Calcified Tubers Research Articles

Laser and the Tuber: Thermal Dynamic and Volumetric Factors Influencing Seizure Outcomes in Pediatric Subjects With Tuberous Sclerosis Undergoing Stereoencephalography-Directed Laser Ablation of Tubers

Abstract INTRODUCTION Tuberous Sclerosis (TSC) is a well-known cause of Medically Refractory Epilepsy (MRE). It is well documented that early surgical management can improve patient outcomes. Stereoencephalography-directed Magnetic Resonance guided Laser Interstitial Thermal Therapy (SEEG-directed MRgLITT) is an emerging minimally invasive technique that appears aptly suited for the surgical management of this condition. Our aims are to present our experiences with patients who had undergone prior SEEG-directed MRgLITT to identify and treat cortical tubers responsible for clinical seizures and to perform an in-depth analysis of volumetric and thermal dynamic factors that may be related to seizure outcomes. METHODS We studied all pediatric patients with MRE due to TSC who underwent SEEG-directed MRgLITT, investigating seizure outcomes in relationship to thermal dynamic and volumetric factors of MRgLITT when applied to cortical tubers. RESULTS About 8 cortical tubers from 3 pediatric patients were analyzed. About 2 out of 3 patients had Engel I outcomes at last follow-up. Median follow-up was 15 mo. Average A/T (ablation volume/tuber volume) ratio for Engel I outcomes was 1.28 (variance, 0.16) and 0.84 (variance < 0.01) for all other outcomes (P = .035). When assessing thermal dynamic properties of cortical tuber tissue, there was a moderate positive correlation when comparing ablation energy to ablation volume (R2 = 0.65). When the calcified tuber is excluded from regression analysis, the correlation is stronger (R2 = 0.77). Thus, the calculated volume to ablate 1 cm3 of cortical tuber tissue is 1263.6 J (calcified tuber) or 1089.5 J (noncalcified tuber). CONCLUSION SEEG-directed MRgLITT is a safe and effective technique in the management of pediatric patients with MRE due to TSC. It appears that the A/T ratio is a useful indicator in predicting seizure outcomes.

"Laser and the Tuber": thermal dynamic and volumetric factors influencing seizure outcomes in pediatric subjects with tuberous sclerosis undergoing stereoencephalography-directed laser ablation of tubers.

Tuberous sclerosis (TSC) is a well-known cause of medically refractory epilepsy (MRE). Stereoencephalography-directed magnetic resonance-guided laser interstitial thermal therapy (SEEG-directed MRgLITT) is an emerging minimally invasive technique that appears aptly suited for the surgical management of TSC. Our aims are to present our experiences with patients who had undergone SEEG-directed MRgLITT to identify and treat cortical tubers responsible for clinical seizures and to perform an in-depth analysis of volumetric and thermal dynamic factors that may be related to seizure outcomes. We studied all pediatric patients with MRE due to TSC who underwent SEEG-directed MRgLITT, investigating seizure outcomes in relation to thermal dynamic and volumetric factors. Eight cortical tubers from three pediatric patients were analyzed. Two of three patients had Engel I outcomes at last follow-up (median 18months). Average A/T (ablation volume/tuber volume) ratio for Engel I outcomes was 1.28 (variance, 0.16) and 0.84 (variance, < 0.01) for all other outcomes (P = 0.035). There was a moderate positive correlation when comparing ablation energy to ablation volume (R2 = 0.65) in cortical tuber tissue. When the calcified tuber is excluded, the correlation is stronger (R2 = 0.77). Thus, the calculated energy needed to ablate 1cm3 of cortical tuber tissue is 1263.6J (calcified tuber) or 1089.5J (non-calcified tuber). SEEG-directed MRgLITT appears to be a safe and effective technique in the management of pediatric patients with MRE due to TSC. The A/T ratio may be a useful indicator in predicting seizure outcomes.

LP31: EEG and MEG source localization of the epileptogenic foci in tuberous sclerosis complex: a pediatric case report

LP31: EEG and MEG source localization of the epileptogenic foci in tuberous sclerosis complex: a pediatric case report

A Three Case Series of Neuroimaging Findings of Patients with Tuberous Sclerosis Complex

Aim and Objective: To study different imaging findings in patients presenting with tuberous sclerosis Materials &Methods: We present neuroimaging findings in three children with tuberous sclerosis showing different brain findings on MRI and ct brain scans. Result:We report the neuroimaging findings of 3 cases, two aged 12 years and one aged 2 years who clinically presented with delayed development and epilepsy with findings of subependymal giant cell astrocytoma, calcified tubers, transmantile cerebral white matter migration lines, subependymal nodules and cerebral atrophy. Conclusion: Tuberous sclerosis also known as Bourneville pringle disease is an autosomal dominant genetic disease that is characterised by the presence of multiple hamartomas in various organs. Two separate genes have been reported that have been mutated or deleted kin patients with TSC. TSC1 gene codes for the protein hamartin and TSC2 which codes for protein tuberin. Neuroimaging plays an important role in making the diagnosis of TSC as around 95% of affected patients show abnormalities in the brain.

Metaplastic bone in a cortical tuber of a young patient with tuberous sclerosis complex

Cortical tubers are the most common brain lesions of the tuberous sclerosis complex (TSC).1 They vary widely in size, location, and appearance, may have a cystic or a calcified component, and are often epileptogenic.2,3 Histologically, tubers are hypomyelinated hamartomas, which are characterized by abnormal cortical lamination and are typically composed of giant or balloon cells, dysplastic neurons, and reactive astrocytes.4 We report the radiologic and pathologic findings of a resected calcified tuber identified as an epileptogenic focus. ### Case report. The patient is a 19-year-old right-handed woman with a known spontaneous TSC1 mutation. She was the product of a normal pregnancy. Seizure onset occurred at the age of 9 months and led to a diagnosis of TSC. Neuropathologic features include numerous cortical tubers and subependymal giant cell tumors (SGCT). The patient has experienced daily seizures since their onset. Multiple antiepileptic medications and other anticonvulsant treatments were tried without significant seizure control. The patient has a history of global developmental impairment. As part of the presurgical evaluation for neurosurgical intervention, an MRI showed SGCT, multiple tubers located in bilateral frontal, parietal, and occipital lobes, and a large (22 mm) T2 hypointense calcified lesion deep to the left superior frontal sulcus (figure). Review of prior scans revealed that the calcified component of this …

Intractable epilepsy in tuberous sclerosis: is the tuber removal not enough?

In tuberous sclerosis, a substantially increased risk of developing epilepsy is present very early in life. Cortical tubers are an extremely important aspect of the tuberous sclerosis phenotype, and may have an age-dependent tendency to become epileptogenic. They can be found in the fetal brain as early as 20 weeks’ gestation and can be detected by fetal magnetic resonance imaging (MRI) at 24 to 26 weeks’ gestation; they are typically stable in size and appearance, and remain proportional to the rest of the brain in growing children. However, recent evidence shows that tubers may have a non-static behaviour; they can degenerate in cystic lesions and can exhibit evolving characteristics over time on subsequent MRIs. Not infrequently they have focal areas of calcifications that can progress changing appearance with time and calcified tubers may act as an epileptogenic focus. Cortical tubers are dysplastic lesions composed of giant cells, maloriented dysmorphic neurons, and atypical astrocytes. These abnormal neuronal populations exhibit reduced GABAergic inhibition and have intrinsic epileptogenicity. An imbalance between excitatory and inhibitory synaptic transmission may be linked with seizure initiation in tubers. However, putative ictogenic mechanisms are still largely unknown. Furthermore, not all tubers are the same, and a spectrum of abnormal cell types in different tubers may present in the same individual, giving a different contribution to epileptogenesis. Immunohistochemical heterogeneity and variability of the cellular phenotype reported in different tubers could explain why in children with tuberous sclerosis only some of several tubers are potentially epileptogenic. Although in many patients one localization is consistently present, epileptogenic foci can shift from one epileptogenic tuber to another during the course of the disease, and different regions can become epileptogenic over time due to maturational phenomena. Age-dependent hyperexcitability of different lesions may lead to age-dependent seizure semiology and there is a specific developmental window during which spasmtype seizures begin. Since seizures at an early age are the only independent risk factor for cognitive impairment, the termination of seizures may have developmental benefits. The surgical treatment of intractable epilepsy has yielded excellent results in tuberous sclerosis. Surgery has a role even in individuals with multiple cortical tubers, and if only one region of epileptogenicity is detected, early surgery is strongly recommended. Seizure freedom after surgery has been reported when both the tuber and the electrically active adjacent cortex were resected. Despite significant progress in defining the epileptogenic tuber by multimodality imaging in individuals with multiple lesions, almost 40% of the patients with tuberous sclerosis suffer from surgical failure, suggesting that gains in surgical prognosis are still needed. Activation of tubers at different ages leads to re-operation and multistage surgery. Risk factors associated with seizure recurrence after surgery are poorly understood, and the perspective of future seizure recurrence should be weighed against that of a temporary relief of severe seizures during a critical period of brain development. Tubers are not the only determinants for epilepsy as demonstrated by a tuber-less infant with tuberous sclerosis suffering from intractable epilepsy. Epilepsy secondary to tuberous sclerosis could be a consequence of disorders of long range neural networks with alterations in cortical-subcortical systems connectivity. This can explain why the removal of the lesion and the epileptogenic zone is not enough to interrupt the epileptogenic networks in a significant proportion of individuals with tuberous sclerosis. Disease-modifying agents such as mTOR inhibitors have proved their efficacy in preventing epilepsy in mouse models and in reducing seizure frequency in a patient with tuberous sclerosis with refractory seizures. Although caution is appropriate, these findings suggest that mTOR inhibitors may have the potential to become a novel antiepileptogenic treatment for individuals with tuberous sclerosis.

Progressive calcified tuber in a young male with tuberous sclerosis complex

Tubers are the most common brain lesions in tuberous sclerosis complex (TSC), and typically remain stable in size and appearance. We present the case of a young male with global developmental impairment and autistic features as well as multiple and mixed daily seizures. The patient had a prominent right frontal cortical tuber characterized by a calcified component, which changed on consecutive magnetic resonance imaging between the age of 4 and 11 years, at which time the patient underwent a lesionectomy. A poor long-term outcome is reported since the patient presents an intractable mixed seizure disorder status post-epilepsy surgery and no significant neuropsychological improvements. Histopathology findings show typical characteristics of tubers in TSC as well as numerous calcifications within the resected nodular lesion. This case supports the notion that tubers with calcified components are not necessarily static lesions and can change with time. Investigation of the relationship between the presence of calcification in tubers and epileptogenecity in a large group of patients would provide insights into the pathogenesis of the seizures and cognitive impairment and hopefully, eventually provide better treatment options for patients with TSC.

Distribution and conspicuity of intracranial abnormalities on MR imaging in adults with tuberous sclerosis complex: A comparison of sequences including ultrafast T2‐weighted images

Tuberous sclerosis complex produces a wide range of intracranial pathologies, the most common being cortical tubers and subependymal nodules. This study evaluates which magnetic resonance (MR) sequences show the pathology best and to see if "ultrafast" sequences can show the pathology robustly. MR imaging was performed on 29 adults with tuberous sclerosis complex. Anatomically matched 5-mm-thick sections were taken in the axial plane using four different sequences, including single shot fast spin echo as the ultrafast method. The ability of those sequences to show cortical tubers and subependymal nodules was assessed by reporting each sequence independently and comparing with the reference standard report based on all of the sequences together. A total of 219 cortical tubers were shown in the 29 people; three did not have cortical tubers. Cortical tubers were best delineated on fluid-attenuated inversion recovery (FLAIR) images (false-negative rate <0.5%) followed by the T(2)-weighted images (false-negative rate 21%). The single-shot fast spin echo and gradient echo T(2)* sequences both failed to show more than 50% of cortical tubers. Subependymal nodules were shown in 24 of 29 people and the gradient echo T(2)* sequence showed that pathology best in all 24 cases. Our study shows that single-shot fast spin echo sequences do not sufficiently show the expected intracranial complications of tuberous sclerosis complex and should not be considered as an alternative to standard sequences in this group. Cortical tubers are shown exceptionally well on FLAIR images, whereas subependymal nodules (and calcified tubers) are best shown on gradient echo T(2)* images.

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.

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

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. 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). 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. 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.

Nonfebrile seizures.

Nonfebrile seizures.

Computed tomography in diagnosis of intracranial tumors versus tubers in tuberous sclerosis.

Intraventricular gliomas producing obstruction of the foramen of Monro were observed by computed tomography in 4 of 8 patients with tuberous sclerosis. Bilateral tumors arising from the caudate nuclei were present in one patient. Characteristic subependymal calcified tubers were also seen, but contrast enhancement occurred only in the tumors and not in the tubers. The location of the tumor prevented communication between the 2 lateral ventricles so that surgical placement of a single ventricular shunt resulted in only unilateral relief of hydrocephalus. Shunting in one case was ineffective because of high cerebrospinal fluid viscosity due to elevated protein concentration.