Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

OBJECTIVE: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery. METHODS: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness. RESULTS: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening. CONCLUSION: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures.

Restoring immune tolerance in neuromyelitis optica: Part I.

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.

Restoring immune tolerance in neuromyelitis optica: Part II.

Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.

A Fully Integrated Wireless Compressed Sensing Neural Signal Acquisition System for Chronic Recording and Brain Machine Interface.

Reliable, multi-channel neural recording is critical to the neuroscience research and clinical treatment. However, most hardware development of fully integrated, multi-channel wireless neural recorders to-date, is still in the proof-of-concept stage. To be ready for practical use, the trade-offs between performance, power consumption, device size, robustness, and compatibility need to be carefully taken into account. This paper presents an optimized wireless compressed sensing neural signal recording system. The system takes advantages of both custom integrated circuits and universal compatible wireless solutions. The proposed system includes an implantable wireless system-on-chip (SoC) and an external wireless relay. The SoC integrates 16-channel low-noise neural amplifiers, programmable filters and gain stages, a SAR ADC, a real-time compressed sensing module, and a near field wireless power and data transmission link. The external relay integrates a 32 bit low-power microcontroller with Bluetooth 4.0 wireless module, a programming interface, and an inductive charging unit. The SoC achieves high signal recording quality with minimized power consumption, while reducing the risk of infection from through-skin connectors. The external relay maximizes the compatibility and programmability. The proposed compressed sensing module is highly configurable, featuring a SNDR of 9.78 dB with a compression ratio of 8×. The SoC has been fabricated in a 180 nm standard CMOS technology, occupying 2.1 mm × 0.6 mm silicon area. A pre-implantable system has been assembled to demonstrate the proposed paradigm. The developed system has been successfully used for long-term wireless neural recording in freely behaving rhesus monkey.

A closed-loop compressive-sensing-based neural recording system.

OBJECTIVE: This paper describes a low power closed-loop compressive sensing (CS) based neural recording system. This system provides an efficient method to reduce data transmission bandwidth for implantable neural recording devices. By doing so, this technique reduces a majority of system power consumption which is dissipated at data readout interface. The design of the system is scalable and is a viable option for large scale integration of electrodes or recording sites onto a single device. APPROACH: The entire system consists of an application-specific integrated circuit (ASIC) with 4 recording readout channels with CS circuits, a real time off-chip CS recovery block and a recovery quality evaluation block that provides a closed feedback to adaptively adjust compression rate. Since CS performance is strongly signal dependent, the ASIC has been tested in vivo and with standard public neural databases. MAIN RESULTS: Implemented using efficient digital circuit, this system is able to achieve >10 times data compression on the entire neural spike band (500-6KHz) while consuming only 0.83uW (0.53 V voltage supply) additional digital power per electrode. When only the spikes are desired, the system is able to further compress the detected spikes by around 16 times. Unlike other similar systems, the characteristic spikes and inter-spike data can both be recovered which guarantes a >95% spike classification success rate. The compression circuit occupied 0.11mm(2)/electrode in a 180nm CMOS process. The complete signal processing circuit consumes <16uW/electrode. SIGNIFICANCE: Power and area efficiency demonstrated by the system make it an ideal candidate for integration into large recording arrays containing thousands of electrode. Closed-loop recording and reconstruction performance evaluation further improves the robustness of the compression method, thus making the system more practical for long term recording.

Challenges and opportunities in designing clinical trials for neuromyelitis optica.

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.

Effect of switching from intramuscular interferon ß-1a to oral fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS.

BACKGROUND: In the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data. OBJECTIVE: To use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon ß-1a (IFNß-1a IM) 30 µg/mL once weekly to oral fingolimod 0.5 or 1.25mg once daily vs. remaining on IFNß-1a IM. METHODS: Post hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time. RESULTS: Log-linear regression model results showed that fingolimod 0.5 and 1.25mg prolonged time to relapse, with an estimated median time to first relapse of 5.07 years (P=0.0026 vs. IFNß-1a IM) and 4.11 years (P=0.0113), respectively, versus 2.26 years with IFNß-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNß-1a IM was 2.09 (95% CI, 1.45-3.04) for switching to fingolimod 0.5mg and 1.84 (95% CI, 1.30-2.65) for switching to fingolimod 1.25mg. CONCLUSION: During the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNß-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data.

Energy-efficient multi-mode compressed sensing system for implantable neural recordings.

Widely utilized in the field of Neuroscience, implantable neural recording devices could capture neuron activities with an acquisition rate on the order of megabytes per second. In order to efficiently transmit neural signals through wireless channels, these devices require compression methods that reduce power consumption. Although recent Compressed Sensing (CS) approaches have successfully demonstrated their power, their full potential is yet to be explored. Built upon our previous on-chip CS implementation, we propose an energy efficient multi-mode CS framework that focuses on improving the off-chip components, including (i) a two-stage sensing strategy, (ii) a sparsifying dictionary directly using data, (iii) enhanced compression performance from Full Signal CS mode and Spike Restoration mode to Spike CS + Restoration mode and; (iv) extension of our framework to the Tetrode CS recovery using joint sparsity. This new framework achieves energy efficiency, implementation simplicity and system flexibility simultaneously. Extensive experiments are performed on simulation and real datasets. For our Spike CS + Restoration mode, we achieve a compression ratio of 6% with a reconstruction SNDR > 10 dB and a classification accuracy > 95% for synthetic datasets. For real datasets, we get a 10% compression ratio with  âˆ¼  10 dB for Spike CS + Restoration mode.

Employment outcomes following resective epilepsy surgery.

PURPOSE: Analyze determinates of employment changes from before to 2 years after surgery in refractory focal epilepsy patients. METHODS: Preoperative employment was prospectively assessed in 375 adults with refractory epilepsy. Two-year postsurgical employment status was obtained for 299; factors potentially associated with employment status change among subgroups unemployed and employed at baseline were analyzed. RESULTS: Presurgical employment status was full-time (n = 148, 39.5%), part-time (n = 26, 6.9%), disabled and unemployed (n = 100, 26.7%), unemployed (n = 44, 11.7%), and other (n = 57, 15.2%). Those with and without 2-year follow-up did not differ on baseline characteristics (all p > 0.10). Two years after surgery, 42.8% were employed full-time and 12.4%, part-time. Among those unemployed before surgery, better seizure outcome was associated with gaining employment at 2 years (p = 0.03). CONCLUSIONS: Net employment gains were modest 2 years after surgery and higher with better seizure outcomes, reinforcing the need for optimizing surgical candidate selection, long-term follow-up studies, and postsurgical vocational rehabilitation.

Postictal neurogenic stunned myocardium.

Neurogenic left ventricular dysfunction is a recognized complication of subarachnoid hemorrhage, but this condition has not been reported after seizure activity. The authors present two cases of neurogenic stunned myocardium after convulsive seizures, suggesting that ictal activity can lead to sympathetically mediated cardiac injury.

Ictal head version in generalized epilepsy.

Focal physical signs may occur with generalized seizures. The authors retrospectively reviewed video-EEG studies of 20 patients with apparent primary generalized epilepsy to assess the frequency of head version during generalized tonic-clonic seizures. Five patients (25%) demonstrated forced head version, including two with turning to the right and left on consecutive seizures. Forced head turning can occur in generalized epilepsy and may not necessarily indicate focal seizure origin.