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Vibration, a potent mechanical stimulus for activating muscle spindle primary afferents, may improve gait performance in persons with multiple sclerosis (MS), but has yet to be developed and deployed for multiple leg muscles with application during walking training. This study explored the development of a cyclic focal muscle vibration (FMV) system, and the deployment feasibility to correct MS walking swing phase deficits in order to determine whether this intervention warrants comprehensive study. The system was deployed during twelve, two-hour sessions of walking with cyclic FMV over six weeks. Participants served as their own control. Blood pressure, heart rate, walking speed, kinematics (peak hip, knee and ankle angles during swing), toe clearance, and step length were measured before and after deployment with blood pressure and heart rate monitored during deployment. During system deployment, there were no untoward sensations and physiological changes in blood pressure and heart rate, and volitional improvements were found in walking speed, improved swing phase kinematics, toe clearance and step length. This FMV training system was developed and deployed to improve joint flexion during walking in those with MS, and it demonstrated feasibility and benefits. Further study will determine the most effective vibration frequency and dose, carryover effects, and those most likely to benefit from this intervention.

Study design Single-subject repeated measures study. Objectives Neuromuscular electrical stimulation (NMES) can enhance walking for people with partial paralysis from incomplete spinal cord injury (iSCI). This single-subject study documents an individual's experience who both received an experimental implanted NMES system and underwent clinical bilateral hinged total knee arthroplasty (TKA). She walked in the community with knee pain prior to either intervention. Walking performance improved with an implanted NMES system. Knee pain and instability continued to worsen over time and eventually required TKA. This study evaluates the effects of these interventions. Setting Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland OH, USA. Methods The differential and combined effects of NMES and hinged knee replacement were assessed in terms of walking speed, toe clearance, knee angle, and participant perceptions with and without stimulation assistance both before and after TKA. Results The combined approach both reduced pain and restored walking ability to levels achieved prior to developing significant knee pain that prevented walking without NMES. There was an interaction effect between NMES and TKA on walking speed. Toe clearance consistently improved with stimulation assistance and TKA prevented significant knee hyperextension. The greatest impact was on endurance. Knee replacement re-enabled long distance walking with the addition of stimulation again more than doubling her maximum walking distance from 214 to 513 m. Conclusions These data support further research of combined implantable interventions that may benefit people with iSCI. Furthermore, joint laxity and pain may not necessarily be contraindications to NMES if addressed with conventional clinical treatments.

Intracortical microelectrodes afford researchers an effective tool to precisely monitor neural spiking activity. Additionally, intracortical microelectrodes have the ability to return function to individuals with paralysis as part of a brain computer interface. Unfortunately, the neural signals recorded by these electrodes degrade over time. Many strategies which target the biological and/or materials mediating failure modes of this decline of function are currently under investigation. The goal of this study is to identify a precise cellular target for future intervention to sustain chronic intracortical microelectrode performance. Previous work from our lab has indicated that the Cluster of Differentiation 14/Toll-like receptor pathway (CD14/TLR) is a viable target to improve chronic laminar, silicon intracortical microelectrode recordings. Here, we use a mouse bone marrow chimera model to selectively knockout CD14, an innate immune receptor, from either brain resident microglia or blood-derived macrophages, in order to understand the most effective targets for future therapeutic options. Using single-unit recordings we demonstrate that inhibiting CD14 from the blood-derived macrophages improves recording quality over the 16 week long study. We conclude that targeting CD14 in blood-derived cells should be part of the strategy to improve the performance of intracortical microelectrodes, and that the daunting task of delivering therapeutics across the blood-brain barrier may not be needed to increase intracortical microelectrode performance.

This study was undertaken to determine if ALS patients evaluated via telemedicine received the same quality of care as patients evaluated by traditional face-to-face encounters.A retrospective cohort study design was used. Participants were patients diagnosed with ALS that received multidisciplinary care at the tertiary Cleveland VA ALS Centre between 1 March 2008- and 31 anuary 2015. Participants were not randomised, but chose telemedicine based on preference, disability level or distance from the clinic. Telemedicine in this study consisted of a video conferencing platform enabling remote rather than face-to-face encounters with participants.There was no significant association between receiving quality ALS care and the mode of care. There was a trend for telemedicine patients to utilise home health care less often than those that received clinic care (AOR 0.50; 95% CI 0.16-1.59). There was no significant difference in survival time between the two groups (log-rank test χPatients managed by telemedicine received the same quality of care and had similar outcomes to those patients seen via traditional face-to-face encounters. Telemedicine is an effective platform for delivering high quality tertiary ALS care.

OBJECTIVE: Test the effect of a multi-joint control with implanted electrical stimulation on walking after spinal cord injury (SCI). DESIGN: Single subject research design with repeated measures. SETTING: Hospital-based biomechanics laboratory and user assessment of community use. PARTICIPANTS: Female with C6 AIS C SCI 30 years post injury. INTERVENTIONS: Lower extremity muscle activation with an implanted pulse generator and gait training. OUTCOME MEASURES: Walking speed, maximum distance, oxygen consumption, upper extremity (UE) forces, kinematics and self-assessment of technology. RESULTS: Short distance walking speed at one-year follow up with or without stimulation was not significantly different from baseline. However, average walking speed was significantly faster (0.22 m/s) with stimulation over longer distances than volitional walking (0.12 m/s). In addition, there was a 413% increase in walking distance from 95 m volitionally to 488 m with stimulation while oxygen consumption and maximum upper extremity forces decreased by 22 and 16%, respectively. Stimulation also produced significant (P ≤ 0.001) improvements in peak hip and knee flexion, ankle angle at foot off and at mid-swing. CONCLUSION: An implanted neuroprosthesis enabled a subject with incomplete SCI to walk longer distances with improved hip and knee flexion and ankle dorsiflexion resulting in decreased oxygen consumption and UE support. Further research is required to determine the robustness, generalizability and functional implications of implanted neuroprostheses for community ambulation after incomplete SCI.

The objective of this work was to quantify the effects of a fully implanted pulse generator to activate or augment actions of hip, knee, and ankle muscles after stroke.The subject was a 64-year-old man with left hemiparesis resulting from hemorrhagic stroke 21 months before participation. He received an 8-channel implanted pulse generator and intramuscular stimulating electrodes targeting unilateral hip, knee, and ankle muscles on the paretic side. After implantation, a stimulation pattern was customized to assist with hip, knee, and ankle movement during gait.The subject served as his own concurrent and longitudinal control with and without stimulation. Outcome measures included 10-m walk and 6-minute timed walk to assess gait speed, maximum walk time, and distance to measure endurance, and quantitative motion analysis to evaluate spatial-temporal characteristics. Assessments were repeated under 3 conditions: (1) volitional walking at baseline, (2) volitional walking after training, and (3) walking with stimulation after training.Volitional gait speed improved with training from 0.29 m/s to 0.35 m/s and further increased to 0.72 m/s with stimulation. Most spatial-temporal characteristics improved and represented more symmetrical and dynamic gait.These data suggest that a multijoint approach to implanted neuroprostheses can provide clinically relevant improvements in gait after stroke.Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to do the following: (1) Describe the rationale for evaluating a multijoint implanted neuroprosthesis to improvewalkingafter stroke; (2)Understand the study design and conclusions that can be inferred as a result of the design; and (3) Discuss the statistical significance and clinical relevance of changes between (a) volitional walking at baseline, (b) volitional walking after training, and (c) walking with stimulation after training.Advanced ACCREDITATION:: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Electrical activation of paralyzed musculature can generate or augment joint movements required for walking after central nervous system trauma. Proper timing of stimulation relative to residual volitional control is critical to usefully affecting ambulation. This study evaluates three-dimensional accelerometers and customized algorithms to detect the intent to step from voluntary movements to trigger stimulation during walking in individuals with significantly different etiologies, mobility limitations, manual dexterities, and walking aids. Three individuals with poststroke hemiplegia or partial spinal cord injury exhibiting varying gait deficits were implanted with multichannel pulse generators to provide joint motions at the hip, knee, and ankle. An accelerometer integrated into the external control unit was used to detect heel strike or walker movement, and wireless accelerometers were used to detect crutch strike. Algorithms were developed for each sensor location to detect intent to step to progress through individualized stimulation patterns. Testing these algorithms produced detection accuracies of at least 90% on both level ground and uneven terrain. All participants use their accelerometer-triggered implanted gait systems in the community; the validation/system testing was completed in the hospital. The results demonstrated that safe, reliable, and convenient accelerometer-based step initiation can be achieved regardless of specific gait deficits, manual dexterities, and walking aids.

A patient with multiple sclerosis-related gait dysfunction was followed over the course of his disease. Despite aggressive treatment, he developed significant weakness in ankle dorsiflexors and hip and knee flexors and was no longer capable of consistently taking a step on his own. With electrical stimulation of hip and knee flexors and ankle dorsiflexors using implanted electrodes, he was able to consistently walk short distances as far as 30 m, thus significantly improving his Expanded Disability Status Scale score. This case study supports further exploration into the potential benefits of an implanted pulse generator to ameliorate gait dysfunction and improve quality of life for people with multiple sclerosis.

Depending on the extent of neuromuscular deficits, interventions to improve or restore upright mobility to persons paralyzed from central nervous system (CNS) disorders can include bracing, neuroprostheses employing surface or implanted neural stimulation, motorized exoskeletons, and hybrid neuroprostheses combining neural stimulation with passive or actively controlled orthotics. Neuroprosthetic interventions can often replace, augment, or surpass the function of conventional bracing and range from simple one- or two-channel systems to address focal deficits at a single joint, such as foot drop, to surgically implanted technologies that interface directly with the peripheral motor nerves to control the actions of multiple joints and muscles. This chapter reviews the current status and future development of these options, with a particular focus on the outcomes of neuroprostheses for standing, stepping, and seated trunk control and balance after spinal cord injury (SCI), stroke, or multiple sclerosis (MS), as well as new options for exercise and recreation in the community.

OBJECTIVE Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

Poor prognosis and decreased survival time correlate with the nutritional status of patients with amyotrophic lateral sclerosis (ALS). Various studies were reviewed which assessed weight, body mass index (BMI), survival time and ALS functional rating scale revised (ALSFRS-R) in order to determine the best nutrition management methods for this patient population. A systematic review was conducted using CINAHL, Medline, and PubMed, and various search terms in order to determine the most recent clinical trials and observational studies that have been conducted concerning nutrition and ALS. Four articles met criteria to be included in the review. Data were extracted from these articles and were inputted into the Data Extraction Tool (DET) provided by the Academy of Nutrition and Dietetics (AND). Results showed that nutrition supplementation does promote weight stabilisation or weight gain in individuals with ALS. Given the low risk and low cost associated with intervention, early and aggressive nutrition intervention is recommended. This systematic review shows that there is a lack of high quality evidence regarding the efficacy of any dietary interventions for promoting survival in ALS or slowing disease progression; therefore more research is necessary related to effects of nutrition interventions.

Activated microglia cells have been implicated in the neurodegenerative process of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis; however, the precise roles of microglia in disease progression are unclear. Despite these diseases having been described for more than a century, current FDA approved therapeutics are symptomatic in nature with little evidence to supporting a neuroprotective effect. Furthermore, identifying novel therapeutics remains challenging due to undetermined etiology, a variable disease course, and the paucity of validated targets. Here, we describe the use of a novel ex vivo spinal cord culture system that offers the ability to screen potential neuroprotective agents, while maintaining the complexity of the in vivo environment. To this end, we treated spinal cord slice cultures with lipopolysaccharide and quantified neuron viability in culture using measurements of axon length and FluoroJadeC intensity. To simulate a microglia-mediated response to cellular debris, antigens, or implanted materials/devices, we supplemented the culture media with increasing densities of microspheres, facilitating microglia-mediated phagocytosis of the particles, which demonstrated a direct correlation between the phagocytic activities of microglia and neuronal health. To validate our model's capacity to accurately depict neuroprotection, cultures were treated with resveratrol, which demonstrated enhanced neuronal health. Our results successfully demonstrate the use of this model to reproducibly quantify the extent of neurodegeneration through the measurement of axon length and FluoroJadeC intensity, and we suggest this model will allow for accurate, high-throughput screening, which could result in expedited success in translational efficacy of therapeutic agents to clinical trials.

Low back pain is a pervasive problem in the adult population. Most patients with low back pain will not require imaging as spontaneous recovery within 12 weeks is the rule. However, a small percentage of patients with low back pain will have serious underlying pathology requiring more intensive investigation. This chapter delineates the signs and symptoms related to potential serious underlying causes and discusses appropriate imaging modalities that should be utilized in patients with low back pain.

Low back pain is a pervasive problem in the adult population. Most patients with low back pain will not require imaging as spontaneous recovery within 12 weeks is the rule. However, a small percentage of patients with low back pain will have serious underlying pathology requiring more intensive investigation. This chapter delineates the signs and symptoms related to potential serious underlying causes and discusses appropriate imaging modalities that should be utilized in patients with low back pain.

Objective: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies. Methods: Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. Results: Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. Interpretation: This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions. ANN NEUROL 2012;72:395–405

Osteopontin (OPN) is a pleotrophic molecule that has been associated with multiple disorders of the central nervous system (CNS). Its roles in CNS malignancy are unclear but suggest that higher levels of OPN expression correlate with increased tumor grade and increased migratory capacity of tumor cells. In this study OPN cDNA was cloned into a retroviral vector and used to infect F98 Fischer rat-derived glioma cells and U87 human-derived glioblastoma multiforme (GBM) cells in vitro. Cells expressing high levels of OPN migrated less distance than control cells in vitro. This effect was not RGD mediated, but was reversed in the presence of c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK1 is an essential component of a negative feedback loop affecting OPN activated signaling cascades. Implantation of tumor cells expressing high levels of OPN into adult Fischer rats and nude rats resulted in morphologically distinct tumors and prolonged host survival relative to controls. We propose that local produced, high level OPN expression limits the malignant character of glioma cells and that the downstream mechanisms involved represent pathways that may have therapeutic value in the treatment of human CNS malignancy.

OBJECTIVES/SPECIFIC AIMS: Evaluate the effect of multijoint functional electrical stimulation (FES) on energy consumption during post-stroke walking. METHODS/STUDY POPULATION: A 67-year-old male with chronic stroke was implanted with an 8-channel implanted pulse generator to stimulate flexor and extensor muscles of the hip, knee, and ankle. Oxygen consumption was measured with a k2b4 portable pulmonary gas analyzer during walking with and without FES assistance. Data were analyzed during steady state oxygen consumption within the last 2 minutes of a 5 minute walk. Distance and walking speed were also measured. RESULTS/ANTICIPATED RESULTS: Electrical stimulation increased walking speed from 0.29 to 0.64 minute/second. Faster walking corresponded with increased oxygen consumption from 10.1 to 14.4 mL O2/kg per minute. Energy cost, consumption as a function of distance, decreased from 3.7 to 2.9 mL O2/kg per minute walking with stimulation compared with without. DISCUSSION/SIGNIFICANCE OF IMPACT: These preliminary data suggest improvements in walking speed with FES are accompanied by increased energy consumption and decreased energy cost. Oxygen consumption during FES assisted walking was

Resident microglia and blood-borne macrophages have both been implicated to play a dominant role in mediating the neuroinflammatory response affecting implanted intracortical microelectrodes. However, the distinction between each cell type has not been demonstrated due to a lack of discriminating cellular markers. Understanding the subtle differences of each cell population in mediating neuroinflammation can aid in determining the appropriate therapeutic approaches to improve microelectrode performance. Therefore, the goal of this study is to characterize the role of infiltrating blood-derived cells, specifically macrophages, in mediating neuroinflammation following intracortical microelectrode implantation. Interestingly, we found no correlation between microglia and neuron populations at the microelectrode-tissue interface. On the other hand, blood-borne macrophages consistently dominated the infiltrating cell population following microelectrode implantation. Most importantly, we found a correlation between increased populations of blood-derived cells (including the total macrophage population) and neuron loss at the microelectrode-tissue interface. Specifically, the total macrophage population was greatest at two and sixteen weeks post implantation, at the same time points when we observed the lowest densities of neuronal survival in closest proximity to the implant. Together, our results suggest a dominant role of infiltrating macrophages, and not resident microglia, in mediating neurodegeneration following microelectrode implantation.

A polymorphic (TGCG)n, tetranucleotide repeat was discovered juxtaposed to the (GT)n dinucleotide repeat that comprises the tumor necrosis factor a microsatellite (TNF) located telomeric to the tumor necrosis factor/lymphotoxin gene cluster. The degree of complexity of this compound tetra-,dinucleotide microsatellite consists of 16 potential alleles of combined length ranging from 24 to 54 bp. The pattern of frequencies of individual alleles belonging to the compound TNFa microsatellite was established from 52 healthy volunteers and was found to be highly heterogeneous. The data diverges significantly from previously published statistics that recognized only a simple variable dinucleotide tandem repeat. The newly recognized compound tetra-, dinucleotide TNFa microsatellite polymorphism establishes a more accurate genetic basis to explore potential linkage with disease susceptibility genes located within this region of the class III major histocompatibility complex. In addition, variable tumor necrosis factor and lymphotoxin production may reflect the more complex polymorphic nature of this microsatellite region. Finally, compound microsatellites probably exist elsewhere, throughout the human genome. Recognition of their presence may have a considerable impact on the validity of past and future microsatellite-based genetic analyses.

Engineered foamy virus (FV) vectors have been lauded for their superior safety profiles and stable integration patterns compared to their gammaretroviral counterparts. The drawback has been the belief that FV incorporation is cell cycle-dependent, thereby limiting its utility in post-mitotic tissues such as the central nervous system. In this brief communication, we challenged this theory by examining FV in vivo. We injected equal titers of FV and lentivirus (LV) into the adult rat brain and found that at 1 week, FV transduced a significantly greater volume of bromodeoxyuridine (BrdU)-negative brain parenchyma than did LV. By 8 weeks, however, the volume of transduced tissue was greatly reduced--comparable to LV-and restricted to BrdU+. Taken together, these data implicate a role for FV in short-term gene delivery strategies to the CNS.

Tumefactive multiple sclerosis (MS) is a rare form of demyelinating disease. The natural course of the disease has been characterized as presenting with a mass-like demyelinating lesion converting to typical relapsing-remitting disease with future exacerbations. Herein we describe a case of a patient whom over a six-year period developed relapsing-remitting tumefactive MS. The natural course, pathophysiology, prognosis and diagnosis are briefly discussed.

Advances in the development of highly infectious, replication-deficient recombinant retroviruses provide an efficient means of stable transfer of gene expression. Coupled with ex vivo transduction, surrogate cell populations can be readily implanted into the brain, thus serving as vehicles for delivering selected gene products into the central nervous system (CNS). Here we report that rat astrocytes can be routinely and safely isolated from brain tissue of a living donor by use of short-term gelatin sponge implants. The mature, nontransformed astrocytes were easily expanded, maintained in long-term tissue cultures and were efficiently transduced with an amphotropic retrovirus harboring a heterologous, fused transgene. In vitro retroviral infection rendered the nontransformed cells essentially 100% viable after exposure. The level of efficiency of infection (30-50% effective genome integration of provirus and expression of transgene in target cell populations) and minimal cell toxicity obviated the need to harvest large numbers of target cells. Cultured transduced astrocytes were resilient and exhibited select peptide expression for up to 1 year. Subsequently, transduced astrocytes were used in a series of experiments in which cells were transplanted intracerebrally in syngeneic animals. Post-implantation, astrocytes seeded locally and either insinuated into the surrounding parenchyma in situ or exhibited a variable degree of migration, depending on the anatomic source of astrocytes and the targeted brain implantation site. Transduced astrocytes remained viable in excess of 8 months post-transplantation and exhibited sustained transgenic peptide expression of green fluorescent protein/neomycin phosphotransferase in vivo. The sequential isolation and culture of nontransformed, mature, adult astrocytes and recombinant retrovirus-mediated transduction in vitro followed by brain reimplantation represents a safe and effective means for transferring genetic expression to the CNS. This study lays the foundation for exploring the utility of using a human autologous transplantation system as a potential gene delivery approach to treat neurological disorders. Prepared and utilized in this manner, autologous astrocytes may serve as a vehicle to deliver gene therapy to the CNS.

INTRODUCTION Amyotrophic lateral sclerosis (ALS), also referred to as Lou Gehrig's disease, is a fatal motor neuron disease characterized by rapidly progressive weakness, dysarthria, dysphagia, and respiratory failure. Fifty percent of patients will die within 3 years of diagnosis and 95 percent within 5 years-- mainly from respiratory failure [1]. The only available treatment, riluzole, has limited efficacy, prolonging survival by 3 months [2-3]. Although familial cases have led to the identification of associated genetic loci, the etiology of sporadic cases is unknown. There is, however, an association between military service and the development of ALS [4]. Hence, in 2008, ALS became a presumptively compensable illness for all Veterans with 90 days or more of continuously active service in the military. This provides the Veteran full access to medical care, medication management, durable medical equipment (DME), and monthly financial compensation. Since this decision in 2008, there has been a growing appreciation for the level of Department of Veterans Affairs (VA) benefits associated with the diagnosis of ALS, and subsequently more Veterans have entered the VA medical system with a diagnosis of ALS, both at the Cleveland VA Medical Center and in Veterans Integrated Service Network (VISN) 10 in Ohio. Between 2005 and 2010, the spinal cord injury (SCI) outpatient clinic treated 19 patients with ALS, compared with 60 patients in years 2011 to 2012 alone. This increased awareness of VA benefits at the outset resulted in Veterans presenting at their first evaluation with advanced stages of ALS, characterized by speech, swallowing, and breathing problems. We found many of the Veterans and their family members psychologically unprepared to cope with the disease progression, often times expressing anger or fear during the initial evaluation. Most patients lacked a clearly defined plan for their future care. The rapid progression of this disease resulted in both the Veteran and the staff being unprepared to cope with the need to make imminent medical decisions regarding percutaneous nutrition, noninvasive versus invasive ventilation, and other complex end-of-life decisions. The processes that were in place to provide care for patients with SCI, although interdisciplinary in nature, lacked the speed and complexity required to care for patients with a rapidly progressive neurodegenerative disorder. The realization that our current paradigm of care needed to be modified to provide excellent medical services to patients with ALS led to the development of a joint workgroup between the SCI and the Neurology Services. The overarching goal of this workgroup was to address care needs and improve processes for Veterans with ALS. This team recognized the complexity of ALS care and looked for solutions to address the unique needs of Veterans with ALS, which included rapid medical management of respiratory issues, nutritional needs, psychological support, education, and providing end-of-life care while expanding the interdisciplinary approach already in place on the SCI service. BACKGROUND ALS and Veterans ALS occurs in all major countries worldwide, with higher rates in the United States and England [5]. Approximately 5,600 new cases are diagnosed in the United States each year. The estimated prevalence in the United States is 5 per 100,000 people [6]. About 5 percent of cases are attributed to the inheritance of genetic defects, many of which have been identified; most of these follow an autosomal dominant inheritance pattern. The remaining 95 percent of cases are considered sporadic (nonfamilial) and of unknown etiology. Interestingly, cohorts have been identified suggesting possible causative relationships between the disease and various factors, including pesticide exposure [7], head trauma [8], strenuous physical activity [9], and heavy metal exposure [10]. …

INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology. However, there is good evidence to validate the theory that military service predisposes the individual to the future development of the disease [1]. As a direct result of these data, in 2008 ALS became a presumptively compensable illness for all veterans with 90 days or more of continuously active service in the military. This decision led to an influx of ALS patients into the Department of Veterans Affairs (VA) healthcare system and the development of a nationwide plan of care [2]. The implementation of this plan at the Cleveland VA Spinal Cord Injury (SCI) Division has been challenging. However, it has offered the opportunity to review current practice parameters that dictate the care of ALS patients in a new context. Using these parameters and considering the strengths and weakness of the VA healthcare system, we have made significant improvements to current practice and applied novel technology to care for ALS patients. Herein we describe these innovations and the foundation we have established to provide high quality ALS care. BACKGROUND ALS is a terminal neurodegenerative disorder. The management of patients with ALS centers almost entirely around symptomatic care. Although many studies have examined the role of particular interventions in prolonging survival after diagnosis or decreasing the rate of decline in physical ability, perhaps the most important studies guiding intervention have investigated quality of life (QoL) over the course of the disease. In 1999, the American Academy of Neurology (AAN) published the first set of formal practice parameters based on a review of the literature [3]. These evidence- based practice parameters were revised in 2009 [4] and included important updates on how care is administered, as well as recommendations regarding the use of the first disease-modifying agent available. The European Federation of Neurological Societies (EFNS) published parallel recommendations in 2005 [5], with revised and updated practice guidelines published in 2012 [6]. A third publication in 2007 also summarized current evidence-based recommendations for care of ALS patients [7]. These three sets of recommendations are nearly identical and in many instances lack precise details in terms of when and how to implement care. This reveals a need for further studies to answer basic questions regarding interventions, such as when a percutaneous endoscopic gastrostomy (PEG) tube should be placed in a patient or how early respiratory support should be provided. This information would help standardize practice parameters and allow for a higher level of symptomatic care in patients with ALS. INNOVATIVE CARE IN VA SYSTEM Early Noninvasive Positive Pressure Ventilation for ALS Patients The majority of patients with ALS will die from respiratory failure [8]. Furthermore, during the course of the disease, respiratory function correlates with QoL and patient survival [9-11]. The survival benefits from noninvasive positive pressure ventilation (NIPPV) supersede those obtained from riluzole or PEG tube insertion [12]. It follows, logically, that aggressive management of respiratory compromise should be part of a comprehensive plan not simply to prolong life (because some patients prefer not to have their life prolonged) but also as a mechanism to improve QoL. The latter goal, which is more consistent with our mission as an ALS center, is supported by several well-designed studies [12-13]. These studies suggest that NIPPV improves QoL by improving a patient's energy, concentration, and sleep quality, decreasing daytime somnolence and physical fatigue. NIPPV also improves lung compliance [14] and decreases the rate of decline in vital capacity [15-16]. Despite this evidence, the ALS Clinical Assessment Research and Education database has documented underutilization of NIPPV by patients with ALS [17]. …

INTRODUCTION Multiple sclerosis (MS) is a chronic and progressive disease of the central nervous system (CNS), in which physical disability progresses over time. It remains the most common cause of nontraumatic neurological disability in young adults and is a significant cause of disability in the U.S. veteran population. The indirect and direct medical costs are an estimated $12 billion annually and include provider healthcare, physical therapy, rehabilitation needs, and medications but also lost productivity, missed workdays, and loss of individual earnings. Healthcare costs, as expected, increase with increasing disability, reflecting frequent complications that occur in disabled patients regardless of the underlying disease [1]. Four distinct clinical courses of MS have been defined [2], but the majority of the disease commences with relapsing-remitting MS (RRMS). The relapsing-remitting course is presumably driven by recurrent waves of focal inflammation into the brain, manifesting as acute disability, which improves, to a varying degree, after the exacerbation. These episodes of acute focal CNS inflammation are mirrored in the magnetic resonance imaging (MRI) of patients with RRMS as T2 hyperintensities, although some of these episodes and MRI sequelae may be clinically silent. Diagnostic criteria are based on the separation of lesions in time and space (different anatomical locations within the CNS). This criterion has not changed, although multiple revisions to the original criteria [3] have included the use of MRI to support this basic clinical tenet [4]. In over half of these patients, the relapsing-remitting disease course will convert to secondary progressive MS (SPMS). Twenty-five years after the diagnosis of RRMS, 75 percent of patients will have converted to SPMS [5]. This change is identified clinically by the absence or near-absence of relapses, with disability continuing to progress. In contrast, approximately 7 to 20 percent of patients [6-7] have primary progressive MS (PPMS) characterized by neurological disability that progressively worsens over time in the absence of acute relapses. Over 80 percent of patients with PPMS will present with a slowly progressive spastic paraparesis. This subtype presumably lacks the intense punctate inflammatory events that result in exacerbations. Rather, PPMS is thought to be either neurodegenerative in nature or related to low-level persistent inflammation. The MRI findings in patients with PPMS are distinct because volume loss is more prominent with a lesser amount of T2 abnormalities compared with patients with RRMS. Diagnostic criteria have been described and include the exclusion of other causes, progression in the absence of relapses, a clinical syndrome consistent with the diagnosis, and supporting MRI and cerebral spinal fluid studies [8]. Interestingly, the clinical course of PPMS is nearly indistinguishable from SPMS. Over time, patients with these two subtypes are equally disabled. This result is true regardless of the severity of the initial relapsing-remitting course for patients with SPMS, suggesting that focal inflammatory events are perhaps less important in determining long-term disability levels [5,9-10]. Figure 1 gives the main characteristics of RRMS, SPMS, and PPMS. Originally, the utility of defining these MS subtypes helped in recruiting appropriate patients for clinical trials. Currently, these distinctions are important because of differences in prognosis between subtypes, as well as differences in responsiveness to Food and Drug Administration (FDA)-approved MS medications. Medications target the inflammatory nature of the disease, and although they have demonstrated the capability to decrease the number of relapses a patient experiences, the evidence that these treatments significantly alter the disease course in terms of disability progression over time is weak [11]. Furthermore, little evidence exists to suggest that these medications are effective for patients with a progressive disease course. …