End-stage Amyotrophic Lateral Sclerosis Research Articles

Quantitative Analysis of Glutathione and Carnosine Adducts with 4-Hydroxy-2-nonenal in Muscle in a hSOD1G93A ALS Rat Model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1G93A ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.

Intrathecal baclofen pump replacements under local anaesthetic: rapid pathway implementation under COVID-19

Intrathecal baclofen pump replacements under local anaesthetic: rapid pathway implementation under COVID-19

Synaptotagmin 13 is neuroprotective across motor neuron diseases

In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

1865 Gastric Perforation During PEG Tube Placement in ALS Patient With Severe Malnutrition

INTRODUCTION: The natural progression of amyotrophic lateral sclerosis (ALS) usually leads to malnutrition because of decreased oral intake from dysphagia, reduced salivation, and anorexia. A decrease in weight of 5-10 kg or BMI < 20 requires intervention to improve nutrition. Intervention includes placing a feeding gastrostomy surgically, endoscopically (percutaneous gastrostomy or PEG), or radiologically. Complications range from dislodgement to parietal necrosis and death. This case involves a patient with severe malnutrition who had a significant gastric perforation during PEG tube placement, which we attribute to a patient’s nutritional status and mucosal/muscular atrophy. CASE DESCRIPTION/METHODS: 80 yr-old man with PMH of end-stage ALS presented to the hospital for failure to thrive and significant weight loss. He underwent an EGD for PEG tube placement. During the EGD, the gastric body was notable for diffuse atrophic mucosa and hiatal hernia. Using standard technique, a 20 Fr EndoVive Safety gastrotomy tube was safely pulled through the mouth using guidewire into the stomach. The trocar needle was removed, and the PEG was pulled out from the stomach through the skin. When confirming position of the PEG tube by relook endoscopy, we found a 4 cm perforation in the stomach at the diaphragmatic hiatus with associated hemorrhagic mucosa. At which point, a large amount of subcutaneous emphysema was seen in the chest and neck. The gastroscope was immediately withdrawn, and surgery was called. The patient was transferred to the ICU. After a discussion with surgery, patient, and his family, they agreed to palliative care as patient adamantly refused further procedures. The patient was transferred to hospice care and expired three days later. DISCUSSION: This case is a rare presentation of a severe complication during PEG tube placement that we attributed to the poor nutritional status of the patient. We believe that the gastric mucosa and muscular atrophy from severe malnutrition led to the large perforation when the guidewire or the internal bumper of the PEG transversed the diaphragmatic hernia. This is the first case describing a complication of PEG tube placement in a severely malnutritioned ALS patient. In conclusion, this case highlights the possibility of altering procedural techniques for PEG tube placement and the necessity for increased caution during PEG tube placement in ALS patients with severe malnutrition.

Baclofen Pump Replacement in a Patient With End-Stage Amyotrophic Lateral Sclerosis: A Case Report Demonstrating Transversus Abdominis Plane Block as the Sole Anesthetic.

A patient with end-stage amyotrophic lateral sclerosis (ALS) presented for Baclofen pump replacement. She underwent a left transversus abdominis plane block to anesthetize the left lower quadrant of the abdomen. No sedatives or analgesics were administered, and the procedure was successfully completed without complication. It is prudent to consider anesthetic plans that avoid complications associated with general or neuraxial anesthesia in patients with ALS. This case report demonstrates successful placement of a transversus abdominis plane block in a patient with ALS and offers a safe anesthetic technique that can be performed in other high-risk patients.

Structural and functional properties of bone are compromised in amyotrophic lateral sclerosis mice

In addition to muscle weakness, amyotrophic lateral sclerosis (ALS) is associated with an increased incidence of skeletal fractures. The SOD1G93A mouse model recapitulates many features of human ALS. These mice also exhibit decreased bone mass. However, the functional, or biomechanical, behavior of the skeleton in SOD1G93A mice has not been investigated. To do so, we examined skeletal phenotypes in end-stage (16-week-old) SOD1G93A female mice and healthy littermate female controls (N = 9–10/group). Outcomes included trabecular and cortical bone microarchitecture by microcomputed tomography; stiffness and strength via three-point bending; resistance to crack growth by fracture toughness testing; and cortical bone matrix properties via cyclic reference point indentation. SOD1G93A mice had similar bone size, but significantly lower trabecular bone mass (–54%), thinner trabeculae (–41%) and decreased cortical bone thickness (–17%) and cortical area (–18%) compared to control mice (all p < 0.01). In line with these bone mass and microstructure deficits, SOD1G93A mice had significantly lower femoral bending stiffness (–27%) and failure moment (–41%), along with decreased fracture toughness (–18%) (all p < 0.001). This is the first study to demonstrate functional deficits in the skeleton of end-stage ALS mice, and imply multiple mechanisms for increased skeletal fragility and fracture risk in patients in ALS. Importantly, our results provide strong rationale for interventions to reduce fracture risk in ALS patients with advanced disease.

MR Imaging-based Estimation of Upper Motor Neuron Density in Patients with Amyotrophic Lateral Sclerosis: A Feasibility Study.

Purpose To determine if magnetic resonance (MR) imaging metrics can estimate primary motor cortex (PMC) motor neuron (MN) density in patients with amyotrophic lateral sclerosis (ALS). Materials and Methods Between 2012 and 2014, in situ brain MR imaging was performed in 11 patients with ALS (age range, 35-81 years; seven women and four men) soon after death (mean, 5.5 hours after death; range, 3.2-9.6 hours). The brain was removed, right PMC (RPMC) was excised, and MN density was quantified. RPMC metrics (thickness, volume, and magnetization transfer ratio) were calculated from MR images. Regression modeling was used to estimate MN density by using RPMC and global MR imaging metrics (brain and tissue volumes); clinical variables were subsequently evaluated as additional estimators. Models were tested at in vivo MR imaging by using the same imaging protocol (six patients with ALS; age range, 54-66 years; three women and three men). Results RPMC mean MN density varied over a greater than threefold range across patients and was estimated by a linear function of normalized gray matter volume (adjusted R2 = 0.51; P = .008; <10% error in most patients). When considering only sporadic ALS, a linear function of normalized RPMC and white matter volumes estimated MN density (adjusted R2 = 0.98; P = .01; <10% error in all patients). In vivo data analyses detected decreases in MN density over time. Conclusion PMC mean MN density varies widely in end-stage ALS possibly because of disease heterogeneity. MN density can potentially be estimated by MR imaging metrics. © RSNA, 2018 Online supplemental material is available for this article.

Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1G93A), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28 days following bilateral intrapleural injections of: 1) CTB-SAP (25 μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162 ± 18%, n = 8 vs. Control: 63 ± 3%; n = 8; p < 0.05), but not 28 days post-injection (CTB-SAP: 64 ± 10%, n = 10 vs. Control: 60 ± 13; n = 8; p > 0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease.

Comparison of Sirtuin 3 Levels in ALS and Huntington's Disease-Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models.

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest.

Electroencephalographic monitoring during sevoflurane anaesthesia in an amyotrophic lateral sclerosis patient with locked-in state

Recently, the cognitive abilities of patients with amyotrophic lateral sclerosis (ALS) have been found to be impaired along with the neurodegeneration of motor neurons. Electroencephalography (EEG) of end-stage ALS patients has reportedly shown specific features based on neuronal network modulations, differing from EEG of other patients with cognitive failure and dementia. However, EEG of end-stage ALS patients during anaesthesia has not yet been reported. A 64-year-old male ALS patient with locked-in state (LIS), supported by tracheostomy positive-pressure ventilation (TPPV) and enteral nourishment for 9years, underwent scheduled general anaesthesia for repair of a fractured mandible. He could blink and open his eyes, but seldom opened or closed his eyes on instruction. Sevoflurane anaesthesia was induced under continuous EEG monitoring with bispectral index (BIS), which is commonly used to examine the level of anaesthesia. Prominent alpha oscillations with lower peak frequency and high amplitude appeared during anaesthesia, differing from the characteristics of EEG seen in patients with general cognitive failure. Conversely, BIS reflected the sevoflurane concentration in this ALS patient, similar to healthy individuals, and BIS monitoring was useful for estimating the depth of anaesthesia. The prominent alpha oscillation revealed in this rare case report may suggest modulation of the functional neuronal network system during anaesthesia in patients with progressive ALS, in a manner quite different from typical dementia patients. EEG abnormalities in the present ALS patient did not influence the availability of BIS monitoring.

MANAGEMENT OF THE PATIENT WITH ADVANCED AMYOTROPHIC LATERAL SCLEROSIS: THE CAREGIVER’S OPINION

Objectives. The possibility of prolonging and augmenting the quality of life of respiratory patients in end-stage disease and in particular neuromuscular disease patients depends on an increased level of care. Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by a fast progressive impairment of respiratory function which leads to mechanical ventilation and high burden of care. A specifically designed questionnaire was administered to caregivers to analyze the level of care provided to these patients in our districts. Patients and methods. The study population consisted of 70 patients (44 males and 26 females). Of the 70 patients, 46 were being treated with non-invasive ventilation and 24 with invasive mechanical ventilation. The questionnaire was divided in two parts: questions 1 to 13 investigated life conditions and 14 to 22 the quality of care provided. Results. The patients studied present a heavy burden of care and this is in relation to the quantity of respiratory aids prescribed. The symptom which created statistically significant problems for care was breathlessness, as is often reported in the literature. The presence of homecare tended to create conditions of greater serenity for the caregivers. Conclusions. This study shows that the burden of care in end-stage ALS patients is very onerous, and it can help to point out problems not sufficiently contemplated in healthcare planning.

Recognizing Psychological Diversity in People with End-Stage Amyotrophic Lateral Sclerosis.

Framing discussions of ALS around the disease rather than the psychologically complex person with the disease focuses attention on symptoms and imagined outcomes rather than patients’ coping strategies and quality of life.

Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1 G93A mouse model of amyotrophic lateral sclerosis.

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating late onset neurodegenerative disorder that is characterised by the progressive loss of upper and lower motor neurons. The mechanisms underlying ALS pathogenesis are unclear; however, there is emerging evidence the innate immune system, including components of the toll-like receptor (TLR) system, may drive disease progression. For example, toll-like receptor 4 (TLR4) antagonism in a spontaneous ‘wobbler mouse’ model of ALS increased motor function, associated with a decrease in microglial activation. This study therefore aimed to extend from these findings and determine the expression and function of TLR4 signalling in hSOD1G93A mice, the most widely established preclinical model of ALS.FindingsTLR4 and one of its major endogenous ligands, high-mobility group box 1 (HMGB1), were increased during disease progression in hSOD1G93A mice, with TLR4 and HMGB1 expressed by activated microglia and astrocytes. hSOD1G93A mice lacking TLR4 showed transient improvements in hind-limb grip strength and significantly extended survival when compared to TLR4-sufficient hSOD1G93A mice.ConclusionThese results suggest that enhanced glial TLR4 signalling during disease progression contributes to end-stage ALS pathology in hSOD1G93A mice.

Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is currently no effective treatment. Studies indicate that enhancing autophagy in mouse models of neurodegenerative disease can ameliorate the behavioral symptoms and pathological damage associated with the accumulation of pathological mutant proteins such as mutant superoxide dismutase (SOD1). This study investigated the effects of trehalose treatment on both early and end-stage disease in a transgenic mouse model of ALS via short-term (30days after administration) and long-term (from 60days after administration to death) trehalose treatment experiments. Sixty-day-old female SOD1-G93A transgenic mice were treated daily with 2% (w/v) trehalose in their drinking water for 30days and monitored until they reached a neurological score of four, whereupon they were euthanized by cervical dislocation. Neurological, rotarod performance test and hanging wire test scores were recorded and body weight monitored. After death, the spinal cord was removed to assess the number of motor neurons and to measure the expression of mutant SOD1, LC3-II and p62. Trehalose significantly reduced the levels of mutant SOD1 and p62 and increased LC3-II in the spinal cords of 90-day-old SOD1-G93A transgenic mice. Furthermore, trehalose treatment significantly postponed disease onset, lengthened the time it took to reach a neurological score of 2 and preserved motor function; however, trehalose became less effective at delaying further disease progression as the disease progressed beyond a neurological score of 2 and it failed to extend the survival of SOD1-G93A transgenic mice. Additionally, independent of autophagy, trehalose consistently inhibited microgliosis and astrogliosis throughout the entire duration of the study. In conclusion, trehalose may be a useful add-on therapy in conjunction with other ALS treatment options to alleviate symptoms in early-stage ALS.

Respiratory function after selective respiratory motor neuron death from intrapleural CTB–saporin injections

Amyotrophic lateral sclerosis (ALS) causes progressive motor neuron degeneration, paralysis and death by ventilatory failure. In rodent ALS models: 1) breathing capacity is preserved until late in disease progression despite major respiratory motor neuron death, suggesting unknown forms of compensatory respiratory plasticity; and 2) spinal microglia become activated in association with motor neuron cell death. Here, we report a novel experimental model to study the impact of respiratory motor neuron death on compensatory responses without many complications attendant to spontaneous motor neuron disease. In specific, we used intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB–SAP) to selectively kill motor neurons with access to the pleural space. Motor neuron survival, CD11b labeling (microglia), ventilatory capacity and phrenic motor output were assessed in rats 3–28days after intrapleural injections of: 1) CTB–SAP (25 and 50μg), or 2) unconjugated CTB and SAP (i.e. control; (CTB+SAP). CTB–SAP elicited dose-dependent phrenic and intercostal motor neuron death; 7days post-25μg CTB–SAP, motor neuron survival approximated that in end-stage ALS rats (phrenic: 36±7%; intercostal: 56±10% of controls; n=9; p<0.05). CTB–SAP caused minimal cell death in other brainstem or spinal cord regions. CTB–SAP: 1) increased CD11b fractional area in the phrenic motor nucleus, indicating microglial activation; 2) decreased breathing during maximal chemoreceptor stimulation; and 3) diminished phrenic motor output in anesthetized rats (7days post-25μg, CTB–SAP: 0.3±0.07V; CTB+SAP: 1.5±0.3; n=9; p<0.05). Intrapleural CTB–SAP represents a novel, inducible model of respiratory motor neuron death and provides an opportunity to study compensation for respiratory motor neuron loss.

Enhanced phrenic long‐term facilitation in rats with motor neuron death from intrapleural CTB‐saporin injections (713.1)

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a model of ALS (SOD1G93A), pLTF following acute intermittent hypoxia is enhanced at disease end‐stage by unknown mechanisms (Nichols et al., ibid, 2010). Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB‐SAP) selectively kills respiratory motor neurons and mimics motor neuron death observed in ALS rats (Nichols et al., ibid, 2013). This CTB‐SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28 days following bilateral intrapleural injections of: 1) CTB‐SAP (25μg), or 2) un‐conjugated CTB and SAP (control). CTB‐SAP enhanced pLTF at 7 (CTB‐SAP: 145±22%, n=10 vs. Control: 54±5%; n=15; p&lt;0.05), but not 28 days post‐injection (CTB‐SAP: 61±14%, n=11 vs. Control: 37±9; n=5; p&gt;0.05). Thus, pLTF at 7 (not 28) days post‐CTB‐SAP more closely resembles pLTF in end‐stage ALS rats, suggesting that processes unique to the period of active motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease.[Supported by NIH HL080209, HL69024 and the Francis Families Foundation]Grant Funding Source: Supported by NIH HL080209, HL69024 and the Francis Families Foundation

Characterization of intercostal muscle pathology in canine degenerative myelopathy: A disease model for amyotrophic lateral sclerosis

Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions, accompanied by atrophic changes in the descending spinal cord tracts. Some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure from severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression, providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology, we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model.

Impaired hypoxic sensor Siah‐1, PHD3, and FIH system in spinal motor neurons of an amyotrophic lateral sclerosis mouse model

We recently reported spinal blood flow-metabolism uncoupling in the Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mouse model of amyotrophic lateral sclerosis (ALS), suggesting relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway in ALS has not been well studied. In the present work, we examined the temporal and spatial changes of hypoxic stress sensor proteins (Siah-1, PHD3, and FIH) following motor neuron (MN) degeneration in the spinal cord of normoxic ALS mice. The expression of Siah-1 and PHD3 proteins progressively increased in the surrounding glial cells of presymptomatic Tg mice (10 weeks, 10 weeks) compared with the large MN of the anterior horn. In contrast, a significant reduction in Siah-1 and PHD3 protein expression was evident in end-stage ALS mice (18 weeks, 18 weeks). Double-immunofluorescence analysis revealed PHD3 plus Siah-1 double-positive cells in the surrounding glia of symptomatic Tg mice (14-18 weeks), with no change in the large MNs. In contrast, FIH protein expression decreased in the surrounding glial cells of Tg mice at end-stage ALS (18 weeks). The present study suggests a partial loss in the neuroprotective response of spinal MNs in ALS results from a relative hypoxia through the Siah-1, PHD3, and FIH system under normoxic conditions. This response could be an important mechanism of neurodegeneration in ALS.

A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating Amyotrophic Lateral Sclerosis: What have we Learned in the Last Decade?

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of adults which preferentially attacks the neuromotor system. Riluzole has been used as the only approved treatment for amyotrophic lateral sclerosis since 1995, but its mechanism(s) of action in slowing the progression of this disease remain obscure. Searching PubMed for "riluzole" found 705 articles published between January 1996 and June 2009. A systematic review of this literature found that riluzole had a wide range of effects on factors influencing neural activity in general, and the neuromotor system in particular. These effects occurred over a large dose range (<1 μM to >1 mM). Reported neural effects of riluzole included (in approximate ascending order of dose range): inhibition of persistent Na(+) current = inhibition of repetitive firing < potentiation of calcium-dependent K(+) current < inhibition of neurotransmitter release < inhibition of fast Na(+) current < inhibition of voltage-gated Ca(2+) current = promotion of neuronal survival or growth factors < inhibition of voltage-gated K(+) current = modulation of two-pore K(+) current = modulation of ligand-gated neurotransmitter receptors = potentiation of glutamate transporters. Only the first four of these effects commonly occurred at clinically relevant concentrations of riluzole (plasma levels of 1-2 μM with three- to four-fold higher concentrations in brain tissue). Treatment of human ALS patients or transgenic rodent models of ALS with riluzole most commonly produced a modest but significant extension of lifespan. Riluzole treatment was well tolerated in humans and animals. In animals, despite in vitro evidence that riluzole may inhibit rhythmic motor behaviors, in vivo administration of riluzole produced relatively minor effects on normal respiration parameters, but inhibited hypoxia-induced gasping. This effect may have implications for the management of hypoventilation and sleep-disordered breathing during end-stage ALS in humans.

Sedation for the imminently dying: Survey results from the AAN Ethics Section

Objectives: Sedation for the imminently dying (SFTID) is a controversial practice that involves the provision of sedation to imminently dying patients with the intent of relieving their suffering when symptoms are refractory to other interventions. The goal of this research was to ascertain the opinions regarding SFTID that are held by neurologists who are interested in ethics and end-of-life care. Methods: Members of the American Academy of Neurology Ethics Section were surveyed regarding their familiarity and experience with SFTID and their opinions pertaining to it. To determine whether their opinions varied in relationship to clinical context, a single stem question for 5 different case scenarios was used. Results: A total of 96% of respondents agreed or strongly agreed that the primary purpose of SFTID was to relieve suffering, 83% disagreed or strongly disagreed that SFTID was morally equivalent to euthanasia, and 85% disagreed or strongly disagreed that SFTID was legally equivalent to euthanasia. For the case scenarios, 92% agreed or strongly agreed that SFTID was acceptable for imminently dying patients with metastatic cancer, while 50% agreed or strongly agreed that SFTID was acceptable for patients with end-stage amyotrophic lateral sclerosis, and only 7% agreed or strongly agreed that SFTID was acceptable for posttraumatic quadriplegic patients not at risk for imminent death. Conclusions: The overwhelming majority of neurologists surveyed endorse the concept that sedation for the imminently dying differs morally and legally from euthanasia and that it is an acceptable therapeutic option for some but not all patients who are imminently dying of a terminal illness.