Neuropsychiatric problems in tuberous sclerosis complex

Tuberous sclerosis complex is an autosomal dominant disorder characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. It is a disease affecting multiple organ systems and typically has brain involvement, causing severe disabilities. This article reviews the literature of the commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, which are discussed in the context of the neuropathology and epilepsy observed in tuberous sclerosis complex. The potential pathogenesis of neuropsychiatric problems is explored, including links to the genetics, neuropathology, neurotrophins, and epilepsy factors associated with tuberous sclerosis complex. Treatment of neuropsychiatric symptoms, including autism-like features, attention deficits, and sleep disorders, is also discussed.     

Epilepsy surgery for children with tuberous sclerosis complex

Tuberous sclerosis complex is associated with medically refractory seizures and developmental delay in children. These epilepsies are often resistant to antiepileptic drugs, can be quite severe, and usually have a negative impact on the child's neurologic and cognitive development. It is believed that functional outcome is improved if seizures can be controlled at an early age. The surgical treatment of intractable epilepsy in children and adults with tuberous sclerosis complex has gained significant interest in recent years. Previously published studies have shown a potential benefit from resection of single tubers, with most of the results noted in relatively older children. All of these reports support the idea that if a single primary epileptogenic tuber or region can be identified, then a surgical approach is appropriate. However, most children with tuberous sclerosis complex have multiple potentially epileptogenic tubers, rendering localization challenging, and they are therefore rejected as possible surgical candidates. We have used a novel surgical approach using invasive intracranial monitoring, which is typically multistaged and bilateral. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in patients with tuberous sclerosis complex with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected patients. Long-term follow-up will determine whether this approach has durable effects. We await better methods for identifying the epileptogenic zone, both noninvasive and invasive.     

Characterization of autism in young children with tuberous sclerosis complex

Both cognitive impairment and autism are common in the tuberous sclerosis complex, but the relationship between the 2 diagnoses has not been formally explored. The authors evaluated 20 clinic-referred children with tuberous sclerosis complex at ages 18, 24, 36, and 60 months and classified them as autism, autism spectrum disorder, or normal on the basis of the Autism Diagnostic Observation Schedule. Using the Mullen Scale of Early Learning, cognitive function in each subgroup was assessed. The authors then analyzed the subscores of the Autism Diagnostic Observation Schedule in children with autism. Children with autism showed significantly more global cognitive impairment than those without autism. In addition, all children had some baseline cognitive impairment and the majority had deficits in play scores. The authors conclude that clinic-referred children with tuberous sclerosis complex and autism are at considerable risk for cognitive impairment. These characteristics may help to guide more tailored services for these high-risk children.     

儿童结节性硬化症合并癫痫临床特点分析

目的 探讨儿童结节性硬化症合并癫痫的临床特征。方法 对36例结节性硬化症合并癫痫患儿的临床资料进行分析。结果 所有患儿均以癫痫发作为首发症状,发病年龄〈1岁23例（63.89%）、1-3岁8例（22.22%）、〉3岁5例（13.89%）;发作类型以部分性发作[12例（33.33%）]、全面性发作[5例（13.89%）]、痉挛发作[7例（19.44%）]和混合性发作[12例（33.33%）]为主,其中伴智力低下或发育落后者19例（67.86%）。MRI可见室管膜下结节（30例）,部分病例[26例（86.67%）]伴皮质和皮质下结节、室管膜下巨细胞型星形细胞瘤2例（6.67%）或巨脑回畸形1例（3.33%）。脑电图显示发作间期样放电[34例（94.44%）],表现为多灶性放电[12例（35.29%）]、广泛性放电[8例（23.53%）]、局限性放电[7例（20.59%）]和高度失律[7例（20.59%）];其中8例监测到临床发作,包括痉挛发作（4例）、局灶性发作（3例）、肌阵挛发作（1例）。17例患儿（47.22%）服用1种抗癫痫药物、12例（33.33%）服用2种药物、7例（19.44%）服用3种药物,其中手术治疗1例;随访0.50~10年,无发作7例（19.44%）,有效16例（44.44%）,无效13例（36.11%）。结论 癫痫发作是儿童结节性硬化症最常见的神经系统表现,多在婴儿期发病,主要发作类型为部分性发作和痉挛发作,多数患儿抗癫痫药物治疗有效。     

Characterizing magnetoencephalographic spike sources in children with tuberous sclerosis complex

PURPOSE: Tuberous sclerosis complex (TSC) often causes medically intractable seizures. Magnetoencephalography (MEG) localizes epileptiform discharges. To evaluate the use of MEG spike sources (MEGSSs) for localizing epileptic zones in TSC patients, we characterized MEGSSs and correlated them to EEG and magnetic resonance imaging (MRI) results. METHODS: We analyzed data from seven children who underwent prolonged video-EEG, MEG, and MRI. We classified MEGSSs as clusters (six or more spike sources, 1 cm between sources regardless of number of sources). RESULTS: A single, unilateral cluster with additional scatters occurred in two patients; these predominantly lateralized dipoles correlated to prominent tubers on MRI and ictal/interictal EEG zones. Bilateral clusters with scatters existed in two patients; cluster locations partly overlapped multiple prominent tubers. These patients also had bilateral or diffuse interictal discharges, bilateral or generalized seizures, and changing seizure types and EEG findings. Only bilateral scatters occurred in three patients; scatters partly overlapped EEG interictal/ictal-onset regions; one patient had coexisting generalized seizures. In one patient with equally bilateral scatters, scatters overlapped a prominent tuber and interictal/ictal-onset zones in the right frontal region. CONCLUSIONS: MEG contributes to information from EEG and MRI for localizing epileptogenic zones in children with TSC. A single cluster with scatters in a unilateral hemisphere predicts a primary epileptogenic zone or hemisphere; bilateral or multiple clusters indicate bilateral primary or potential epileptogenic zones; and bilateral scatters without clusters may indicate epileptogenic zones that are hidden within extensive areas of scattered MEGSSs.     

Seizure remission and antiepileptic drug discontinuation in children with tuberous sclerosis complex

BACKGROUND: Epilepsy is a common neurologic complication of tuberous sclerosis complex (TSC) and it is often refractory to treatment. Therefore, treating physicians are often reluctant to discontinue antiepileptic drugs (AEDs) in individuals with TSC who have attained seizure remission. To our knowledge, seizure remission and AED discontinuation in children with TSC has not been studied. OBJECTIVE: To characterize seizure remission and AED discontinuation in children with TSC. METHODS: Retrospective medical record and neuroimaging analysis of 15 children with TSC and epilepsy who had seizure remission, with a subsequent trial of discontinuation of AED treatment. RESULTS: The seizure remission rate for the group of patients with TSC and epilepsy was 14.2%. From the group of 15 patients who had a remission, the absolute relapse rate was 26.7% after a mean follow-up of 5 years 7 months. Patients with sustained remission were more likely to have normal intelligence and only a few cortical or subcortical lesions on neuroimaging. CONCLUSIONS: The proportion of children with TSC and epilepsy who achieve seizure remission is small. Nevertheless, some do attain seizure remission, and AEDs may be successfully discontinued. Mild cerebral involvement is a general clinical marker for seizure remission. The relapse rate in those who have undergone a trial of discontinuation of AED therapy is comparable with the rate in the general pediatric population with epilepsy.     

Proton spectroscopic findings in children with epilepsy owing to tuberous sclerosis complex

Tuberous sclerosis complex is an autosomal dominant disorder that often causes refractory seizures. The presence of multiple lesions makes it difficult to identify a single lesion responsible for the epilepsy. Our purpose is to assess the single-voxel proton spectroscopic findings of the tubers in 11 children with tuberous sclerosis complex. Prior to age 4 years, all of the patients had presented with epileptic seizures and multiple bilateral tubers in magnetic resonance images. Single-voxel proton spectroscopy was performed from the tubers especially showing epileptogenic activity using both the long and short echo time and in 14 controls. The results were analyzed using the Mann-Whitney U-test. Compared with the control group, the spectroscopic findings of tubers were characterized by decreased N-acetylaspartate to creatine ratios (1.43 +/- 0.33; P < .001) in both the long and short echo time spectra, increased choline to creatine ratios (0.91 +/- 0.082; P < .05), and myo-inositol to creatine ratios (0.97 +/- 0.19; P < .01) in the short echo time spectra. A lactate peak was detected in the regions corresponding to an epileptic focus on electroencephalography in six patients. Single-voxel proton spectroscopy could be a useful noninvasive method to evaluate epileptogenic tubers.     

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.     

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.     

Interdependence of clinical factors predicting cognition in children with tuberous sclerosis complex

Cognitive development in patients with tuberous sclerosis complex is highly variable. Predictors in the infant years would be valuable to counsel parents and to support development. The aim of this study was to confirm factors that have been reported to be independently correlated with cognitive development. 102 patients included in this study were treated at the ENCORE-TSC expertise center of the Erasmus Medical Center-Sophia Children’s Hospital. Data from the first 24 months of life were used, including details on epilepsy, motor development and mutation status. Outcome was defined as cognitive development (intellectual equivalent, IE) as measured using tests appropriate to the patients age and cognitive abilities (median age at testing 8.2 years, IQR 4.7–12.0). Univariable and multivariable regression analyses were used. In a univariable analysis, predictors of lower IE were: the presence of infantile spasms (β = ?18.3, p = 0.000), a larger number of antiepileptic drugs used (β = ?6.3, p = 0.000), vigabatrin not used as first drug (β = ?14.6, p = 0.020), corticosteroid treatment (β = ?33.2, p = 0.005), and a later age at which the child could walk independently (β = ?2.1, p = 0.000). An older age at seizure onset predicted higher IE (β = 1.7, p = 0.000). In a multivariable analysis, only age at seizure onset was significantly correlated to IE (β = 1.2, p = 0.005), contributing to 28% of the variation in IE. In our cohort, age at seizure onset was the only variable that independently predicted IE. Factors predicting cognitive development could aid parents and physicians in finding the appropriate support and schooling for these patients.     

Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome

PURPOSE: Children with tuberous sclerosis complex (TSC) benefit from excisional surgery if seizures can be localized to a single tuber. We evaluated the role of noninvasive studies to localize the epileptogenic tuber/region (ET/R) and the outcome of focal resection. METHODS: We identified 21 children with TSC, ages 3 months to 15 years (mean 4.8 years). All had video-(electroencephalogram) EEG and magnetic resonance imaging (MRI) scans, and 18 also had ictal single photon emission-computed tomography (SPECT) studies. An ET/R was localized in 17 patients. Thirteen patients underwent resection guided by intraoperative electrocorticography (n = 7) or subdural monitoring (n = 6). RESULTS: Interictal EEG revealed a principal spike focus (PSF) that corresponded to the ET/R in 14 children. In seven, PSFs occurred in rhythmic runs. PSFs were not observed remote from the ET/R. Focal polymorphic slowing and attenuation occurred in the region of the PSF in 11 patients. Sixteen patients demonstrated an ictal focus corresponding to the ET/R. Ictal SPECT revealed focal hyperperfusion correlating with the ET/R in 10 patients. Although the MRIs in all children revealed multiple tubers, the ET/R corresponded to a large discrete tuber in 8 patients and a calcified tuber in 13 patients. Patchy calcified tubers were also seen elsewhere in six patients. At a mean follow-up of 26 months, 9 of the 13 children who underwent surgery were seizure-free, one had greater than 75% reduction in seizures, two were unchanged, and one was lost to follow-up. New seizures developed in one child from a contralateral tuber. CONCLUSIONS: Surgical resection of an ET/R alleviates seizures in most children with TSC and intractable epilepsy. The scalp EEG and MRI help define the ET/R and improve case selection when ictal SPECT is nonlocalizing.     

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.     

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.     

Quality of life following epilepsy surgery for children with tuberous sclerosis complex

Parents of children with tuberous sclerosis complex who underwent multistage resections for treatment of refractory seizures were offered a telephone questionnaire regarding quality of life (QOL) of child and family since surgery. Of 53 families, 39 responded. Age at epilepsy onset was birth to 3 months. Average duration of epilepsy before the first surgery was 5.1 years, and average age at surgery was 5.8. The average follow-up was 3.9. Seventy-seven percent had a >90% reduction in disabling seizures. In all outcome categories, 46-85% had at least a moderate improvement in QOL. There was a significant correlation between QOL variables and Engel outcome class. Despite the potential burden posed by the aggressive surgical approach, including multiple surgeries and long hospitalization periods, 94% of parents would choose the same course once again. We conclude that aggressive surgical treatment of tuberous sclerosis complex-related refractory seizures is associated with significant control of epilepsy as well as improved QOL for the patient and family.     

Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is frequently associated with focal epilepsy due to cerebral tubers. Seizures are the first symptoms in most patients with brain involvement. These epilepsies are frequently severe, drug-resistant and may have a negative impact on the child's global development. Although most epilepsies are multicentric, these patients may be candidates for epilepsy surgery, if it is possible to determine a leading epileptogenic tuber. Nine patients with TSC were examined with long-term video-EEG monitoring, different neuroimaging techniques and neuropsychological tests. A main epileptogenic tuber could be identified in all of our patients. We found good correlations between neuroimaging and EEG. Surgery was performed in eight patients. Seizure outcome was good in all. Two patients became seizure-free, one patient had a single prolonged seizure five days postoperatively, four patients had a significant seizure reduction of more than 75 % and one patient had a seizure reduction of more than 50 % after surgery without additional neurologic deficits. In conclusion, patients with TSC and drug-resistant epilepsy may benefit from epilepsy surgery with reduction in frequency and severity of seizures as well as improved mental and behavioural development leading to a better quality of life. In view of recent developments in functional and metabolic imaging, primary epileptogenic lesions will be more easily detectable in patients with diffuse brain involvement in TSC and surgical treatment may be more specifically applied at an earlier age to a selected subgroup of patients with this disorder.     

The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC)

Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder associated with a wide range of physical features and very high rates of numerous neurocognitive manifestations. However, there is great variability of expression of these features and understanding of the mechanisms underlying this variability is still limited. Mental retardation (MR) and male gender are known to be associated with increased risks of psychopathologies in the general population, but no study has examined these subgroups in TSC as possible contributors to the variable expression observed. It has also remained unclear whether familial-sporadic differences may contribute to variable expression. In this postal survey, UK families reported the frequency and range of physical and behavioural abnormalities in 265 children and adolescents with TSC. Analysis revealed no gender or familial-sporadic differences. Children with MR were significantly more likely to have an autism spectrum disorder, attention deficit-related symptoms and speech and language difficulties. They were more likely to have a history of epilepsy, facial angiofibromata and shagreen patches and tended to have a greater number of physical features of the disorder. However, about one third of the children without MR had features suggestive of a developmental disorder. Anxiety symptoms, depressed mood and aggressive outbursts occurred at equally high rates in those with and without MR. These findings show that TSC can place any child or adolescent at significantly increased risk of a range of neurodevelopmental disabilities. These difficulties, often not recognised, require significant clinical and research attention.