Faculty Bibliography

OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC. METHODS: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics. RESULTS: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002). SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

OBJECTIVE: /st> To determine the feasibility and toxicity profile of topotecan administered as a seven-day continuous intrathecal infusion for patients with leptomeningeal metastasis secondary to recurrent or progressive central nervous system cancer. Study design Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria. RESULTS: /st> Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44-fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis. CONCLUSION: /st> A seven-day continuous intrathecal infusion of topotecan is well tolerated and has the potential of maximizing central nervous system drug exposure.

OBJECTIVE: Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism. METHODS: Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens. RESULTS: Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination. SIGNIFICANCE: Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex.

BACKGROUND:: Surgical resection of epileptic foci relies on accurate localization of the epileptogenic zone, often achieved by subdural and depth electrodes. Our epilepsy center has treated selected children with poorly localized medically refractory epilepsy with a staged surgical protocol, with at least one phase of invasive monitoring for localization and resection of epileptic foci. OBJECTIVE:: To evaluate the safety of staged surgical treatments for refractory epilepsy among children. METHODS:: Data were retrospectively collected, including surgical details and complications of all patients who underwent invasive monitoring. RESULTS:: 161 children underwent 200 admissions including staged procedures (>1 surgery during one hospital admission), and 496 total surgeries. Average age at surgery was 7y (8m-16.5y). 250 surgeries included resections (and invasive monitoring), and 189 involved electrode placement only. Cumulative total number of surgeries per patient was 2-10 (average 3). Average duration of monitoring was 10 days (1-30). There were no deaths. Follow-up ranged from 1m to 10y. Major complications included unexpected new permanent mild neurological deficits (2%/admission), CNS or bone flap infections (1.5%/admission), intracranial hemorrhage, CSF leak, and a retained strip (each 0.5%/admission). Minor complications included bone absorption (5%/admission), positive surveillance sub/epidural cultures in asymptomatic patients (5.5%/admission), non-infectious fever (5%/admission), and wound complications (3%/admission). 30 complications necessitated additional surgical treatment. CONCLUSION:: Staged epilepsy surgery, with invasive electrode monitoring, is safe in children with poorly localized medically refractory epilepsy. The rate of major complications is low, and appears comparable to that associated with other elective neurosurgical procedures.

Object Subependymal giant cell astrocytomas (SEGAs) are benign tumors, most commonly associated with tuberous sclerosis complex (TSC). The vast majority of these tumors arise from the lateral ependymal surface adjacent to the foramen of Monro, therefore potentially encroaching on one or both foramina, and resulting in obstructive hydrocephalus that necessitates surgical decompression. The indications for surgery, intraoperative considerations, and evolution of the authors' management paradigm are presented. Methods Patients with TSC who underwent craniotomy for SEGA resection at New York University Langone Medical Center between January 1997 and March 2011 were identified. Preoperative imaging, clinical characteristics, management decisions, operative procedures, and outcomes were reviewed. Results Eighteen patients with TSC underwent 22 primary tumor resections for SEGAs. The indication for surgery was meaningful radiographic tumor progression in 16 of 21 cases. The average age at the time of operation was 10.3 years. Average follow-up duration was 52 months (range 12-124 months). The operative approach was intrahemispheric-transcallosal in 16 cases, transcortical-transventricular in 5, and neuroendoscopic in 1. Nine tumors were on the right, 9 on the left, and 3 were bilateral. Gross-total resection was documented in 16 of 22 cases in our series, with radical subtotal resection achieved in 4 cases, and subtotal resection (STR) in 2 cases. Two patients had undergone ventriculoperitoneal shunt placement preoperatively and 7 patients required shunt placement after surgery for moderate to severe ventriculomegaly. Two patients experienced tumor progression requiring reoperation; both of these patients had initially undergone STR. Conclusions The authors present their management strategy for TSC patients with SEGAs. Select patients underwent microsurgical resection of SEGAs with acceptable morbidity. Gross-total resection or radical STR was achieved in 90.9% of our series (20 of 22 primary tumor resections), with no recurrences in this group. Approximately half of our patient series required CSF diversionary procedures. There were no instances of permanent neurological morbidity associated with surgery.

BACKGROUND: Tuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. METHODS: In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas. CONCLUSIONS: Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma-related conditions favor a certain treatment.

Object In patients with tuberous sclerosis complex (TSC), the tuber-to-brain proportion (TBP) is a marker of seizure severity and cognitive function. However, few studies have quantified the TBP. Furthermore, authors of these studies have measured the TBP at only a single time point, despite the fact that tuber cells were found to express proliferation markers, suggesting that they may be dynamic lesions. Authors of the present study used a semi-automated tuber segmentation program to determine whether the TBP changes over time. Methods Axial FLAIR MR images were retrospectively identified for patients with TSC who had undergone imaging at the authors' institution between February 1998 and June 2009. Using FireVoxel software, the TBP was measured for each patient at a minimum interval of 2 years. Results Twelve patients meeting the study inclusion criteria were identified. The mean TBP was 1.88% (range 0.38%-3.70%). Eight patients demonstrated minimal changes and 3 patients demonstrated small increases in TBP. The remaining patient exhibited a decrease of 1.00%, which correlated with a visible decrease in the size of 2 cerebellar lesions. Conclusions Semi-automated brain segmentation is a valuable tool in the longitudinal study of tubers. A subset of patients with TSC, particularly those with cerebellar lesions, may exhibit changes in the TBP over time.