Neurology India, Vol. 59, No. 5, September-October, 2011, pp. 748-752
Multimodal approach in the surgical treatment of refractory epilepsy associated with tuberous sclerosis complex: A series of three cases
Qiang Li, Chao You, Yuan Fang, Jianguo Xu
Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
Keywords: Electroencephalogram, epilepsy, surgical treatment, tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a genetic disorder and affects multiple systems, and is associated with medically refractory seizures in children, often leading to neuropsychological impairments. Reports of surgical treatment in TSC-related refractory epilepsy have been limited.  Because most patients harbor multiple epileptogenic tubers, it is difficult to localize them with non-lateralizing electroencephalogram (EEG), and novel approaches have been adopted. ,, Pre-operative evaluation using multiple modalities may define target tuber better and improve outcomes. We report three patients with TSC-related refractory epilepsy, with special focus on the multimodal approach in the surgical management.
In the period between 2006 and 2008, five patients with TSC were considered as candidates for surgical treatment, and three of them had pre-surgical workup [Table - 1]. All the three patients had regular scalp EEG and magnetic resonance imaging (MRI) in an outpatient clinic. Patients were admitted for scalp video-EEG (VEEG) for 24-72 h (mean, 43 h). These patients were subjected to stage 2 evaluation when the baseline evaluation showed concordant information, which included intracranial VEEG monitoring, [18F]-FDG-positron emission tomography 18F-FDG-PET and magnetoencephalogram (MEG). Based on scalp VEEG recordings, 24-channel intracranial VEEG was performed with intracranial electrodes positioned on the bilateral frontal and temporal lobes. The recordings lasted 72-96 h (mean, 80 h). The data, clinical symptoms, intracranial VEEG recordings, localization of tuber, PET and MEG results were analyzed together, and only patients with concordant data were finally selected for operation under general anesthesia. During operation, EEG monitoring was done before and after each tuber resection. When residual discharge was recorded after target tuber resection, cortex surrounding the tubers was cauterized at 4-6 watts and 1-2 s, followed by repeat EEG until no abnormal discharge was recorded.
All the patients had medically refractory seizures with skin pigmentation or facial angiofibroma. MRI showed hypointense sub-ependymal nodules and hyperintense cortical tubers on T2-weighted imaging [Figure - 1]. MEG showed focal discharge in regions near the epileptogenic lesions. All resected tubers were at least 1 cm away from the eloquent areas. Pathological diagnosis was confirmed as loss of normal six layers, disorganized large pyramidal or "giant" cells in reactive gliosis with eosinophilic neurofibrils. Follow-up was through outpatient clinic visits [Table - 2]. The study was approved by the Ethics Committee of the West China Hospital, and parents of the patients gave informed consent.
A 6-year-old boy with a 3-year history of seizures had daily episodes of atypical absence and weekly generalized tonic-clonic seizures (GTCS) and no family history of TSC. His intelligent quotient (IQ) was 83. Pre-operative MRI showed two subcortical tubers in the right temporal lobe and others in the subependyma [Figure - 1]a and b. Intracranial ictal VEEG showed generalized irregular spikes and waves in the right temporal lobe and PET scan showed hypometabolism in the corresponding region [Table - 1]. Tubers in the right temporal lobe were identified as epileptogenic, and the patient underwent total resection and cortex cauterization under EEG surveillance. Follow-up was 13 months, and he had 60% reduction in seizure frequency (Engel class III).
A 8-year-old girl with a 4.5-year history of seizures had simple and complex partial motor seizures and drop attacks almost every day and GTCS every week. She had a family history of TSC and her IQ was 79. MRI showed one tuber each in the left frontal and temporal lobes, and other tubers in the right frontal lobe [Figure - 1]c, d. Intracranial VEEG showed generalized irregular spikes and waves in the left frontal and temporal lobes and PET scan revealed hypometabolism in the corresponding regions [Table - 1]. Tubers in the left frontal and temporal lobes were identified as epileptogenic and were resected under EEG surveillance. She also underwent cortex cauterization. She had only four seizures during 35 months follow-up after operation, with significantly reduced severity and duration (Engel class II).
An 11-year-old boy with a 5-year history of seizures had simple and complex partial seizures and absence seizures everyday and no GTCS. His IQ was 75 [Table - 1]. Pre-operative MRI revealed one tuber in the right frontal lobe and others in the subependyma [Figure - 1]e, f. Interictal scalp EEG showed high sharp waves in the right frontal lobe [Figure - 2]a and VEEG showed sharp and slow waves in the right frontal lobe [Figure - 2]c and d. Intracranial ictal VEEG showed 2.5-4 Hz-high spike waves in the right frontal lobe [Figure - 3]. PET scan revealed hypometabolism in the right fontal and temporal lobes [Figure - 2]b. Because there was no identifiable tuber in MRI and VEEG showed no primary ictal discharge in the right temporal lobe, the tuber in the right frontal lobe was identified as epileptogenic and was resected. The patient did not undergo cortex cauterization and had no seizure relapse after operation (Engel class I).
TSC-related seizures when uncontrolled cause neuropsychological impairments and are critical problems for such patients.  Thus, seizure control is a cardinal issue in the management of TSC. However, TSC-related seizures are often medically refractory, and surgical treatment is a treatment option.
Identification of epileptogenic tuber is of utmost importance in the surgical management of TSC-related seizures. However, most often, patients with TSC may have more than one epileptogenic tuber, and localization of epileptogenic tuber is quite challenging. Nevertheless, several novel approaches have been described to facilitate this process. ,, Wu et al.  reported a non-invasive approach using magnetic source imaging (MSI) and PET/MRI co-registration for localization of epileptogenic tuber. In their study of the 28 patients, 18 (64%) patients had surgery based on the concordant data and 12 (67%) had seizure freedom post-operatively. MEG with synthetic aperture magnetometry (SAM) has been shown to be useful in localizing complex epileptogenic zones; of the seven patients in this study, six were seizure-free after resection.  For better localization of the epileptogenic zone, invasive surgical approach including 3-staged epilepsy surgery has been proposed.  More than 68% of the patients undergoing multistage epilepsy surgery were in Engel class I at mean follow-up of 28 months. Four of the five patients who were earlier considered as not candidates for surgery because of the multifocal epileptogenic zones were seizure-free when operated by this novel approach. However, with the advancement of technology, non-invasive methods may be the future for pre-operative evaluation of epileptogenic tubers in patients with TSC.
The principle of epileptogenic zone localization is concordance of data from different modalities. High-resolution MRI provides precise anatomical location and structural evidence for sclerotic tubers in TSC, and is essential in surgical planning. Intericatal scalp EEG may seldom catch ictal discharges, but may help in hemispherical lateralization if not lobar localization. Scalp VEEG is very useful in documenting the clinical events and the associated ictal discharge patterns. Based on this data, the next stage of pre-surgical workup, including intracranial VEEG, PET and MEG, could be planned. If scalp VEEG fails to localize the epileptogenic zone, intracranial VEEG would be necessary for accurate localization. Intracranial electrodes can be placed in a relatively pre-defined area based on the scalp VEEG information thus avoiding large craniotomy. Intraoperative electrocorticography determines the exact location of the epileptogenic and may also guide and determine cortex cauterization. PET and MEG are accessory investigative modalities for better localization of epileptogenic tubers. However, in our view, surgical indications should adhere to the classical triad of clinical seizure semiology, MRI and VEEG, and PET or MEG provides extra data in surgical management of TSC-related seizures.
There is growing consensus that TSC-related epilepsy may be treated surgically.  However, resection of epileptogenic tubers in the eloquent region often results in neurological deficits, and low-power cauterization with bipolar on this region may be used to reduce seizure frequency.  If epileptogenic tuber is not suitable for surgical resection, stereotactic radiosurgery could be an alternative to craniotomy surgery,  and its effect is more of irradiation in the epileptogenic zone than radiation dose to the tubers.  In the report by Romanelli et al., a 40% reduction of seizure frequency was observed in one patient who had little benefit from subtotal tuber resection. 
Based on our experience and review of the literature, multiple epileptogenic tubers are not necessarily a contraindication for surgical resection, and the outcome is not related to the number of tubers. In the series by Weiner et al.,  92% of the patients, even with multiple epileptogenic foci, had Engel Class I and II outcome in both short- and long-term follow-up. One of our patients had Class III outcome, and it is quite possible in him that one of the other tubers might have evolved to epileptogenic tuber, thus, emphasizing the need for long term follow-up of these patients. When seizures relapse or the seizure frequency increases, these patients may require re-evaluation for possible second surgery.
We would like to thank D Zhou for pre-operative evaluation and Q Zhou for defining the pathological characteristics of the resected lesions.
Copyright 2011 - Neurology India
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