogenic activity to disrupt seizure development, which progressively reduces the frequency of partial-onset seizures in adults.75 In 1 study of 5 adult TSC patients treated with RNS, the frequency of disabling seizures was reduced 58% 1 year postimplantation and 88% at the last follow-up (median follow-up time 17 months), with all having at least a 50% reduction.59

Limitations

Although a relatively large number of studies were included, none of which were deemed to have a high risk of bias (Table 4), this systematic review has several limitations. First, the quality varied across included studies, as both retrospective and prospective studies of differing sample sizes were included. Second, the studies were heterogeneous, limiting interstudy comparisons. Third, some patients may not be unique due to partially overlapping study periods between different included studies. Moreover, demographic information and seizure outcomes were not consistently defined among the included studies, which precluded the pooling and synthesis of all available data extracted. Additionally, surgical techniques were reported but not quantified, and surgeon experience was not assessed. Furthermore, each group had patients treated with different techniques, which may have biased the outcome results. Nevertheless, we believe that this bias is small due to most patients being treated by resection in group 1 and VNS in group 2.

TABLE 4.

Risk of bias assessment for observational studies (ROBINS-I tool)

Authors & YearConfoundingSelectionClassification of InterventionsDeviations From Intended InterventionsMissing DataMeasurement of DataSelection of the Reported Result
Koh et al., 200019ModerateModerateLowLowLowLowLow
Asano et al., 200020ModerateModerateLowLowLowLowLow
Karenfort et al., 200221ModerateModerateLowLowLowLowLow
Mackay et al., 200322ModerateModerateLowLowModerateLowLow
Jarrar et al., 200423ModerateModerateLowLowModerateLowLow
Lachhwani et al., 200524ModerateModerateLowLowModerateLowLow
Kagawa et al., 200525ModerateModerateLowLowLowLowLow
Asano et al., 200526ModerateModerateLowLowLowLowLow
Weiner et al., 200627ModerateModerateLowLowLowLowLow
Madhavan et al., 200728ModerateModerateLowLowLowLowLow
Teutonico et al., 200829ModerateModerateLowLowLowLowLow
Sugiyama et al., 200930ModerateModerateLowLowModerateLowLow
Moshel et al., 201031ModerateModerateLowLowLowLowLow
Hemb et al., 201032ModerateModerateLowLowModerateLowLow
van der Heide et al., 201033ModerateModerateLowLowLowLowLow
Aboian et al., 201134ModerateModerateLowLowLowLowLow
Ochi et al., 201135ModerateModerateLowLowLowLowLow
Kassiri et al., 201136ModerateModerateLowLowLowLowLow
Mohamed et al., 201237ModerateModerateLowLowLowLowLow
Krsek et al., 201338ModerateModerateLowLowLowLowLow
Kargiotis et al., 201439ModerateModerateLowLowLowLowLow
Arya et al., 201540ModerateModerateLowLowLowLowLow
Fallah et al., 201510ModerateModerateLowLowModerateLowLow
Lewis et al., 201541ModerateModerateLowLowLowLowLow
Kannan et al., 20167ModerateModerateLowLowLowLowLow
Iwasaki et al., 201642ModerateModerateLowLowLowLowLow
Tovar-Spinoza et al., 201843ModerateModerateLowLowLowLowLow
Koptelova et al., 201844ModerateModerateLowLowLowLowLow
Fohlen et al., 201845ModerateModerateLowLowLowLowLow
Okanishi et al., 201946ModerateModerateLowLowLowLowLow
Neal et al., 20205ModerateModerateLowLowLowLowLow
Grayson et al., 202047ModerateModerateLowLowModerateLowLow
Liu et al., 20206ModerateModerateLowLowModerateLowLow
Stomberg et al., 202148ModerateModerateLowLowModerateLowLow
Vannicola et al., 202149ModerateModerateLowLowLowLowLow
Hulshof et al., 202150ModerateModerateLowLowLowLowLow
Huang et al., 202151ModerateModerateLowLowLowLowLow
Wang et al., 202152ModerateModerateLowLowModerateLowLow
Luo et al., 202253ModerateModerateLowLowLowLowLow
Mouthaan et al., 202254ModerateModerateLowLowLowLowLow
Parain et al., 200155ModerateModerateLowLowLowLowLow
Major & Thiele, 200856ModerateModerateLowLowLowLowLow
Elliott et al., 200957ModerateModerateLowLowLowLowLow
Zamponi et al., 201058ModerateModerateLowLowLowLowLow
McDermott et al., 202159ModerateModerateLowLowLowLowLow
Tong et al., 202260ModerateModerateLowLowLowLowLow

Conclusions

Epilepsy is a highly prevalent and challenging clinical manifestation of TSC that often requires neurosurgical intervention. To meet this challenge, a wide variety of surgical strategies incorporating traditional and emerging techniques have been utilized. Although these are effective for many TSC patients, advancements in technology and understanding of TSC-associated epilepsy highlight promising avenues for improving surgical outcomes.

Disclosures

Dr. Alden: honoraria from Takeda Pharmaceutical.

Author Contributions

Conception and design: Karras, Nie. Acquisition of data: Nie. Analysis and interpretation of data: Nie. Drafting the article: Nie. Critically revising the article: Karras, Nie, Trybula, Texakalidis. Reviewed submitted version of manuscript: Karras, Nie, Alden. Approved the final version of the manuscript on behalf of all authors: Karras. Study supervision: Alden.

References

  • 1

    Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125127.

  • 2

    Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):13451356.

  • 3

    Cotter JA. An update on the central nervous system manifestations of tuberous sclerosis complex. Acta Neuropathol. 2020;139(4):613624.

  • 4

    Weiner HL. Tuberous sclerosis and multiple tubers: localizing the epileptogenic zone. Epilepsia. 2004;45(suppl 4):4142.

  • 5

    Neal A, Ostrowsky-Coste K, Jung J, et al. Epileptogenicity in tuberous sclerosis complex: a stereoelectroencephalographic study. Epilepsia. 2020;61(1):8195.

  • 6

    Liu S, Yu T, Guan Y, et al. Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain. 2020;143(2):570581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kannan L, Vogrin S, Bailey C, Maixner W, Harvey AS. Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. Brain. 2016;139(Pt 10):26532667.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cusmai R, Chiron C, Curatolo P, Dulac O, Tran-Dinh S. Topographic comparative study of magnetic resonance imaging and electroencephalography in 34 children with tuberous sclerosis. Epilepsia. 1990;31(6):747755.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Bollo RJ, Kalhorn SP, Carlson C, Haegeli V, Devinsky O, Weiner HL. Epilepsy surgery and tuberous sclerosis complex: special considerations. Neurosurg Focus. 2008;25(3):E13.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Fallah A, Rodgers SD, Weil AG, et al. Resective epilepsy surgery for tuberous sclerosis in children: determining predictors of seizure outcomes in a multicenter retrospective cohort study. Neurosurgery. 2015;77(4):517524.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Zhang K, Hu WH, Zhang C, Meng FG, Chen N, Zhang JG. Predictors of seizure freedom after surgical management of tuberous sclerosis complex: a systematic review and meta-analysis. Epilepsy Res. 2013;105(3):377383.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Fallah A, Guyatt GH, Snead OC III, et al. Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis. PLoS One. 2013;8(2):e53565.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Jansen FE, van Huffelen AC, Algra A, van Nieuwenhuizen O. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia. 2007;48(8):14771484.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Curatolo P, Nabbout R, Lagae L, et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol. 2018;22(5):738748.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Engel J, ed.Surgical Treatment of Epilepsies. 2nd ed. Raven Press;1993.

  • 16

    Wieser HG, Blume WT, Fish D, et al.ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42(2):282286.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    McHugh JC, Singh HW, Phillips J, Murphy K, Doherty CP, Delanty N. Outcome measurement after vagal nerve stimulation therapy: proposal of a new classification. Epilepsia. 2007;48(2):375378.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343(7829):d5928.

  • 19

    Koh S, Jayakar P, Dunoyer C, et al. Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia. 2000;41(9):12061213.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Asano E, Chugani DC, Muzik O, et al. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000;54(10):19761984.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Karenfort M, Kruse B, Freitag H, Pannek H, Tuxhorn I. Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex. Neuropediatrics. 2002;33(5):255261.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Mackay MT, Becker LE, Chuang SH, et al. Malformations of cortical development with balloon cells: clinical and radiologic correlates. Neurology. 2003;60(4):580587.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology. 2004;62(3):479481.

  • 24

    Lachhwani DK, Pestana E, Gupta A, Kotagal P, Bingaman W, Wyllie E. Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology. 2005;64(9):16511654.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kagawa K, Chugani DC, Asano E, et al. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with α-[11C]methyl-L-tryptophan positron emission tomography (PET). J Child Neurol. 2005;20(5):429438.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Asano E, Juhász C, Shah A, et al. Origin and propagation of epileptic spasms delineated on electrocorticography. Epilepsia. 2005;46(7):10861097.

  • 27

    Weiner HL, Carlson C, Ridgway EB, et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics. 2006;117(5):14941502.

  • 28

    Madhavan D, Schaffer S, Yankovsky A, et al. Surgical outcome in tuberous sclerosis complex: a multicenter survey. Epilepsia. 2007;48(8):16251628.

  • 29

    Teutonico F, Mai R, Devinsky O, et al. Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome. Childs Nerv Syst. 2008;24(12):14371445.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Sugiyama I, Imai K, Yamaguchi Y, et al. Localization of epileptic foci in children with intractable epilepsy secondary to multiple cortical tubers by using synthetic aperture magnetometry kurtosis. J Neurosurg Pediatr. 2009;4(6):515522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Moshel YA, Elliott R, Teutonico F, et al. Do tubers contain function? Resection of epileptogenic foci in perirolandic cortex in children with tuberous sclerosis complex. Epilepsia. 2010;51(7):12421251.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hemb M, Velasco TR, Parnes MS, et al. Improved outcomes in pediatric epilepsy surgery: the UCLA experience, 1986-2008. Neurology. 2010;74(22):17681775.

  • 33

    van der Heide A, van Huffelen AC, Spetgens WPJ, Ferrier CH, van Nieuwenhuizen O, Jansen FE. Identification of the epileptogenic zone in patients with tuberous sclerosis: concordance of interictal and ictal epileptiform activity. Clin Neurophysiol. 2010;121(6):842847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Aboian MS, Wong-Kisiel LC, Rank M, Wetjen NM, Wirrell EC, Witte RJ. SISCOM in children with tuberous sclerosis complex-related epilepsy. Pediatr Neurol. 2011;45(2):8388.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Ochi A, Hung R, Weiss S, et al. Lateralized interictal epileptiform discharges during rapid eye movement sleep correlate with epileptogenic hemisphere in children with intractable epilepsy secondary to tuberous sclerosis complex. Epilepsia. 2011;52(11):19861994.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kassiri J, Snyder TJ, Bhargava R, Wheatley BM, Sinclair DB. Cortical tubers, cognition, and epilepsy in tuberous sclerosis. Pediatr Neurol. 2011;44(5):328332.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mohamed AR, Bailey CA, Freeman JL, Maixner W, Jackson GD, Harvey AS. Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology. 2012;79(23):22492257.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Krsek P, Jahodova A, Kyncl M, et al. Predictors of seizure-free outcome after epilepsy surgery for pediatric tuberous sclerosis complex. Epilepsia. 2013;54(11):19131921.

  • 39

    Kargiotis O, Lascano AM, Garibotto V, et al. Localization of the epileptogenic tuber with electric source imaging in patients with tuberous sclerosis. Epilepsy Res. 2014;108(2):267279.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Arya R, Tenney JR, Horn PS, et al. Long-term outcomes of resective epilepsy surgery after invasive presurgical evaluation in children with tuberous sclerosis complex and bilateral multiple lesions. J Neurosurg Pediatr. 2015;15(1):2633.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Lewis EC, Weil AG, Duchowny M, Bhatia S, Ragheb J, Miller I. MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesional epilepsy. Epilepsia. 2015;56(10):15901598.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Iwasaki M, Uematsu M, Hino-Fukuyo N, et al. Clinical profiles for seizure remission and developmental gains after total corpus callosotomy. Brain Dev. 2016;38(1):4753.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Tovar-Spinoza Z, Ziechmann R, Zyck S. Single and staged laser interstitial thermal therapy ablation for cortical tubers causing refractory epilepsy in pediatric patients. Neurosurg Focus. 2018;45(3):E9.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Koptelova A, Bikmullina R, Medvedovsky M, et al. Ictal and interictal MEG in pediatric patients with tuberous sclerosis and drug resistant epilepsy. Epilepsy Res. 2018;140:162165.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Fohlen M, Taussig D, Ferrand-Sorbets S, et al. Refractory epilepsy in preschool children with tuberous sclerosis complex: early surgical treatment and outcome. Seizure. 2018;60:7179.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Okanishi T, Fujimoto A, Okanari K, et al. Corpus callosotomy for drug-resistant spasms associated with tuberous sclerosis complex. Epilepsy Behav. 2019;98(Pt A):228232.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Grayson LE, Peters JM, McPherson T, et al. Pilot study of neurodevelopmental impact of early epilepsy surgery in tuberous sclerosis complex. Pediatr Neurol. 2020;109:3946.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Stomberg M, Bien CG, Kalbhenn T, Polster T, May TW. Epilepsy associated with tuberous sclerosis complex in childhood: long-term outcome in children after epilepsy surgery and children non-eligible for epilepsy surgery. Epilepsy Behav. 2021;122:108210.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Vannicola C, Tassi L, Barba C, et al. Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study. J Neurol Sci. 2021;427(117506):117506.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Hulshof HM, Benova B, Krsek P, et al. The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia. Epilepsia Open. 2021;6(4):663671.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Huang Q, Zhou J, Wang X, et al. Predictors and long-term outcome of resective epilepsy surgery in patients with tuberous sclerosis complex: a single-centre retrospective cohort study. Seizure. 2021;88:4552.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Wang Y, Yuan L, Zhang S, et al. Fast ripples as a biomarker of epileptogenic tuber in tuberous sclerosis complex patients using stereo-electroencephalograph. Front Hum Neurosci. 2021;15:680295.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Luo T, Wang X, Wang J, et al. Optimization and high-density array of stereoelectroencephalography-guided radiofrequency thermocoagulation for the treatment of pediatric tuberous sclerosis complex with epilepsy. CNS Neurosci Ther. Published online January 15, 2022. doi: 10.1111/cns.13804

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Mouthaan BE, Jansen FE, Colon AJ, et al. High-resolution electric source imaging for presurgical evaluation of tuberous sclerosis complex patients. Clin Neurophysiol. 2022;133:126134.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55

    Parain D, Penniello MJ, Berquen P, Delangre T, Billard C, Murphy JV. Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol. 2001;25(3):213216.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Major P, Thiele EA. Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav. 2008;13(2):357360.

  • 57

    Elliott RE, Carlson C, Kalhorn SP, et al. Refractory epilepsy in tuberous sclerosis: vagus nerve stimulation with or without subsequent resective surgery. Epilepsy Behav. 2009;16(3):454460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    Zamponi N, Petrelli C, Passamonti C, Moavero R, Curatolo P. Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol. 2010;43(1):2934.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    McDermott DS, Mirro EA, Fetrow K, et al. Brain-Responsive Neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: a case series. Epilepsia Open. 2021;6(2):419424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Tong X, Wang X, Qin L, et al. Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex. Epilepsy Behav. 2022;126:108431.

  • 61

    Stephenson SEM, Maixner WJ, Barton SM, et al. Resection of tuber centers only for seizure control in tuberous sclerosis complex. Epilepsy Res. 2021;171(106572):106572.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Jahodova A, Krsek P, Kyncl M, et al. Distinctive MRI features of the epileptogenic zone in children with tuberous sclerosis. Eur J Radiol. 2014;83(4):703709.

  • 63

    Sun K, Cui J, Wang B, et al. Magnetic resonance imaging of tuberous sclerosis complex with or without epilepsy at 7 T. Neuroradiology. 2018;60(8):785794.

  • 64

    Chalifoux JR, Perry N, Katz JS, et al. The ability of high field strength 7-T magnetic resonance imaging to reveal previously uncharacterized brain lesions in patients with tuberous sclerosis complex. J Neurosurg Pediatr. 2013;11(3):268273.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Jansen FE, Braun KPJ, van Nieuwenhuizen O, et al. Diffusion-weighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis. Arch Neurol. 2003;60(11):15801584.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Yogi A, Hirata Y, Karavaeva E, et al. DTI of tuber and perituberal tissue can predict epileptogenicity in tuberous sclerosis complex. Neurology. 2015;85(23):20112015.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Shao X, Zhang X, Xu W, et al. Neurite orientation dispersion and density imaging parameters may help for the evaluation of epileptogenic tubers in tuberous sclerosis complex patients. Eur Radiol. 2021;31(8):56055614.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Jacobs J, Rohr A, Moeller F, et al. Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEG-fMRI. Epilepsia. 2008;49(5):816825.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Okanishi T, Akiyama T, Tanaka S, et al. Interictal high frequency oscillations correlating with seizure outcome in patients with widespread epileptic networks in tuberous sclerosis complex. Epilepsia. 2014;55(10):16021610.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Fujiwara H, Leach JL, Greiner HM, et al. Resection of ictal high frequency oscillations is associated with favorable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex. Epilepsy Res. 2016;126:9097.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Despouy E, Curot J, Denuelle M, et al. Neuronal spiking activity highlights a gradient of epileptogenicity in human tuberous sclerosis lesions. Clin Neurophysiol. 2019;130(4):537547.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Kasasbeh AS, Smyth MD, Steger-May K, Jalilian L, Bertrand M, Limbrick DD. Outcomes after anterior or complete corpus callosotomy in children. Neurosurgery. 2014;74(1):1728.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73

    Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51(5):899908.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Zheng H, Chengcheng W, Bin J, et al. Deep brain stimulation of anterior thalamic nucleus for treatment of patient with tuberous sclerosis-related refractory epilepsy. World Neurosurg. 2020;138:141144.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75

    Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014;55(3):432441.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Figure from Shahrestani et al. (E3). Created with Biorender.com.

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    PRISMA search flow diagram.

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    Seizure outcomes versus mean or median follow-up time. Each point is a seizure outcome and follow-up time pair. Point size is scaled by the sample size of each study within each group (larger point represents larger sample). Proportion of patients with excellent (A) and worthwhile (B) seizure reductions in group 1. Proportion of patients with excellent (C) and worthwhile (D) seizure reductions in group 2.

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    Summary of localization and surgical strategies used to treat TSC-associated epilepsy.

  • 1

    Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125127.

  • 2

    Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):13451356.

  • 3

    Cotter JA. An update on the central nervous system manifestations of tuberous sclerosis complex. Acta Neuropathol. 2020;139(4):613624.

  • 4

    Weiner HL. Tuberous sclerosis and multiple tubers: localizing the epileptogenic zone. Epilepsia. 2004;45(suppl 4):4142.

  • 5

    Neal A, Ostrowsky-Coste K, Jung J, et al. Epileptogenicity in tuberous sclerosis complex: a stereoelectroencephalographic study. Epilepsia. 2020;61(1):8195.

  • 6

    Liu S, Yu T, Guan Y, et al. Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain. 2020;143(2):570581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kannan L, Vogrin S, Bailey C, Maixner W, Harvey AS. Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. Brain. 2016;139(Pt 10):26532667.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Cusmai R, Chiron C, Curatolo P, Dulac O, Tran-Dinh S. Topographic comparative study of magnetic resonance imaging and electroencephalography in 34 children with tuberous sclerosis. Epilepsia. 1990;31(6):747755.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Bollo RJ, Kalhorn SP, Carlson C, Haegeli V, Devinsky O, Weiner HL. Epilepsy surgery and tuberous sclerosis complex: special considerations. Neurosurg Focus. 2008;25(3):E13.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Fallah A, Rodgers SD, Weil AG, et al. Resective epilepsy surgery for tuberous sclerosis in children: determining predictors of seizure outcomes in a multicenter retrospective cohort study. Neurosurgery. 2015;77(4):517524.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Zhang K, Hu WH, Zhang C, Meng FG, Chen N, Zhang JG. Predictors of seizure freedom after surgical management of tuberous sclerosis complex: a systematic review and meta-analysis. Epilepsy Res. 2013;105(3):377383.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Fallah A, Guyatt GH, Snead OC III, et al. Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis. PLoS One. 2013;8(2):e53565.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Jansen FE, van Huffelen AC, Algra A, van Nieuwenhuizen O. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia. 2007;48(8):14771484.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Curatolo P, Nabbout R, Lagae L, et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol. 2018;22(5):738748.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Engel J, ed.Surgical Treatment of Epilepsies. 2nd ed. Raven Press;1993.

  • 16

    Wieser HG, Blume WT, Fish D, et al.ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42(2):282286.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    McHugh JC, Singh HW, Phillips J, Murphy K, Doherty CP, Delanty N. Outcome measurement after vagal nerve stimulation therapy: proposal of a new classification. Epilepsia. 2007;48(2):375378.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343(7829):d5928.

  • 19

    Koh S, Jayakar P, Dunoyer C, et al. Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia. 2000;41(9):12061213.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Asano E, Chugani DC, Muzik O, et al. Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology. 2000;54(10):19761984.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Karenfort M, Kruse B, Freitag H, Pannek H, Tuxhorn I. Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex. Neuropediatrics. 2002;33(5):255261.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Mackay MT, Becker LE, Chuang SH, et al. Malformations of cortical development with balloon cells: clinical and radiologic correlates. Neurology. 2003;60(4):580587.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology. 2004;62(3):479481.

  • 24

    Lachhwani DK, Pestana E, Gupta A, Kotagal P, Bingaman W, Wyllie E. Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology. 2005;64(9):16511654.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kagawa K, Chugani DC, Asano E, et al. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with α-[11C]methyl-L-tryptophan positron emission tomography (PET). J Child Neurol. 2005;20(5):429438.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Asano E, Juhász C, Shah A, et al. Origin and propagation of epileptic spasms delineated on electrocorticography. Epilepsia. 2005;46(7):10861097.

  • 27

    Weiner HL, Carlson C, Ridgway EB, et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics. 2006;117(5):14941502.

  • 28

    Madhavan D, Schaffer S, Yankovsky A, et al. Surgical outcome in tuberous sclerosis complex: a multicenter survey. Epilepsia. 2007;48(8):16251628.

  • 29

    Teutonico F, Mai R, Devinsky O, et al. Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome. Childs Nerv Syst. 2008;24(12):14371445.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Sugiyama I, Imai K, Yamaguchi Y, et al. Localization of epileptic foci in children with intractable epilepsy secondary to multiple cortical tubers by using synthetic aperture magnetometry kurtosis. J Neurosurg Pediatr. 2009;4(6):515522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Moshel YA, Elliott R, Teutonico F, et al. Do tubers contain function? Resection of epileptogenic foci in perirolandic cortex in children with tuberous sclerosis complex. Epilepsia. 2010;51(7):12421251.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hemb M, Velasco TR, Parnes MS, et al. Improved outcomes in pediatric epilepsy surgery: the UCLA experience, 1986-2008. Neurology. 2010;74(22):17681775.

  • 33

    van der Heide A, van Huffelen AC, Spetgens WPJ, Ferrier CH, van Nieuwenhuizen O, Jansen FE. Identification of the epileptogenic zone in patients with tuberous sclerosis: concordance of interictal and ictal epileptiform activity. Clin Neurophysiol. 2010;121(6):842847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Aboian MS, Wong-Kisiel LC, Rank M, Wetjen NM, Wirrell EC, Witte RJ. SISCOM in children with tuberous sclerosis complex-related epilepsy. Pediatr Neurol. 2011;45(2):8388.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Ochi A, Hung R, Weiss S, et al. Lateralized interictal epileptiform discharges during rapid eye movement sleep correlate with epileptogenic hemisphere in children with intractable epilepsy secondary to tuberous sclerosis complex. Epilepsia. 2011;52(11):19861994.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kassiri J, Snyder TJ, Bhargava R, Wheatley BM, Sinclair DB. Cortical tubers, cognition, and epilepsy in tuberous sclerosis. Pediatr Neurol. 2011;44(5):328332.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mohamed AR, Bailey CA, Freeman JL, Maixner W, Jackson GD, Harvey AS. Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology. 2012;79(23):22492257.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Krsek P, Jahodova A, Kyncl M, et al. Predictors of seizure-free outcome after epilepsy surgery for pediatric tuberous sclerosis complex. Epilepsia. 2013;54(11):19131921.

  • 39

    Kargiotis O, Lascano AM, Garibotto V, et al. Localization of the epileptogenic tuber with electric source imaging in patients with tuberous sclerosis. Epilepsy Res. 2014;108(2):267279.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Arya R, Tenney JR, Horn PS, et al. Long-term outcomes of resective epilepsy surgery after invasive presurgical evaluation in children with tuberous sclerosis complex and bilateral multiple lesions. J Neurosurg Pediatr. 2015;15(1):2633.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Lewis EC, Weil AG, Duchowny M, Bhatia S, Ragheb J, Miller I. MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesional epilepsy. Epilepsia. 2015;56(10):15901598.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Iwasaki M, Uematsu M, Hino-Fukuyo N, et al. Clinical profiles for seizure remission and developmental gains after total corpus callosotomy. Brain Dev. 2016;38(1):4753.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Tovar-Spinoza Z, Ziechmann R, Zyck S. Single and staged laser interstitial thermal therapy ablation for cortical tubers causing refractory epilepsy in pediatric patients. Neurosurg Focus. 2018;45(3):E9.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Koptelova A, Bikmullina R, Medvedovsky M, et al. Ictal and interictal MEG in pediatric patients with tuberous sclerosis and drug resistant epilepsy. Epilepsy Res. 2018;140:162165.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Fohlen M, Taussig D, Ferrand-Sorbets S, et al. Refractory epilepsy in preschool children with tuberous sclerosis complex: early surgical treatment and outcome. Seizure. 2018;60:7179.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Okanishi T, Fujimoto A, Okanari K, et al. Corpus callosotomy for drug-resistant spasms associated with tuberous sclerosis complex. Epilepsy Behav. 2019;98(Pt A):228232.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Grayson LE, Peters JM, McPherson T, et al. Pilot study of neurodevelopmental impact of early epilepsy surgery in tuberous sclerosis complex. Pediatr Neurol. 2020;109:3946.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Stomberg M, Bien CG, Kalbhenn T, Polster T, May TW. Epilepsy associated with tuberous sclerosis complex in childhood: long-term outcome in children after epilepsy surgery and children non-eligible for epilepsy surgery. Epilepsy Behav. 2021;122:108210.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Vannicola C, Tassi L, Barba C, et al. Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study. J Neurol Sci. 2021;427(117506):117506.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Hulshof HM, Benova B, Krsek P, et al. The epileptogenic zone in children with tuberous sclerosis complex is characterized by prominent features of focal cortical dysplasia. Epilepsia Open. 2021;6(4):663671.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Huang Q, Zhou J, Wang X, et al. Predictors and long-term outcome of resective epilepsy surgery in patients with tuberous sclerosis complex: a single-centre retrospective cohort study. Seizure. 2021;88:4552.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Wang Y, Yuan L, Zhang S, et al. Fast ripples as a biomarker of epileptogenic tuber in tuberous sclerosis complex patients using stereo-electroencephalograph. Front Hum Neurosci. 2021;15:680295.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Luo T, Wang X, Wang J, et al. Optimization and high-density array of stereoelectroencephalography-guided radiofrequency thermocoagulation for the treatment of pediatric tuberous sclerosis complex with epil