Michael Kohrman

Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. METHODS In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. FINDINGS 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). INTERPRETATION These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. FUNDING Novartis Pharmaceuticals.

Seizure anticipation in pediatric epilepsy: use of kolmogorov entropy

The purpose of this paper is to demonstrate feasibility of using trends in Kolmogorov entropy to anticipate seizures in pediatric patients with intractable epilepsy. Surface and intracranial recordings of preseizure and seizure activity were obtained from five patients and subjected to time series analysis using Kolmogorov entropy. This metric was compared with correlation dimension and power indices, both known to predict seizures in some adult patients. We used alarm levels and introduced regression analysis as a quantitative approach to the analysis of trends. Surrogate time series evaluated data nonlinearity, as a precondition to the use of nonlinear measures. Seizures were anticipated before clinical or electrographic seizure onset for three of the five patients from the intracranial recordings, and in two of five patients from the scalp recordings. Anticipation times varied between 2 and 40 minutes. This is the first report in which simultaneous surface and intracranial recording are used for seizure prediction in children. We conclude that the Kolmogorov entropy and power indices were as effective as the more commonly used correlation dimension in anticipating seizures. Further, regression analysis of the Kolmogorov entropy time series is feasible, making the analysis of data trends more objective.

Neocortical seizure foci localization by means of a directed transfer function method

Purpose:  Determination of the origin of extratemporal neocortical onset seizures is often challenging due to the rapid speed at which they propagate throughout the cortex. Typically, these patients are poor surgical candidates and many times experience recurrences of seizure activity following resection of the assumed seizure focus.

Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study

BACKGROUND In the EXIST-1 trial, initiated on Aug 10, 2009, more than 35% of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex had at least 50% reduction in SEGA volume after 9·6 months of treatment with everolimus. In this Article, we report interim data (up to Jan 11, 2013) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1. METHODS We assessed data from a prospective, open-label extension of a multicentre, phase 3, randomised, double-blind, placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment. In this extension study, we included all patients who had been assigned everolimus during the double-blind, randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase. All patients received oral everolimus at a starting dose of 4·5 mg/m(2) per day. Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL. An independent central radiology review team assessed SEGA response (at least a 50% reduction from baseline in total volume of all target SEGAs; the primary endpoint) by MRI at 12, 24, and 48 weeks, then every year thereafter in all patients who received at least one dose of everolimus. This study was registered with ClinicalTrials.gov, number NCT00789828. FINDINGS Of the original 117 randomly assigned patients, 111 were given everolimus between Aug 20, 2009, and Jan 11, 2013 (date of data cutoff); we included these patients in our longer-term analysis. Median duration of everolimus exposure was 29·3 months (IQR 19·4-33·8). Median follow-up was 28·3 months (IQR 19·3-33·0). 54 (49%) patients had a response of 50% or greater reduction in SEGA volume (95% CI 39·0-58·3), and duration of response was between 2·1 and 31·1 months (median not reached). SEGA volume was reduced by 50% or more in 39 (37%) of 105 patients at 24 weeks, 48 (46%) of 104 patients at 48 weeks, 36 (47%) of 76 patients at 96 weeks, and 11 (38%) of 29 patients at 144 weeks. Stomatitis (48 [43%] patients) and mouth ulceration (33 [30%] patients) were the most frequent treatment-related adverse events; infections were the most commonly reported treatment-related serious adverse event, occurring in 15 (14%) patients. 35 (32%) patients reported treatment-related grade 3 or 4 adverse events, the most common of which were stomatitis (nine [8%]) and pneumonia (nine [8%]). 18 (16%) patients had treatment-related serious adverse events. Six (5%) patients withdrew because of adverse events. INTERPRETATION These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations. Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA. FUNDING Novartis Pharmaceuticals.

Identification of epileptogenic foci from causal analysis of ECoG interictal spike activity.

OBJECTIVE In patients with intractable epilepsy, the use of interictal spikes as surrogate markers of the epileptogenic cortex has generated significant interest. Previous studies have suggested that the cortical generators of the interictal spikes are correlated with the epileptogenic cortex as identified from the ictal recordings. We hypothesize that causal analysis of the functional brain networks during interictal spikes are correlated with the clinically-defined epileptogenic zone. METHODS We employed a time-varying causality measure, the adaptive directed transfer function (ADTF), to identify the cortical sources of the interictal spike activity in eight patients with medically intractable neocortical-onset epilepsy. The results were then compared to the foci identified by the epileptologists. RESULTS In all eight patients, the majority of the ADTF-calculated source activity was observed within the clinically-defined SOZs. Furthermore, in three of the five patients with two separate epileptogenic foci, the calculated source activity was correlated with both cortical sites. CONCLUSIONS The ADTF method identified the cortical sources of the interictal spike activity as originating from the same cortical locations as the recorded ictal activity. SIGNIFICANCE Evaluation of the sources of the cortical networks obtained during interictal spikes may provide information as to the generators underlying the ictal activity.

Three-dimensional Brain Current Source Reconstruction from Intra-cranial ECoG Recordings

We have investigated 3-dimensional brain current density reconstruction (CDR) from intracranial electrocorticogram (ECoG) recordings by means of finite element method (FEM). The brain electrical sources are modeled by a current density distribution and estimated from the ECoG signals with the aid of a weighted minimum norm estimation algorithm. A series of computer simulations were conducted to evaluate the performance of ECoG-CDR by comparing with the scalp EEG based CDR results. The present computer simulation results indicate that the ECoG-CDR provides enhanced performance in localizing single dipole sources which are located in regions underneath the implanted subdural ECoG grids, and in distinguishing and imaging multiple separate dipole sources, in comparison to the CDR results as obtained from the scalp EEG under the same conditions. We have also demonstrated the applicability of the present ECoG-CDR method to estimate 3-dimensional current density distribution from the subdural ECoG recordings in a human epilepsy patient. Eleven interictal epileptiform spikes (seven from the frontal region and four from parietal region) in an epilepsy patient undergoing surgical evaluation were analyzed. The present promising results indicate the feasibility and applicability of the developed ECoG-CDR method of estimating brain sources from intracranial electrical recordings, with detailed forward modeling using FEM.

A Comparison of Polysomnography and a Portable Home Sleep Study in the Diagnosis of Obstructive Sleep Apnea Syndrome

OBJECTIVE: To validate the role of a portable sleep monitor device (SNAP) in the diagnosis of obstructive sleep apnea syndrome (OSAS). Inter-reader variability was also assessed for both PSG and SNAP. STUDY DESIGN AND SETTING: Sixty consecutive adults referred for PSG at The University of Chicago Sleep Disorder Clinic were prospectively enrolled. RESULTS: There was no significant difference between total number of apnea and hypopnea, respiratory disturbance index (RDI), and minimum oxygen obtained by PSG and SNAP, but there was a significant difference between sleep time and mean oxygen. Pearsons correlation coefficient for RDI ≥ 15 was 0.92. CONCLUSION: There was a significant correlation of RDIs between SNAP and PSG. SNAP has good sensitivity, specificity, positive and negative predictive values. Differences between SNAP and PSG could be attributed to inter-reader variability and not necessarily due to technical limitations of SNAP. SNAP is an excellent tool for the diagnosis of OSAS in the laboratory setting. Future studies should be performed to evaluate SNAPs accuracy in the home setting in the diagnosis of OSAS. EBM rating: B-2. (Otolaryngol Head Neck Surg 2004;131:844–50.)

The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1

BACKGROUND Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC. METHODS EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually. RESULTS Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively). CONCLUSIONS Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

Outcomes of resecting subependymal giant cell astrocytoma (SEGA) among patients with SEGA-related tuberous sclerosis complex: a national claims database analysis

Abstract Objective: To examine the outcomes following resection of subependymal giant cell astrocytoma (SEGA) among patients with SEGA-associated tuberous sclerosis complex (TSC). Methods: Using three large US national healthcare claims databases, we retrospectively examined the outcomes of SEGA surgery among TSC patients who underwent SEGA surgery between 2000 and 2009. The examined outcomes were: prevalence rates of post-surgery SEGA, repeated SEGA surgery, and postoperative complications (surgical procedure complications, nervous system complications, postoperative infections, complications of subdural empyemas, and complications of epidural abscesses). Descriptive data analysis and two-sided one sample t-test for mean or proportion were used to assess the characteristics of patients and the outcomes of SEGA surgery. Results: The selected patients (N = 47) had a mean age of 11.6 years at their first SEGA surgery and 66% were male. During the third through twelfth months following surgery, 34% had post-surgery SEGA (diagnosis) and 12% underwent repeated SEGA surgeries. During the first post-surgery year, 48.9% of patients developed postoperative complications (34.0% had complications relating to the surgical procedure, 12.8% had nervous system complications, 6.4% developed postoperative infections, 17.0% had complications of subdural empyemas, and 2.1% had complications of epidural abscesses). Conclusions: SEGA surgery was associated with statistically significant risks of developing post-surgery SEGA, requiring repeated SEGA surgery and developing postoperative complications. Future efforts in reducing these outcomes, either through improving surgical procedures or through alternative treatments, are urgently needed. Limitations: This study has its limitation in data source representativeness and measurement accuracy.

Emerging treatments in the management of tuberous sclerosis complex.

Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease.