Efficacy and safety of the Spiration Valve System™ for the treatment of severe emphysema in patients with Alpha-1 antitrypsin deficiency (EMPROVE).

OBJECTIVES: Alpha-1 antitrypsin deficiency (AATD) is a hereditary condition associated with emphysema. This study analyzed the efficacy and safety of Spiration Valve System TM (SVS) among AATD patients with severe emphysema. METHODS: This multicenter prospective study included 20 patients demonstrating AATD as assessed by quantitative levels of AAT and genotype containing two ZZ alleles. Most diseased lobe based on high resolution computed tomography was selected for treatment with endobronchial SVS. The change from baseline in forced expiratory volume in 1 s (FEV1) at 6 months (Primary outcome) and at 12 months, quality-of-life (QoL) measured by St. George's Respiratory Questionnaire (SGRQ) as health status, dyspnea scale measured by mMRC, Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) and safety were assessed. RESULTS: Lung function (FEV1) significantly improved at 6 months (P = 0.02); but did not reach statistical significance at 12 months (P = 0.22). Significant improvement was observed in dyspnea (at all time points), QoL measures (3, 6, and 12 months), CAT score and PCS of SF-36 (1, 3 and 6 months). Response rates based on minimal clinically important difference reached 50-80% for all variables. Overall, 4.4 valves/patient were used to isolate the target lobe, with a mean procedure time of 20.3 min. Serious adverse events included COPD exacerbations (5%), pneumonia (10%), pneumothorax (15%) and death (5%), occurring within first three months. CONCLUSION: SVS endobronchial valve treatment showed improvement in lung function, dyspnea, and QoL in AATD patients with severe emphysema.

Sustained Clinical Benefits of Spiration Valve System in Patients with Severe Emphysema: 24-Month Follow-Up of EMPROVE.

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Interictal spikes and epileptic seizures: their relationship and underlying rhythmicity.

We report on a quantitative analysis of electrocorticography data from a study that acquired continuous ambulatory recordings in humans over extended periods of time. The objectives were to examine patterns of seizures and spontaneous interictal spikes, their relationship to each other, and the nature of periodic variation. The recorded data were originally acquired for the purpose of seizure prediction, and were subsequently analysed in further detail. A detection algorithm identified potential seizure activity and a template matched filter was used to locate spikes. Seizure events were confirmed manually and classified as either clinically correlated, electroencephalographically identical but not clinically correlated, or subclinical. We found that spike rate was significantly altered prior to seizure in 9 out of 15 subjects. Increased pre-ictal spike rate was linked to improved predictability; however, spike rate was also shown to decrease before seizure (in 6 out of the 9 subjects). The probability distribution of spikes and seizures were notably similar, i.e. at times of high seizure likelihood the probability of epileptic spiking also increased. Both spikes and seizures showed clear evidence of circadian regulation and, for some subjects, there were also longer term patterns visible over weeks to months. Patterns of spike and seizure occurrence were highly subject-specific. The pre-ictal decrease in spike rate is not consistent with spikes promoting seizures. However, the fact that spikes and seizures demonstrate similar probability distributions suggests they are not wholly independent processes. It is possible spikes actively inhibit seizures, or that a decreased spike rate is a secondary symptom of the brain approaching seizure. If spike rate is modulated by common regulatory factors as seizures then spikes may be useful biomarkers of cortical excitability.

Human focal seizures are characterized by populations of fixed duration and interval.

OBJECTIVE: We report on a quantitative analysis of data from a study that acquired continuous long-term ambulatory human electroencephalography (EEG) data over extended periods. The objectives were to examine the seizure duration and interseizure interval (ISI), their relationship to each other, and the effect of these features on the clinical manifestation of events. METHODS: Chronic ambulatory intracranial EEG data acquired for the purpose of seizure prediction were analyzed and annotated. A detection algorithm identified potential seizure activity, which was manually confirmed. Events were classified as clinically corroborated, electroencephalographically identical but not clinically corroborated, or subclinical. K-means cluster analysis supplemented by finite mixture modeling was used to locate groupings of seizure duration and ISI. RESULTS: Quantitative analyses confirmed well-resolved groups of seizure duration and ISIs, which were either mono-modal or multimodal, and highly subject specific. Subjects with a single population of seizures were linked to improved seizure prediction outcomes. There was a complex relationship between clinically manifest seizures, seizure duration, and interval. SIGNIFICANCE: These data represent the first opportunity to reliably investigate the statistics of seizure occurrence in a realistic, long-term setting. The presence of distinct duration groups implies that the evolution of seizures follows a predetermined course. Patterns of seizure activity showed considerable variation between individuals, but were highly predictable within individuals. This finding indicates seizure dynamics are characterized by subject-specific time scales; therefore, temporal distributions of seizures should also be interpreted on an individual level. Identification of duration and interval subgroups may provide a new avenue for improving seizure prediction.

The dynamics of the epileptic brain reveal long-memory processes.

The pattern of epileptic seizures is often considered unpredictable and the interval between events without correlation. A number of studies have examined the possibility that seizure activity respects a power-law relationship, both in terms of event magnitude and inter-event intervals. Such relationships are found in a variety of natural and man-made systems, such as earthquakes or Internet traffic, and describe the relationship between the magnitude of an event and the number of events. We postulated that human inter-seizure intervals would follow a power-law relationship, and furthermore that evidence for the existence of a long-memory process could be established in this relationship. We performed a post hoc analysis, studying eight patients who had long-term (up to 2 years) ambulatory intracranial EEG data recorded as part of the assessment of a novel seizure prediction device. We demonstrated that a power-law relationship could be established in these patients (ß = - 1.5). In five out of the six subjects whose data were sufficiently stationary for analysis, we found evidence of long memory between epileptic events. This memory spans time scales from 30 min to 40 days. The estimated Hurst exponents range from 0.51 to 0.77 ± 0.01. This finding may provide evidence of phase-transitions underlying the dynamics of epilepsy.

Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study.

BACKGROUND: Seizure prediction would be clinically useful in patients with epilepsy and could improve safety, increase independence, and allow acute treatment. We did a multicentre clinical feasibility study to assess the safety and efficacy of a long-term implanted seizure advisory system designed to predict seizure likelihood and quantify seizures in adults with drug-resistant focal seizures. METHODS: We enrolled patients at three centres in Melbourne, Australia, between March 24, 2010, and June 21, 2011. Eligible patients had between two and 12 disabling partial-onset seizures per month, a lateralised epileptogenic zone, and no history of psychogenic seizures. After devices were surgically implanted, patients entered a data collection phase, during which an algorithm for identification of periods of high, moderate, and low seizure likelihood was established. If the algorithm met performance criteria (ie, sensitivity of high-likelihood warnings greater than 65% and performance better than expected through chance prediction of randomly occurring events), patients then entered an advisory phase and received information about seizure likelihood. The primary endpoint was the number of device-related adverse events at 4 months after implantation. Our secondary endpoints were algorithm performance at the end of the data collection phase, clinical effectiveness (measures of anxiety, depression, seizure severity, and quality of life) 4 months after initiation of the advisory phase, and longer-term adverse events. This trial is registered with ClinicalTrials.gov, number NCT01043406. FINDINGS: We implanted 15 patients with the advisory system. 11 device-related adverse events were noted within four months of implantation, two of which were serious (device migration, seroma); an additional two serious adverse events occurred during the first year after implantation (device-related infection, device site reaction), but were resolved without further complication. The device met enabling criteria in 11 patients upon completion of the data collection phase, with high likelihood performance estimate sensitivities ranging from 65% to 100%. Three patients' algorithms did not meet performance criteria and one patient required device removal because of an adverse event before sufficient training data were acquired. We detected no significant changes in clinical effectiveness measures between baseline and 4 months after implantation. INTERPRETATION: This study showed that intracranial electroencephalographic monitoring is feasible in ambulatory patients with drug-resistant epilepsy. If these findings are replicated in larger, longer studies, accurate definition of preictal electrical activity might improve understanding of seizure generation and eventually lead to new management strategies. FUNDING: NeuroVista.

Predicting functional gains in a stroke trial.

BACKGROUND AND PURPOSE: A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment. METHODS: Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains. RESULTS: Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment. CONCLUSIONS: Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention.

Use of functional MRI to guide decisions in a clinical stroke trial.

BACKGROUND AND PURPOSE: An investigational trial examined safety and efficacy of targeted subthreshold cortical stimulation in patients with chronic stroke. The anatomical location for the target, hand motor area, varies across subjects, and so was localized with functional MRI (fMRI). This report describes the experience of incorporating standardized fMRI into a multisite stroke trial. METHODS: At 3 enrollment centers, patients moved (0.25 Hz) the affected hand during fMRI. Hand motor function was localized at a fourth center guiding intervention for those randomized to stimulation. RESULTS: The fMRI results were available within 24 hours. Across 12 patients, activation site variability was substantial (12, 23, and 11 mm in x, y, and z directions), exceeding stimulating electrode dimensions. CONCLUSIONS: Use of fMRI to guide decision-making in a clinical stroke trial is feasible.

Mapping individual brains to guide restorative therapy after stroke: rationale and pilot studies.

Some treatments under development to improve motor outcome after stroke require information about organization of individual subject's brain. The current study aimed to characterize normal inter-subject differences in localization of motor functions, and to consider these findings in relation to a potential treatment of motor deficits after stroke. Functional MRI (fMRI) scanning in 14 subjects examined right index finger tapping, shoulder rotation, or facial movement. The largest activation cluster in left sensorimotor cortex was identified for each task, and its center expressed in Talairach stereotaxic coordinates. Across subjects, each task showed considerable variability in activation site coordinates. For example, during finger tapping, the range for center of activation was 7 mm in the x-axis, 19 mm in the y-axis, and 11 mm in the z-axis. The mean value for center of activation was significantly different for all three coordinates for all pairwise task comparisons. However, the distribution of activation site centers for the finger task overlapped with the other two tasks in the x- and y-axes, and with the shoulder task in the z-axis. On average, the center of activation for the three motor tasks were spatially separated and somatotopically distributed. However, across the population, there was considerable overlap in the center of activation site, especially for finger and shoulder movements. Restorative therapies that aim to target specific body segments, such as the hand, in the post-stroke motor system may need to map the individual brain rather than rely on population averages. Initial details are presented of a study using this approach to evaluate such a therapy.