Joyce Y. Wu

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.

FDG-PET/MRI coregistration improves detection of cortical dysplasia in patients with epilepsy.

Objective: Patients with cortical dysplasia (CD) are difficult to treat because the MRI abnormality may be undetectable. This study determined whether fluorodeoxyglucose (FDG)-PET/MRI coregistration enhanced the recognition of CD in epilepsy surgery patients. Methods: Patients from 2004–2007 in whom FDG-PET/MRI coregistration was a component of the presurgical evaluation were compared with patients from 2000–2003 without this technique. For the 2004–2007 cohort, neuroimaging and clinical variables were compared between patients with mild Palmini type I and severe Palmini type II CD. Results: Compared with the 2000–2003 cohort, from 2004–2007 more CD patients were detected, most had type I CD, and fewer cases required intracranial electrodes. From 2004–2007, 85% of type I CD cases had normal non–University of California, Los Angeles (UCLA) MRI scans. UCLA MRI identified CD in 78% of patients, and 37% of type I CD cases had normal UCLA scans. EEG and neuroimaging findings were concordant in 52% of type I CD patients, compared with 89% of type II CD patients. FDG-PET scans were positive in 71% of CD cases, and type I CD patients had less hypometabolism compared with type II CD patients. Postoperative seizure freedom occurred in 82% of patients, without differences between type I and type II CD cases. Conclusions: Incorporating fluorodeoxyglucose-PET/MRI coregistration into the multimodality presurgical evaluation enhanced the noninvasive identification and successful surgical treatment of patients with cortical dysplasia (CD), especially for the 33% of patients with nonconcordant findings and those with normal MRI scans from mild type I CD. GLOSSARY: AED = antiepileptic drug; CD = cortical dysplasia; FDG = fluorodeoxyglucose; mMCD = mild malformations of cortical development; TLE = temporal lobe epilepsy; UCLA = University of California, Los Angeles.

Removing interictal fast ripples on electrocorticography linked with seizure freedom in children

Background: Fast ripples (FR, 250–500 Hz) detected with chronic intracranial electrodes are proposed biomarkers of epileptogenesis. This study determined whether resection of FR-containing neocortex recorded during intraoperative electrocorticography (ECoG) was associated with postoperative seizure freedom in pediatric patients with mostly extratemporal lesions. Methods: FRs were retrospectively reviewed in 30 consecutive pediatric cases. ECoGs were recorded at 2,000 Hz sampling rate and visually inspected for FR, with reviewer blinded to the resection and outcome. Results: Average age at surgery was 9.1 ± 6.7 years, ECoG duration was 11.8 ± 8.1 minutes, and postoperative follow-up was 27 ± 4 months. FRs were undetected in 6 ECoGs with remote or extensive lesions. FR episodes (n = 273) were identified in ECoGs from 24 patients, and in 64% FRs were independent of spikes, sharp waves, voltage attenuation, and paroxysmal fast activity. Of these 24 children, FR-containing cortex was removed in 19 and all became seizure-free, including 1 child after a second surgery. The remaining 5 children had incomplete FR resection and all continued with seizures postoperatively. In 2 ECoGs, the location of electrographic seizures matched FR location. FR-containing cortex was found outside of MRI and FDG-PET abnormalities in 6 children. Conclusion: FRs were detected during intraoperative ECoG in 80% of pediatric epilepsy cases, and complete resection of FR cortex correlated with postoperative seizure freedom. These findings support the view that interictal FRs are excellent surrogate markers of epileptogenesis, can be recorded during brief ECoG, and could be used to guide future surgical resections in children.

Surgery for symptomatic infant-onset epileptic encephalopathy with and without infantile spasms

Children undergoing surgery with infant-onset epilepsy were classified into those with medically refractory infantile spasms (IS), successfully treated IS, and no IS history, and the groups were compared for pre- and postsurgery clinical and Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ). Children without an IS history were older at surgery and had longer epilepsy durations than those with IS despite similar substrates, surgeries, and seizure frequencies. In all groups, better postsurgery VABS-DQ scores were associated with early surgical intervention indicating that infant-onset epilepsy patients with or without IS are at risk for seizure-induced encephalopathy.

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex : A preliminary report

Summary:  Purpose: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG‐PET/MRI coregistration and diffusion‐tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients.

Improved outcomes in pediatric epilepsy surgery The UCLA experience, 1986–2008

Objective: Epilepsy neurosurgery is a treatment option for children with refractory epilepsy. Our aim was to determine if outcomes improved over time. Methods: Pediatric epilepsy surgery patients operated in the first 11 years (1986–1997; pre-1997) were compared with the second 11 years (1998–2008; post-1997) for differences in presurgical and postsurgical variables. Results: Despite similarities in seizure frequency, age at seizure onset, and age at surgery, the post-1997 series had more lobar/focal and fewer multilobar resections, and more patients with tuberous sclerosis complex and fewer cases of nonspecific gliosis compared with the pre-1997 group. Fewer cases had intracranial EEG studies in the post-1997 (0.8%) compared with the pre-1997 group (9%). Compared with the pre-1997 group, the post-1997 series had more seizure-free patients at 0.5 (83%, +16%), 1 (81%, +18%), 2 (77%, +19%), and 5 (74%, +29%) years, and more seizure-free patients were on medications at 0.5 (97%, +6%), 1 (88%, +9%), and 2 (76%, +29%), but not 5 (64%, +8%) years after surgery. There were fewer complications and reoperations in the post-1997 series compared with the pre-1997 group. Logistic regression identified post-1997 series and less aggressive medication withdrawal as the main predictors of becoming seizure-free 2 years after surgery. Conclusions: Improved technology and surgical procedures along with changes in clinical practice were likely factors linked with enhanced and sustained seizure-free outcomes in the post-1997 series. These findings support the general concept that clearer identification of lesions and complete resection are linked with better outcomes in pediatric epilepsy surgery patients.

Children with ESES: Variability in the Syndrome

OBJECTIVE We undertook a retrospective study of children who present with significant activation of paroxysmal discharges during sleep to examine the clinical spectrum of disorders that present with such an EEG abnormality. BACKGROUND Electrical status epilepticus in sleep (ESES) is an electrographic pattern characterized by nearly continuous spike-wave discharges in slow wave sleep, usually with a frequency of 1.5-3 Hz and usually diffuse and bilateral in distribution. A variety of neurocognitive and behavioral problems have been associated with this EEG pattern. METHODS We conducted a retrospective review of 1497 EEG records of patients admitted to University of California, Los Angeles (UCLA) for overnight video-EEG monitoring during a 5 year interval. Demographic, clinical and electroencephalographic variables were evaluated. RESULTS EEG records for 102 patients meeting criteria were identified. Clinical information was available for 90 of those patients. Eighteen of these patients could be diagnosed with Landau-Kleffner syndrome (LKS). Key findings include: (1) neuroimaging abnormalities were uncommon in our LKS patients; (2) among children who do not fit the specific diagnostic criteria for LKS, a spike-wave index (SWI) >50% was more likely to be associated with global developmental disturbances than SWI < or =50% (p<0.05); (3) Children with generalized discharges were more likely to experience severe or global developmental disturbance than those with focal abnormalities, without reaching statistical significance (p=0.07). CONCLUSIONS Severity of ESES can vary over time between and within patients and clinical status does not always directly correlate with SWI. However, the prognosis of LKS is substantially better than CSWS and these two disorders could be classified in a dichotomous manner rather than be seen as two points along a continuum.

Association of Duchenne Muscular Dystrophy With Autism Spectrum Disorder

We hypothesize that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur with a greater than random frequency. In this study, we set out to reject the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur no more often than expected by chance. Two index cases and six additional boys with concomitant Duchenne muscular dystrophy and autism spectrum disorder were identified in a muscular dystrophy clinic that approximates the total number of Duchenne muscular dystrophy boys (158) in the state of Massachusetts. The rate of prevalence (6 of 158) was compared with the prevalence rate of autism spectrum disorder in boys in the general population (1.6 in 1000). We rejected the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder co-occurrence was likely to be explained by chance (P = .006). We identify a previously unrecognized association of Duchenne muscular dystrophy with autism spectrum disorder. Further work might elucidate the level of association between these two conditions, either at the genetic or at the protein level, and might clarify, at least partially, the neurobiologic mechanisms associated with autism spectrum disorder. (J Child Neurol 2005;20:790—795).

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.

Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort.

Traumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video‐EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS.