Magnetic source imaging localizes epileptogenic zone in children with tuberous sclerosis complex

The authors assessed whether magnetoencephalography/magnetic source imaging (MEG/MSI) identified epileptogenic zones in patients with tuberous sclerosis complex (TSC). In six TSC children with focal seizures, ictal video-EEG predicted the region of resection with 56% sensitivity, 80% specificity, and 77% accuracy (p = 0.02), whereas interictal MEG/MSI fared better (100%, 94%, and 95%, respectively; p < 0.0001). Interictal MEG/MSI seems to identify epileptogenic zones more accurately in children with TSC and focal intractable epilepsy.     

Local epileptogenic networks in tuberous sclerosis complex: a case review

OBJECTIVE: Cortical tubers are a pathognomonic finding in some patients with tuberous sclerosis complex (TSC), and are believed to be epileptogenic foci. Surgery is an effective option in selected patients with TSC who are refractory to medical therapy. This article describes three patients with TSC who underwent three-stage epilepsy surgery at our center, with the intention of examining local electrophysiological changes after each stage of the procedure. METHODS: Magnetic resonance images were obtained after initial implantation of electrodes and after resection and electrode reimplantation. These images were co-registered and overlaid. The intracranial grids were overlaid in a similar procedure and manually traced, and then added to the volumetric image. Mean spike counts were obtained for each patient and expressed in spikes per minute. Statistical analysis was performed on spike counts prior to and after resection. RESULTS: All three patients displayed intense spiking in the regions around the dominant epileptogenic tuber. On tuber removal, spike counts diminished significantly. In each case, new areas of spiking emerged in regions remote from the tuber periphery after tuber resection, with the emergence of secondary ictal onset zones in the resection margin. CONCLUSION: This retrospective study highlights some common electrophysiological features among the patients examined. The observed epileptogenic activity and regions of ictal onset suggest that it may be the region of brain tissue surrounding the tuber that is responsible for the majority of epileptogenic activity in these patients.     

结节性硬化所致婴儿痉挛症脑电图特征及术前定位探讨

目的探讨结节性硬化所致婴儿痉挛症患者的脑电图特征及术前定位。方法回顾性分析已接受手术治疗的31例结节硬化所致婴儿痉挛症脑电图背景构型,与年龄的相关性及痫灶定位情况。结果 1岁以内为典型高幅失律,1～3岁呈现多元化为典型失律、变异失律及正常背景活动,3岁以后以变异失律和正常背景为主导,合计占该年龄段的86%,少数演变成慢棘-慢约占10%,极少数残留为典型失律约占4%。定位局灶性放电（单灶）6例,一侧双灶7例,一侧多灶7例,双侧改变以一侧优势11例。本组随访3个月至6年,平均3.5年。31例患者中20例无发作,7例发作减少90%,3例减少75%,1例无改变。平均智商（IQ）从术前52.6分提高到61.8分。结论结节性硬化所致婴儿痉挛症脑电图背景构型可随年龄的增长由典型失律转归成变异失律和正常节律。EEG放电广泛,以双灶或多灶性改变为主,但可综合背景、发作间期及发作期定位找出痫灶放电优势侧,并结合临床表现、影像学特点等,找出致痫结节并予以手术切除,可获得良好的治疗效果。     

Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEG-fMRI

PURPOSE: Ninety percent of patients with tuberous sclerosis complex (TSC) have epilepsy. Identification of epileptogenic areas can be difficult and studies are needed to characterize the epileptogenic network in more detail. METHODS: Five children with TSC and focal epilepsy were studied using simultaneous EEG and functional MRI recordings. Tubers were marked by a neuroradiologist on the anatomical MRI. Spike-associated BOLD (blood oxygenation level-dependent) responses were superimposed with lesions. RESULTS: Thirteen different types of interictal epileptiform discharges (IED) were analyzed with 12 showing a BOLD response, all involving more than one tuber. Five studies had tubers with activations exclusively within the lesion, three studies had lesional activations extending to perilesional areas, and two studies had activations involving exclusively perilesional areas of at least one tuber. Deactivations exclusively within a tuber were found in six studies, lesional deactivations extending to perilesional areas were found in four studies, and tubers with exclusively perilesional deactivations were found in five studies. A BOLD response was found in at least one tuber in the lobe of IED generation and presumed seizure onset (according to telemetry) in all patients. In four patients, the same tubers were involved following different IED localizations. The observed changes were always multifocal, sometimes involving tubers distant from the IED field. DISCUSSION: These findings suggest extended epileptogenic networks in patients with TSC, which exceed networks described in PET and SPECT studies. It was possible to identify specific interictally active tubers. EEG-fMRI provides a noninvasive method to select tubers and areas at their borders for further presurgical investigations.     

Magnetic resonance imaging in relation to EEG epileptic foci in tuberous sclerosis

In 20 patients with tuberous sclerosis (TS), who were sequentially treated for epilepsy at our clinic, the high signal lesions in the cerebral cortex and subcortex detected on T2 weighted magnetic resonance imaging (MRI) were compared with the interictal EEG findings. In four cases who showed a unilateral distribution of the MRI lesions, there was a good correlation between the laterality of the affected lobes and the localization of the EEG epileptic foci. Thirteen cases with more than four affected lobes in both hemispheres also showed bilateral epileptic foci on EEG. The MRI lesions in the occipital lobes showed the best correlation with the EEG epileptic foci, while the worst correlation was seen in the frontal lobes. In addition, the cases with four or more affected lobes without laterality on MRI are more likely to show bilateral synchronization on EEG. The prognosis of epilepsy in these cases was found to be rather poor.     

Diffusion-weighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis

BACKGROUND: Patients with tuberous sclerosis complex and drug-resistant epilepsy may be considered candidates for epilepsy surgery. This demands the unambiguous demonstration of the epileptogenicity of one of the tubers. OBJECTIVE: To test whether diffusion-weighted magnetic resonance imaging enables differentiation of epileptogenic tubers from inert ones. METHODS: In 4 patients with clear unifocal interictal spike activity, fluid-attenuated inversion recovery and diffusion-weighted magnetic resonance imaging were performed. Apparent diffusion coefficient maps were calculated in the identified epileptogenic tuber and compared withthose in nonepileptogenic tubers and regions of normal-appearing cortex. RESULTS: A significant increase in the apparent diffusion coefficient was found in the epileptogenic tubers. Furthermore, the apparent diffusion coefficient of the nonepileptogenic tubers was significantly higher than the trace apparent diffusion coefficient of regions of normal-appearing cortex. CONCLUSION: Diffusion-weighted magnetic resonance imaging may be of clinical importance for the identification of epileptogenic tubers in patients with tuberous sclerosis and intractable epilepsy.     

Vigabatrin for tuberous sclerosis complex.

Vigabatrin (VGB) was found to be an effective anti-epileptic drug to reduce infantile spasms in about 50% of patients and it has been found most effective in infantile spasms due to tuberous sclerosis (TSC) in which up to 95% of infants had complete cessation of their spasms. VGB was synthesized to enhance inhibitory gamma-aminobutyric acidergic (GABAergic) transmission by elevating GABA levels via irreversible inhibition of GABA transaminase. The mechanism underlying the particular efficacy of VGB in TSC is still unknown. However, its efficacy suggests that epileptogenesis in TSC may be related to an impairment of GABAergic transmission. VGB should be considered as the first line monotheraphy for the treatment of infantile spasms in infants with confirmed diagnosis of TSC. The efficacy of VGB treatment can be assessed in less than 10 days, but usually a few days treatment with a dose of about 100 mg/kg/day stops infantile spasms. The cessation of the spasms is associated with a marked improvement of behaviour and mental development. Unfortunately, it has become clear that the use of VGB is associated with a late appearance of visual-field defects in up to 50% of patients. Currently the minimum duration and doses of VGB treatment that can produce side effects are unknown. The feasibility of using short treatment periods (2-3 months) should be investigated.     

Neuroimaging in tuberous sclerosis complex

PURPOSE OF REVIEW: In this review we discuss recent advances in the neuroimaging of patients with tuberous sclerosis complex (TSC), highlighting its application in improving clinical management, particularly in the case of intractable epilepsy. RECENT FINDINGS: Progress in structural and functional imaging has led to further characterization of the brain lesions in TSC. New magnetic resonance imaging techniques that can delineate the extent of structural brain abnormalities in TSC have been developed. Diffusion tensor imaging unveils the microstructural abnormalities of the brain lesions and of the morphologically normal appearing white matter in TSC. It can potentially identify the epileptogenic zone. Positron emission tomography scanning with 2-deoxy-2-[18F]fluoro-D-glucose can assess the full extent of functional brain abnormalities in TSC. The use of alpha [11C] methyl-L-tryptophan positron emission tomography scanning has proven to be a useful tool in the identification of epileptogenic tubers and has improved the outcome of surgery for epilepsy in TSC. SUMMARY: Major advances of neuroimaging in TSC have shown evidence of widespread structural and functional brain abnormalities. In TSC patients with intractable epilepsy, new neuroimaging modalities can now provide an accurate assessment of the epileptogenic zone, thereby permitting improved identification of patients who can have good seizure outcome following surgery for epilepsy.     

Hemimegalencephaly in tuberous sclerosis complex

The purpose of this case report is to describe the computed tomographic and magnetic resonance imaging findings of the brain of a 16-month-old girl with an uncommon association between hemimegalencephaly and tuberous sclerosis complex. When a large calcification is found within a hemimegalencephalic cerebral hemisphere, further investigation of a suspected associated tuberous sclerosis complex or another phakomatosis is required to determine pertinent treatment options and genetic counseling.     

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report

PURPOSE: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG-PET/MRI coregistration and diffusion-tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients. METHODS: FDG-PET/MRI coregistration and/or DTI for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were utilized in 15 TSC patients. Presurgery scalp EEG and postsurgery seizure control identified epileptogenic tubers (n = 27) and these were compared with nonepileptogenic tubers (n = 204) for MRI tuber volume, volume of FDG-PET hypometabolism on MRI coregistration, DTI, ADC, and FA values. RESULTS: Compared with nonepileptogenic tubers, epileptogenic regions had increased volume of FDG-PET hypometabolism (p < 0.0001), and increased ADC values in subtuber white matter (p < 0.0001). In contrast, the largest MRI identified tuber (p = 0.046) and decreased FA values (p = 0.58) were less accurate in identifying epileptogenic regions. Larger volumes of FDG-PET hypometabolism correlated positively with increased ADC values (p = 0.029), and localized to areas of cortical dysplasia adjacent to the tuber in four cases. CONCLUSIONS: Larger volumes of FDG-PET hypometabolism relative to MRI tuber size and higher ADC values identified epileptogenic tubers and adjoining cortex containing cortical dysplasia in TSC patients with improved accuracy compared with largest tuber by MRI or lowest FA values. Used in conjunction with ictal scalp EEG and interictal magnetoencephalography, these newer neuroimaging techniques should improve the noninvasive evaluation of TSC patients with intractable epilepsy in distinguishing epileptogenic sites for surgical resection.     

Diagnosis of tuberous sclerosis complex

Tuberous sclerosis complex is a dominantly inherited disorder affecting multiple organs; because of its phenotypic variability, the diagnosis of tuberous sclerosis complex can be difficult in the young or in individuals with subtle findings. Recently revised consensus diagnostic criteria for tuberous sclerosis complex reflect an improved understanding of its clinical manifestations and its genetic and molecular mechanisms. The diagnostic criteria are based on the premise that there are probably no truly pathognomonic clinical signs for tuberous sclerosis complex; signs that were once regarded as specific occur as isolated findings in individuals with no other clinical or genetic evidence of tuberous sclerosis complex. Consequently, the revised criteria require tuberous sclerosis complex-associated lesions of two or more organ systems or at least two dissimilar lesions of the same organ to confirm the diagnosis. The addition of DNA testing complements clinical diagnosis and allows more precise genetic counseling and, in some individuals, prenatal diagnosis. Nevertheless, the 15% false-negative rate for DNA testing and the occurrence of germline mosaicism in about 2% of individuals with tuberous sclerosis complex make it difficult to exclude the diagnosis of tuberous sclerosis complex in family members.     

Current management for epilepsy in tuberous sclerosis complex

PURPOSE OF REVIEW: This article reviews the most significant advances in the field of epilepsy associated with tuberous sclerosis complex, with emphasis on new advances in the knowledge of the pathophysiological mechanisms of epileptogenicity, progress in identifying the epileptogenic zone, and the rationale for surgical management in individuals with intractable seizures. RECENT FINDINGS: Advances in our understanding of the mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with tuberous sclerosis complex may facilitate more effective interventions. Early effective seizure control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice in the short-term treatment of infantile spasms. Some individuals, however, develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with tuberous sclerosis complex remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. Epilepsy surgery is often associated with significant improvement of the neurologic outcome. SUMMARY: Epilepsy in tuberous sclerosis seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition. Understanding the mechanisms of epileptogenesis might increase the availability of development of a more specific and efficacious treatment. New evidence suggests that it is possible to noninvasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment.     

Arachnoid cysts in tuberous sclerosis complex

Objective: Some clinical findings in tuberous sclerosis complex (TSC), such as hypomelanotic macules or angiofibromas are related to problems in development of the neural crest, which is also the origin of cranial leptomeninges. Arachnoid cysts have been reported in two TSC patients to date. The purpose of this study was to assess the prevalence and characteristics of arachnoid cysts in a large cohort of TSC. Materials and method: We performed a review of brain MRIs of 220 TSC patients searching for arachnoid cysts. Results: Arachnoid cysts were found in 12 (5.5%) (general population: 0.5%), including ten males (83.3%). Four patients (33.3%) had also autosomal dominant polycystic kidney disease (ADPKD) due to a contiguous deletion of the TSC2–PKD1 genes. Three patients (25%) had two or more arachnoid cysts, of whom two also had ADPKD. One patient with an arachnoid cyst did not have tubers, subependymal nodules or white matter migration lines. Conclusion: Our study suggests that arachnoid cysts are part of the clinical spectrum of TSC and may be also present in TSC patients without other typical TSC brain lesions.     

Brain abnormalities in tuberous sclerosis complex

Tuberous sclerosis complex is an autosomal dominant multisystem disorder. Spontaneous mutations occur in up to 60% of patients with gene loci located on chromosomes 9q34 (TSC1) and 16p13 (TSC2). Diagnosis is established with the identification of various neurocutaneous markers and multiple organ system hamartomas. The variable expression of severity, the potential for cognitive dysfunction, and epilepsy compound the clinical picture. The intracranial abnormalities include the identification of migration and hamartomatous brain lesions, such as tubers, subependymal nodules, and subependymal giant cell astrocytomas. A number of other neuroimaging and morphometric abnormalities coexist, which can be identified with current neuroimaging techniques. This review examines the spectrum of brain abnormalities encountered in tuberous sclerosis complex and presents them as not merely a collection of lesions but more cohesively in the context of a global neuronal migration disorder.     

Magnetic resonance imaging in tuberous sclerosis

Twenty-five patients with tuberous sclerosis were studied with magnetic resonance imaging (MRI), and these findings were compared with those of computed cranial tomography (CCT) and with the clinical severity of the disease. Multiple high-signal MRI lesions involving the cerebral cortex are characteristic of tuberous sclerosis and probably correspond to the hamartomas and gliotic areas seen pathologically. These cortical lesions were only occasionally seen with CCT. The periventricular calcific lesions characteristic of tuberous sclerosis are better visualized with CCT than with MRI, but the larger periventricular calcifications produce low-signal MRI abnormalities. Seven patients had high-signal MRI lesions of the cerebellum; small calcific cerebellar lesions were also noted with CCT in three patients. As in earlier studies, no clear correlation was seen between the number of abnormalities visible with CCT and the clinical severity of the disease. By contrast, the more severely affected patients tend to have a higher number of cerebral cortical lesions detected with MRI. Thus, MRI may be useful in predicting the eventual clinical severity of younger children with newly diagnosed tuberous sclerosis.