Tuber Burden Research Articles

Multimodal Analysis of the Retinal Manifestations of Tuberous Sclerosis Complex: A Case Series.

We used a multi-modal imaging approach including fundus fluorescein angiography (FFA) to assess the retinal lesions in tuberous sclerosis complex (TSC) and evaluate their correlation with intracranial tuber burden on magnetic resonance imaging (MRI). Participants with TSC underwent bilateral fundus photography, optical coherence tomography (OCT), infrared (IR) imaging, and FFA. Participants' most recent MRI brain scans were analyzed to determine intracranial tuber load. Nine participants were included. OCT identified all retinal astrocytic hamartoma (RAH) lesions, IR identified 75%, fundus photography identified 63%, and FFA detected just 57%. On FFA, 20% of flat-type hamartomas and all multi-nodular and transitional types were hyperfluorescent. There were significant positive correlations between the quantities of intracranial tubers and all TSC-retinal lesions (r = 0.8, P < 0.01) and all RAH lesions (r = 0.8, P = 0.01). A multimodal imaging-based approach with fundal photography, IR imaging, and OCT should be used to assess the retina in TSC as it may indicate the intracranial tuber burden. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis.

Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms. We delineated tuber locations for 115 TSC participants with ASD (n=31) and without ASD (n=84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at 8 regions of interest derived from the ASD neuroimaging literature, including the anterior cingulate, orbitofrontal and posterior parietal cortices, inferior frontal and fusiform gyri, superior temporal sulcus, amygdala, and supplemental motor area. Next, we performed an unbiased data-driven voxelwise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses. There were no significant ASD-related differences in tuber burden across the whole brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis, we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. Although TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. ANN NEUROL 2023;93:577-590.

Convolutional neural network‐aided tuber segmentation in tuberous sclerosis complex patients correlates with electroencephalogram

One of the clinical hallmarks of tuberous sclerosis complex (TSC) is radiologically identified cortical tubers, which are present in most patients. Intractable epilepsy may require surgery, often involving invasive diagnostic procedures such as intracranial electroencephalography (EEG). Identifying the location of the dominant tuber responsible for generating epileptic activities is a critical issue. However, the link between cortical tubers and epileptogenesis is poorly understood. Given this, we hypothesized that tuber voxel intensity may be an indicator of the dominant epileptogenic tuber. Also, via tuber segmentation based on deep learning, we explored whether an automatic quantification of the tuber burden is feasible. We annotated tubers from structural magnetic resonance images across 29TSC subjects, summarized tuber statistics in eight brain lobes, and determined suspected epileptogenic lobes from the same group using EEG monitoring data. Then, logistic regression analyses were performed to demonstrate the linkage between the statistics of cortical tuber and the epileptogenic zones. Furthermore, we tested the ability of a neural network to identify and quantify tuber burden. Logistic regression analyses showed that the volume and count of tubers per lobe, not the mean or variance of tuber voxel intensity, were positively correlated with electrophysiological data. In 47.6% of subjects, the lobe with the largest tuber volume concurred with the epileptic brain activity. A neural network model on the test dataset showed a sensitivity of .83 for localizing individual tubers. The predicted masks from the model correlated highly with the neurologist labels, and thus may be a useful tool for determining tuber burden and searching for the epileptogenic zone. We have proven the feasibility of an automatic segmentation of tubers and a derivation of tuber burden across brain lobes. Our method may provide crucial insights regarding the treatment and outcome of TSC patients.

Alterations in resting-state functional connectivity in pediatric patients with tuberous sclerosis complex.

ObjectiveTo investigate resting‐state functional connectivity (FC) in pediatric patients with tuberous sclerosis complex and intractable epilepsy requiring surgery.MethodsResting‐state functional MRI was utilized to investigate functional connectivity in 13 pediatric patients with tuberous sclerosis complex (TSC) and intractable epilepsy requiring surgery.ResultsThe majority of patients demonstrated a resting‐state network architecture similar to those reported in healthy individuals. However, preoperative differences were evident between patients with high versus low tuber burden, as well as those with good versus poor neurodevelopmental outcomes, most notably in the cingulo‐opercular and visual resting‐state networks. One patient with high tuber burden and poor preoperative development and seizure control had nearly normal development and seizure resolution after surgery. This was accompanied by significant improvement in resting‐state network architecture just one day postoperatively.SignificanceAlthough many patients with tuberous sclerosis complex and medically refractory epilepsy demonstrate functional connectivity patterns similar to healthy children, relationships within and between RSNs demonstrate clear differences in patients with higher tuber burden and worse outcomes. Improvements in resting‐state network organization postoperatively may be related to epilepsy surgery outcomes, providing candidate biomarkers for clinical management in this high‐risk population.

Tuber Locations Associated with Infantile Spasms Map to a Common Brain Network.

Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms. We segmented tubers from 123 children with (n = 74) and without (n = 49) infantile spasms from a prospective observational cohort. We used voxelwise lesion symptom mapping to test for an association between spasms and tuber location. We then used lesion network mapping to test for an association between spasms and connectivity with tuber locations. Finally, we tested the discriminability of identified associations with logistic regression and cross-validation as well as statistical mediation. Tuber locations associated with infantile spasms were heterogenous, and no single location was significantly associated with spasms. However, >95% of tuber locations associated with spasms were functionally connected to the globi pallidi and cerebellar vermis. These connections were specific compared to tubers in patients without spasms. Logistic regression found that globus pallidus connectivity was a stronger predictor of spasms (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10-3.50, p = 0.02) than tuber burden (OR = 1.65, 95% CI = 0.90-3.04, p = 0.11), with a mean receiver operating characteristic area under the curve of 0.73 (±0.1) during repeated cross-validation. Connectivity between tuber locations and the bilateral globi pallidi is associated with infantile spasms. Our findings lend insight into spasm pathophysiology and may identify patients at risk. ANN NEUROL 2021;89:726-739.

Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex

Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype–phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.

Clinical patterns and outcomes of status epilepticus in patients with tuberous sclerosis complex.

IntroductionRefractory epilepsy is a common clinical manifestation in patients with tuberous sclerosis complex (TSC), which can be complicated by many life-threatening conditions, such as status epilepticus (SE). However, very few reports mention the patterns and semiology of SE in those patients.ObjectiveTo study the clinical characteristics and outcomes of SE in TSC patients.Materials and methodsThis observational, prospective study was carried out on 36 Egyptian children with definite TSC. Clinical history, general and neurological examination and psychometric evaluation by standard questionnaires were used to explore characteristics of epileptic manifestations and clinical patterns of SE. All included patients were required to have long-term video electroencephalograms (EEGs) and brain MRI performed.ResultsA total of 32 attacks of SE were recorded in 21 patients (58.3%) in our cohort during a follow-up period of 2.8±1.1 years; of those patients, 15 had convulsive status, 7 had non-convulsive SE, 6 had refractory/super-refractory SE and 14 patients had a history of infantile spasms (epileptic spasms). The duration of status ranged from 40 to 150 min (mean ± standard deviation: 90±15). Fourteen patients with SE had severe mental retardation, 9 had autistic spectrum disorder and 22 had severe epileptogenic EEG findings. Patients with SE had higher tuber numbers (mean: 9.6), 5 patients had subependymal giant cell astrocytomas and 2 patients had their SE after receiving everolimus.ConclusionsThe incidence of SE in our patient sample is high (>50%); severe mental retardation, autistic features, history of infantile spasm (epileptic spasms) and high tuber burden are risk factors for developing SE.

Evolution of Surgical Management for Intractable Epileptic Spasms

The understanding and management of epileptic spasms has considerably evolved since the mid 19th century. The realization that epileptic spasms can be generated from a focal brain lesion played a pivotal role in the development of neurosurgical management for intractable forms of this epilepsy. During pre-surgical planning, the addition of functional FDG PET imaging has further refined the electroencephalographic localization of epileptogenic lesions. In some cases, neurosurgical resection of a focus that is co-localized by the FDG PET scan and electroencephalography can lead to partial or complete reversal of developmental delay along with reduced seizure frequency or seizure freedom. In cases where near-complete hemispheric cortex is implicated in spasm generation, subtotal hemispherectomy has shown encouraging results. Moreover, palliative resection of the major perpetrating focus in carefully chosen patients with bilateral multifocal spasms has also led to favorable outcomes. However, in patients with tuberous sclerosis with high tuber burden, the localizing value of FDG PET imaging may be limited. In such cases, employment of AMT PET technology has become a valuable tool for localization of actively epileptogenic tubers. This article highlights the historic steps in the successful advancements of neurosurgical interventions for the treatment of intractable epileptic spasms.

Cognitive delay in children with tuberous sclerosis in a developing country: Clinical correlations

Cognitive delayisa frequent neurobehavioral manifestation inchildrenwith tuberoussclerosiscomplex (TSC). This study aimed todeterminethe relationshipsbetweencognitive delaywithrespecttoseizurecharacteristics,interictal electroencephalography (EEG)changes, behavioralabnormalities andbrain tubers'count and location. Thisstudy included24childrenwithTSC witha mean age of 6.2 ± 2.55 yr. Children underwent clinical, psychometric, interictal EEG and magnetic resonance imaging or magnetic reso- nance imaging of the brain. Nearly 58.33% of children had cognitive delay and 45.83% had autism. Compared to children without cognitive delay, children with cognitive delay were younger (P < 0.01), had higher frequencies of seizures (particularly infantile spasms with onset predominantly below 6 mo of age) (P < 0.01), severe epileptogenic EEG changes, high tuber burden (particularly in the left hemisphere with frontal and temporal predominance) (P < 0.01) and frequent behavioral abnormalities as autism (P < 0.001) and attention deficit hyperactivity disorders (P < 0.05). Cognitive scores were correlated with age of seizures' onset (r = 0.432, P = 0.01), presence of infantile spasms (r = −0.675, P = 0.001), autism (r = −0.350, P = 0.05), and number of brain tubers (r = −0.865, P = 0.0001) but non correlated to age nor gender. In multivariate analysis, only the age of seizure onset (odds ratio 1.90; 95% confidence interval 1.02 to 3.55, P = 0.044) and the number of brain tubers (odds ratio 2.36; 95% confidence interval 0.95 to 5.81; P= 0.06) increased the oddsforcognitive delay among TSC patients. The knowledgeofthe clinical features of TSC can help in early diagnosis and management of patients with a multidisciplinary consultation.

The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex

To clarify the relationship between neuroimaging findings, neuropsychiatric comorbidities, and epilepsy in patients with tuberous sclerosis complex (TSC) in Taiwan. Medical records from 32 patients with TSC were retrospectively reviewed, including mutational analysis, neuroimaging findings, electroencephalogram findings, and neuropsychiatric comorbidities. Of these patients, six (18.75%) were diagnosed to have autism spectrum disorders (ASD), and 10 (31.25%) were diagnosed to have attention-deficit-hyperactivity disorder. In the latter patients, there were no differences in the regional distribution of tuber burden. In addition to a high prevalence of cystic-like tubers, tubers in insular and temporal areas were associated with ASD. Nonsense mutations in the TSC2 gene group had a correlation with autistic behavior. In 26 (81.25%) patients with a history of epilepsy, infantile spasms and partial seizures were the predominant type of epilepsy. Most of them developed seizures prior to age 1 year. ASD is a common comorbidity in TSC. Cortical tubers in the temporal lobe and insular area were associated with ASD. The presence of cystic-like tubers on magnetic resonance imaging may also offer a structural marker for ASD in TSC.

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder, which affects 1 in 6000 people. About half of these patients are affected by mental retardation, which has been associated with TSC2 mutations, epilepsy severity and tuber burden. The bimodal intelligence distribution in TSC populations suggests the existence of subgroups with distinct pathophysiologies, which remain to be identified. Furthermore, it is unknown if heterozygous germline mutations in TSC2 can produce the neurocognitive phenotype of TSC independent of epilepsy and tubers. Genotype-phenotype correlations may help to determine risk profiles and select patients for targeted treatments. A retrospective chart review was performed, including a large cohort of 137 TSC patients who received intelligence assessment and genetic mutation analysis. The distribution of intellectual outcomes was investigated for selected genotypes. Genotype-neurocognitive phenotype correlations were performed and associations between specific germline mutations and intellectual outcomes were compared. Results showed that TSC1 mutations in the tuberin interaction domain were significantly associated with lower intellectual outcomes (P<0.03), which was also the case for TSC2 protein-truncating and hamartin interaction domain mutations (both P<0.05). TSC2 missense mutations and small in-frame deletions were significantly associated with higher IQ/DQs (P<0.05). Effects related to the mutation location within the TSC2 gene were found. These findings suggest that TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles, providing further evidence that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.

Autism In Tuberous Sclerosis: Are Risk Factors Identifiable and Preventable?

Evaluation of: Numis AL, Major P, Montenegro MA, Muzykevicz DA, Pulsifer MB, Thiele EA. Identification of risk factors for autism spectrum disorder in tuberous sclerosis complex. Neurology 76(11), 981–987 (2011). Autism spectrum disorders (ASDs) are much more frequent in individuals with tuberous sclerosis complex (TSC) than in the general population. However, the underlying reasons for this association remain largely unclear. This study aimed to identify some risk factors leading to autism in children with TSC. The authors analyzed epidemiological, genetic, electrophysiological and neuroanatomical risk factors in a cohort of 103 TSC patients. ASDs were diagnosed in 41 of the TSC patients (40%). Individuals with ASD had earlier age at seizure onset and a lower IQ (p &lt; 0.001). There was a trend for patients with ASD to have the largest tuber burden in the left temporal lobe and mutations inactivating the hamartin domain of the TSC2 gene. They concluded that autism in TSC may be associated with early and persistent seizure activity in specific brain regions, particularly in the left temporal lobe, where areas responsible for social communication are localized. Cyst-like tubers were more common in TSC patients with ASD.

Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex

The purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC). A total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden. Of the 103 patients with TSC, 40%were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers. The development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed.

Seizures and intellectual outcome: Clinico-radiological study of 30 Egyptian cases of tuberous sclerosis complex

Background and objectives Tuberous sclerosis complex (TSC) is a multi-systemic disorder that involves primarily CNS, skin, kidney and heart. The aim of this study is to determine whether seizures type, interictal EEGs and tubers burden in MRI are correlated to seizure and intellectual outcome, and to identify the clinical risk factors for mental retardation and developing autism in these patients. Methods This was a prospective study that was conducted on 30 Egyptian children with tuberous sclerosis complex (TSC), diagnosed according to the criteria of National Institutes of Health consensus conference revised the diagnostic criteria for TSC. All patients underwent clinical and psychometric evaluation, interictal EEG, and MRI brain. Results and conclusions We found that poor intellectual outcome is related to early onset of seizures, infantile spasms, severely epileptogenic EEG findings and tuber burden on the Left side. Autistic behavior is related to seizure type (more with infantile spasms), severely epileptogenic EEG findings, frontal location of tubers and higher number of tubers (>8).

Associations between electroencephalographic and magnetic resonance imaging findings in tuberous sclerosis complex

Nearly 90% of patients with tuberous sclerosis complex (TSC) develop epilepsy; however the mechanisms of epileptogenesis remain unclear. Some cortical tubers are thought to be epileptogenic while others are not. This study aimed to evaluate whether tuber burden, size or type seen on magnetic resonance imaging (MRI) co-registers with interictal epileptiform discharges on electroencephalogram (EEG). EEG and MRI data from 69 patients with TSC were reviewed by dividing the cerebrum into four quadrants. Quadrants containing greatest tuber burden, largest tuber, calcified tubers, cyst-like tubers, and no tubers were identified on MRI. For EEG analysis, spikes and sharp waves were counted and averaged to a value per minute, and each quadrant was assigned a score. MRI and EEG findings were compared in each patient. The presence of a cyst-like tuber in a quadrant correlated with a higher incidence of epileptiform activity in the same quadrant (p=0.002). This finding supports the notion that cyst-like cortical tubers may contribute to the more severe epilepsy profile seen in TSC patients with these lesions. Quadrants containing greatest tuber burden, largest tubers, and calcified tubers were not predictive of regional interictal epileptiform activity. Furthermore, quadrants without any apparent tuber co-registered with interictal epileptiform discharges in two patients, suggesting a multifactorial component of epileptogenicity in TSC.

Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex

In patients with tuberous sclerosis complex (TSC), the high rates of mental retardation are associated with cortical tubers, seizure activity, and genetic factors. The goal of the study was to investigate the relationship between bilateral cortical tubers and seizure variables and mental retardation in individuals with TSC. The records of 27 patients with TSC (age 6 months to 33 years) undergoing neuropsychological assessment and the following clinical variables were examined: bilateral versus non-bilateral cortical tubers, the age of seizure onset, and presence of infantile spasms. Results were statistically analyzed. Bilateral cortical tubers (p=0.02) and early age of seizure onset (p=0.04) were significantly related to impaired cognitive functioning. Only one of the seven patients with normal cognitive functioning had bilateral tubers, whereas 13/21 patients with intellectual impairment had bilateral tubers. Patients with normal cognitive functioning experienced a mean age of seizure onset after 6 years. A trend was observed between infantile spasms and cognitive functioning (p=0.06); the lack of statistical significance likely reflects the small sample size. Neither age nor gender was related to cognitive status. Further investigation incorporating additional neuroimaging factors, antiepileptic treatment effects, and genetic variables, is needed.

Topical Review: Cognitive and Behavioral Correlates of Tuberous Sclerosis Complex

Tuberous sclerosis complex is a multisystem disorder in which neurologic problems cause the greatest disability. High rates of mental retardation and autism spectrum disorders are associated with the diagnosis. Early-onset seizures and increased tuber burden are risk factors for cognitive impairment. Early-onset seizures, particularly infantile spasms, are risk factors for autism. Tubers within the temporal lobe and cerebellum are often mentioned as risk factors for autism, although the findings are inconsistent. Seizure control is important for developmental outcome and quality of life. Early behavioral assessment and therapeutic intervention, as well as seizure control, are the most effective means of promoting neurodevelopmental outcome.