Patients with amyotrophic lateral sclerosis (ALS) face many difficult, timing-sensitive decisions over the course of their illness, weighing present versus future harms and benefits. Supplemented by interviews with people with ALS, we argue for a relational approach to understanding these decisions and their effects on identity. We highlight two critical aspects of the patient–caregiver relationship: (1) the extent to which each may rely on the other leaves their wellbeing intimately intertwined and (2) patients often require others to (...) help with the imaginative task of considering possible futures for each therapeutic option. We show why family involvement in decisionmaking practices can be so critical, and shed light on the ways intimate others help preserve and protect people’s identities amidst the destabilizing uncertainty illness and treatment can bring. (shrink)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, primarily leading to the degeneration of motor neurons. The traditional focus on motor neuron‐centric mechanisms has recently shifted towards understanding the contribution of non‐neuronal cells, such as microglia, in ALS pathophysiology. Advances in induced pluripotent stem cell (iPSC) technology have enabled the generation of iPSC‐derived microglia monocultures and co‐cultures to investigate their role in ALS pathogenesis. Here, we briefly review the insights gained from these studies into the role of (...) microglia in ALS. While iPSC‐derived microglia monocultures have revealed intrinsic cellular dysfunction due to ALS‐associated mutations, microglia‐motor neuron co‐culture studies have demonstrated neurotoxic effects of mutant microglia on motor neurons. Based on these findings, we briefly discuss currently unresolved questions and how they could be addressed in future studies. iPSC models hold promise for uncovering disease‐relevant pathways in ALS and identifying potential therapeutic targets. (shrink)

Because our actions change, our responsibility is modified; because our responsibility is modified, we need to question the ethics of the action. Our action is situated right there between announcing a diagnosis, the theoretical and practical result of identification, the determining and naming of a fact and voicing the disease which is a human action where medical and technical expertise comes up against a life and its story. Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is a (...) degenerative disease of the motor neurons leading to paralysis. In the absence of any curative treatment, the natural course always results in death. Since 1989, progress in the management of this disease in France has been exponential, resulting in the creation of 17 expert centres throughout the country in 2003. Guidelines have been drawn up through consensus conferences and coordination meetings. For the delicate stage of the announcement, three requirements have been adopted: the quality of receptiveness of the medical practitioner and his team, their ability to listen and to adapt to the particularities of the patient in their care; their commitment with regard to legal obligations as to how and to whom to transmit information; and the need for a multidisciplined approach to be able to rapidly support the patient and his family. Questioning in the field of applied ethics has led us to examine whether having a benevolent and non-harmful attitude towards these patients, respecting their autonomy and legal rights are parameters required in this specialized practice. Through a transversal thematic analysis of the experiences of the medical practitioners at the Centres, we would like to explore a hypothesis of the remarkable epistemological progression of the neurologist in this form of care in the pure Hippocratic tradition. Through the compassionate experience of the other by these committed doctors and their teams, we will try to outline the view of anthropological phenomenology with regard to the ALS patient, their awareness of the future paralysis of the body that is being announced, their awareness of the temporality and will characteristic of the ALS patient and of his finality that they will be accompanying. (shrink)

The present article is based on a interview with a Japanese experienced caregiver who specializes in patients with amyotrophic lateral sclerosis, which generally leads to the locked-in syndrome. Professional caregivers for ALS patients with ventilator experience two particular temporalities in their practice. First, they must monitor the patient continuously during a seven-hour stay. Because a single problem in the ventilator can have fatal consequences, the care of an ALS patient with a ventilator requires long periods of sustained (...) concentration. Second, trying to understand the signs of a patient with a ventilator sometimes requires three hours to go through ten alphabets. In addition to the huge effort that such communication requires, caregivers must complete the meaning of the signs with their imagination: the ten alphabets are not sufficient to understand what the patient really wants to say. This imaginative capacity, however, is based on a long relationship, which started when the patient was still able to speak and move. That is why, as this article will show, even when a patient has entered total LIS, the caregiver can continue to realize his or her wishes. (shrink)

It is well known that close relatives of terminally ill patients endure great emotional stress. Many factors, such as existential concerns, contribute to the distress of these relatives. In this study, interviews were conducted to explore experiences concerning life restrictions, emotional distress, and limited support, in a group of close relatives of patients with amyotrophic lateral sclerosis (ALS). The purpose was to identify, illuminate and clarify ethical problems related to these experiences. The results indicate that close relatives (...) of patients with ALS need someone to talk to, as well as more information about the disease and its process. Furthermore, the study illustrates how ethical problems are related to choices and conflicts, and that a process including shared decision making is often an ideal when trying to find a solution to ethical problems. (shrink)

ObjectiveApproximately half of all people living with amyotrophic lateral sclerosis experience persistent or recurrent emotional distress, yet little is known about the psychological processes that maintain emotional distress in this population. The self-regulatory executive functioning model specifies that maladaptive metacognitive beliefs and processes are central to the development and maintenance of emotional distress. This study explored whether maladaptive metacognitive beliefs are associated with emotional distress after controlling for demographic factors, time since diagnosis, and current level of physical (...) functioning.DesignIn a cross-sectional design, 75 adults with a diagnosis of ALS completed self-report questionnaires. Participants had a mean age of 60.40 years, mean duration of symptoms 63.92 months, and male:female gender ratio of 14:11.Main Outcome MeasuresQuestionnaires assessed emotional distress, physical functioning, repetitive negative thinking, metacognitive beliefs, and demographic factors.ResultsMaladaptive metacognitive beliefs explained additional variance in emotional distress after controlling for age, gender, time since diagnosis, physical functioning, and repetitive negative thinking. Repetitive negative thinking partially mediated the relationships between positive and negative metacognitive beliefs and emotional distress.ConclusionsThese data support the utility of the metacognitive model in understanding emotional distress in people with ALS. Examination of the temporal relationship between maladaptive metacognitive beliefs and emotional distress in people living with ALS may help to guide the development of therapeutic approaches. (shrink)

BackgroundThe aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test in non-demented patients with amyotrophic lateral sclerosis.MaterialsA total of 61 consecutive patients and 50 healthy controls were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task, which encompasses three subtests targeting Causal Inference, Emotion Attribution, and Intention Attribution, as well as global cognitive [the Edinburgh Cognitive (...) and Behavioral ALS Screen ] and behavioral screening [the Frontal Behavioral Inventory ; the Dimensional Apathy Scale ; the Beck Depression Inventory ; and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance.ResultsThe RMET was solely predicted by the SET-EA and SET-IA. RMET scores showed high accuracy both in discriminating patients from HCs and in identifying patients with a defective SET-EA score, with adequate-to-optimal both intrinsic and post-test properties.DiscussionThe RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios. (shrink)

This hypothesis proposes that increased extracellular glutamate in Amyotrophic Lateral Sclerosis (ALS) and cerebral ischemia, currently viewed as a trigger for excitotoxicity, is actually beneficial as it stimulates the utilization of glutamate as metabolic fuel. Renewed appreciation of glutamate oxidation by ischemic neurons has raised questions regarding the role of extracellular glutamate in ischemia. Is it detrimental, as suggested by excitotoxicity in early in vitro studies, or beneficial, as suggested by its oxidation in later in vivo studies? (...) The answer may depend on the activity of N‐methyl‐D‐aspartate (NMDA) glutamate receptors. Early in vitro procedures co‐activated NMDA receptors (NMDARs) containing 2A (GluN2A) and 2B (GluN2B) subunits, an event now believed to trigger excitotoxicity; however, during in vivo ischemia D‐serine and zinc molecules are released and these ensure only GluN2B receptors are stimulated. This not only prevents excitotoxicity but also initiates signaling cascades that allow ischemic neurons to import and oxidize glutamate. (shrink)

Aim: Patients with advanced cancer need information about end-of-life treatment options in order to make informed decisions. Clinicians vary in the frequency with which they initiate these discussions.Patients and methods: As part of a long-term longitudinal study, patients with an expected 2-year survival of less than 50% who had advanced gastrointestinal or lung cancer or amyotrophic lateral sclerosis were interviewed. Each patient’s medical record was reviewed at enrollment and at 3 months for evidence of the discussion of (...) patient wishes concerning ventilator support, artificial nutrition and hydration , resuscitation and hospice care. A Kaplan–Meier analysis was also performed and 2-year survival calculated.Results: 60 cancer and 32 ALS patients were enrolled. ALS patients were more likely than cancer patients to have evidence of discussion about their wishes for ventilator support , ANH , DNR and hospice care . At 6 months, 91% of ALS patients were alive compared with 62% of cancer patients; at 2 years, 63% of ALS patients were alive compared with 23% of cancer patients .Conclusions: Cancer patients were less likely than ALS patients to have had documented advanced care planning discussions despite worse survival. This may reflect perceptions that ALS has a more predictable course, that advanced cancer has a greater number of treatment options, or differing views about hope. Nevertheless, cancer patients may be less adequately prepared for end-of-life decision-making. (shrink)

Tracheostomy with invasive ventilation may be required for the survival of patients at advanced stages of amyotrophic lateral sclerosis. In Japan it has been shown that a proactive approach toward TIV may prolong the survival of ALS patients by over 10 years by preventing the lethal respiratory failure that generally occurs within 3-5 years of the onset of the disease. Measures to prolong life expectancy without foregoing quality of life have produced better results in Japan than in (...) other developed countries. This ‘Japanese bias’ has been attributed to socio-cultural and religious factors as well as to the availability of material resources in Japan. In this article, we use the concepts of onozukara in kadō and amae to illuminate features of patient care that may contribute to this ‘Japanese bias’. (shrink)

Currently in Japan, discontinuing an invasive mechanical ventilator (IMV) is illegal; therefore IMV-related decision making is a crucial issue. This study examined IMV decision-making factors and psychological conflict in 50 patients with amyotrophic lateral sclerosis. The Herth Hope Index was used for the assessment of pre- and post-IMV conflict. Interviews identified some decision-making factors: patient’s decision, patient’s and family’s mutual decision, family’s decision, and emergency-induced without patient’s or family’s consent. Participants who experienced no IMV-related regret received sufficient (...) prior IMV education from physicians and nurses, and time for reflection and family consultation. Their hope was similar to their pre-onset levels. Patients who received no prior IMV education accepted treatment as a natural progression. Their hope levels were lower than pre-onset. Those who received only a brief prior IMV explanation rejected the ventilator, experiencing regret if they were given an emergency IMV. Their hope levels were among the lowest. However, some of these patients managed to overcome their regret through being helped by nurses. Sufficient physician explanation and nursing advocacy for autonomous patient decision making are critical for improving hope in this patient group. (shrink)

BackgroundThe present study aimed at assessing the diagnostic properties of the Montreal Cognitive Assessment in non-demented ALS patients and at exploring the MoCA administrability according to motor-functional status.MaterialsN = 348 patients were administered the MoCA and Edinburgh Cognitive and Behavioural ALS Screen. Administrability rates and prevalence of defective MoCA scores were compared across King’s and Milano-Torino clinical stages. Regression models were run to test whether the non-administrability of the MoCA and a defective score on it were predicted, net of the (...) ECAS-Total, by disease duration, ALS Functional Rating Scale-Revised and progression rate, computed as /disease duration. Intrinsic and post-test diagnostics were tested against a below-cut-off ECAS-total score.ResultsThe 79.9% of patients successfully underwent the MoCA, whose administrability rates decreased with advanced clinical stages, at variance with its defective score prevalence. The probability of the FAB not being administrable was predicted only by lower ALSFRS-R-bulbar and-upper-limb scores; no motor features, but the ECAS-Total, predicted a defective MoCA performance. The MoCA showed high accuracy and good intrinsic and post-test properties—being slightly more specific than sensitive.DiscussionIn non-demented ALS patients, the MoCA is featured by optimal diagnostics as a screener for cognitive impairment, especially for ruling-out its occurrence, as long as patients are in the early stages of the disease and have sufficiently spared bulbar and upper-limb functions. (shrink)

Patientenselbstbestimmung und Patientenverfügungen haben zunehmende Bedeutung und Beachtung erfahren. In der vorliegenden qualitativen Studie wurden 15 Patientinnen und Patienten mit amyotropher Lateralsklerose —einer unheilbaren, chronisch-degenerativen Erkrankung mit vorhersehbarer Symptomatik—interviewt, um zu erfahren, welche Werte und Kriterien sie bei prospektiven Entscheidungen am Lebensende und bei der Abfassung von PV zugrunde legen. Die Auswertung erfolgte nach der Methode der „grounded theory“. Die befragten Patientinnen und Patienten befürworteten einen Verzicht auf lebenserhaltende Behandlungen, wenn sie keine hinreichenden Lebensmöglichkeiten mehr sahen, d. h. wenn sie (...) die aktuelle Lebensqualität für unzureichend erachteten und die Chance auf Besserung als gering einschätzten. Dem Patientenwillen sprachen sie bei der Entscheidungsfindung ein Vetorecht zu. Patientenverfügungen fassten sie erst ab, als sie keine Hoffnung mehr auf Besserung ihrer Erkrankung hatten. Sie verstanden diese als Instrumente zur vorsorglichen Erklärung ihres Wunsches, auf lebensverlängernde Maßnahmen zu verzichten, wenn die LM inakzeptabel geworden sind. Damit wollten sie sich gegenüber dem Arzt absichern, den sie in der Rolle eines Anwalts des Lebens sahen und mit dem sie daher ihre Behandlungswünsche nicht besprochen haben. Trotz vorhersehbarer Symptomatik legten sie in ihren PV keine spezifischen Behandlungswünsche nieder, sondern verwendeten allgemeine Formularmuster ohne konkreten Bezug zu ihrer Erkrankung. Daher bestehen auch bei dieser Patientengruppe Zweifel, ob die PV in einer konkreten Behandlungssituation hilfreich sind. (shrink)

Discussions of withdrawal of life support often revolve around a patient’s perceived level of suffering or lack of experience. Personhood, however, is often linked to personal agency. In the present study, 279 laypeople estimated the amount of agency and experience in hypothetical patients differing in degree of consciousness. Participants also indicated whether they would choose to maintain or terminate life support. Patients were more likely to terminate life support for a patient in a persistent vegetative state, followed by one with (...) amyotrophic lateral sclerosis and in a minimally conscious state. The decision to maintain life support was reliably predicted by perceptions of a patient’s agency but life support decisions were not significantly predicted by ratings of experience. In sum, decisions regarding maintaining life support are more influenced by perceptions of a patient’s ability to plan and act than by perceptions of a patient’s ability to feel or experience. (shrink)

Neurological diseases (NDs), featured by progressive dysfunctions of the nervous system, have become a growing burden for the aging populations. N‐Deacetylase and N‐sulfotransferase 3 (NDST3) is known to catalyze deacetylation and N‐sulfation on disaccharide substrates. Recently, NDST3 is identified as a novel deacetylase for tubulin, and its newly recognized role in modulating microtubule acetylation and lysosomal acidification provides fresh insights into ND therapeutic approaches using NDST3 as a target. Microtubule acetylation and lysosomal acidification have been reported to be critical for (...) activities in neurons, implying that the regulators of these two biological processes, such as the previously known microtubule deacetylases, histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), could play important roles in various NDs. Aberrant NDST3 expression or tubulin acetylation has been observed in an increasing number of NDs, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), schizophrenia and bipolar disorder, Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting that NDST3 is a key player in the pathogenesis of NDs and may serve as a target for development of new treatment of NDs. (shrink)

Amyotrophic lateral sclerosis (ALS; also called motor neuron disease) is a devastating medical condition that progressively robs patients of their ability to move, speak and eventually breathe. At present, many physicians are hesitant to propose tracheostomy and respiratory support in the terminal phase of ALS. In accordance with the principle of patient autonomy, physicians should respect the right of the ALS patient to accept or refuse any treatment, including mechanical ventilation. Also, in environments where euthanasia or physician-assisted (...) death is legal, such requests can be acceptable. At least two conditions are necessary for full autonomy. To have a claim on full autonomy, people need to have intact cognitive abilities, and to exercise this right they must be able to communicate. In the past, the first condition was in doubt (indeed, overlap with other neurodegenerative diseases is sometimes suspected and some patients with ALS are thought to have associated frontotemporal dementia) and the second was severely compromised in patients with devastating motor impairment (communication being limited to the twitch of a finger or the blink of an eye). In this issue of J Neurol Neurosurg Psychiatry, Lakerveld and colleagues1 investigated cognition in 11 patients with late stage ALS (see page 25). They showed preserved cognitive functioning (ie, language, executive function, intelligence, learning and long term memory) compared with healthy controls. Assessments were exclusively based on a ‘‘yes–no’’ response mode. Because of the absence of verbal and motor communication, the neuropsychological assessment of these patients is complicated, and adapted testing is needed. By using a ‘‘yes–no’’ response mode based on the remaining motor abilities of the patient, this study proves the possibility of assessing patients with minimal motor capacities. (shrink)

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits (...) serve as gatekeepers for motor neurone survival. BioEssays 30:1185–1192, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Brain-Computer Interface is a set of technologies that are of increasing interest to researchers. BCI has been proposed as assistive technology for individuals who are non-communicative or paralyzed, such as those with amyotrophic lateral sclerosis or spinal cord injury. The technology has also been suggested for enhancement and entertainment uses, and there are companies currently marketing BCI devices for those purposes as well as health-related purposes. The unprecedented direct connection created by BCI between human brains and computer (...) hardware raises various ethical, social, and legal challenges that merit further examination and discussion. To identify and characterize the key issues associated with BCI use, we performed a scoping review of biomedical ethics literature, analyzing the ethics concerns cited across multiple disciplines, including philosophy and medicine. Based on this investigation, we report that BCI research and its potential translation to therapeutic intervention generate significant ethical, legal, and social concerns, notably with regards to personhood, stigma, autonomy, privacy, research ethics, safety, responsibility, and justice. Our review of the literature determined, furthermore, that while these issues have been enumerated extensively, few concrete recommendations have been expressed. We conclude that future research should focus on remedying a lack of practical solutions to the ethical challenges of BCI, alongside the collection of empirical data on the perspectives of the public, BCI users, and BCI researchers. (shrink)

The objective of this study was to reveal the problems related to interpersonal relationships which patients with obstinate diseases face, and consider the behavior, attitude and medical intervention that healthcare and healthcare-related professions should take in regards to these problems. Semi-structured individual interviews were conducted with patients with obstinate neurological diseases and observation of outpatient care was also conducted. Data were analyzed by qualitative content analysis. Patient diseases included Parkinson Disease , Amyotrophic Lateral Sclerosis , myasthenia gravis, (...) spinocerebellar ataxia , and progressive supranuclear palsy . Findings highlighted that patients’ disease and suffering was not understood fully by patients’ families, that patients feel a lack of family support and cooperation, and that society’s level of understanding of their disease was also insufficient. Again, findings revealed that patients recognized their inability to perform personal activities and to behave competently within the contexts of family and society. This lowered their self evaluation. These findings highlight three needs: “the need for empathy,” “the need for self the “the need for empathy” and “the need for self esteem.”This study was supported by a great-in-aid by Ministry of Health, Labor and Welfare in Japan, “Outcomes Research of Specific Diseases”（PI:S.Fukuhara）（Grand no: H14-44）. (shrink)

Implantable brain-computer interfaces are being developed to restore speech capacity for those who are unable to speak. Patients with locked-in syndrome or amyotrophic lateral sclerosis could be able to use covert speech – vividly imagining saying something without actual vocalisation – to trigger neural controlled systems capable of synthesising speech. User control has been identified as particularly pressing for this type of BCI. The incorporation of machine learning and statistical language models into the decoding process introduces a (...) contribution to the output that is beyond the user’s control. Whilst this type of ‘shared control’ of BCI action is not unique to speech BCIs, the automated shaping of what a user ‘says’ has a particularly acute ethical dimension, which may differ from parallel concerns surrounding automation in movement BCIs. This paper provides an analysis of the control afforded to the user of a speech BCI of the sort under development, as well as the relationships between accuracy, control, and the user’s ownership of the speech produced. Through comparing speech BCIs with BCIs for movement, we argue that, whilst goal selection is the more significant locus of control for the user of a movement BCI, control over process will be more significant for the user of the speech BCI. The design of the speech BCI may therefore have to trade off some possible efficiency gains afforded by automation in order to preserve sufficient guidance control necessary for users to express themselves in ways they prefer. We consider the implications for the speech BCI user’s responsibility for produced outputs and their ownership of token outputs. We argue that these are distinct assessments. Ownership of synthetic speech concerns whether the content of the output sufficiently represents the user, rather than their morally relevant, causal role in producing that output. (shrink)

Background: In Switzerland, non-medical right-to-die organisations such as Exit Deutsche Schweiz and Dignitas offer suicide assistance to members suffering from incurable diseases. Objectives: First, to determine whether differences exist between the members who received assistance in suicide from Exit Deutsche Schweiz and Dignitas. Second, to investigate whether the practices of Exit Deutsche Schweiz have changed since the 1990s. Methods: This study analysed all cases of assisted suicide facilitated by Exit Deutsche Schweiz (E) and Dignitas (D) between 2001 and 2004 and (...) investigated by the University of Zurich’s Institute of Legal Medicine (E: n = 147; D: n = 274, total: 421). Furthermore, data from the Exit Deutsche Schweiz study which investigated all cases of assisted suicide during the period 1990–2000 (n = 149) were compared with the data of the present study. Results: More women than men were assisted in both organisations (D: 64%; E: 65%). Dignitas provided more assistance to non-residents (D: 91%; E: 3%; p = 0.000), younger persons (mean age in years (SD): D: 64.5 (14.1); E: 76.6 (13.3); p = 0.001), and people suffering from fatal diseases such as multiple sclerosis and amyotrophic lateral sclerosis (D: 79%; E: 67%; p = 0.013). Lethal medications were more often taken orally in cases assisted by Dignitas (D: 91%; E: 76%; p = 0.000). The number of women and the proportion of older people suffering from non-fatal diseases among suicides assisted by Exit Deutsche Schweiz has increased since the 1990s (women: 52% to 65%, p = 0.031; mean age in years (SD): 69.3 (17.0) to 76.9 (13.3), p = 0.000), non-fatal diseases: 22% to 34%, p = 0.026). Conclusions: Weariness of life rather than a fatal or hopeless medical condition may be a more common reason for older members of Exit Deutsche Schweiz to commit suicide. The strong over-representation of women in both Exit Deutsche Schweiz and Dignitas suicides is an important phenomenon so far largely overlooked and in need of further study. (shrink)

Background: In Switzerland, non-medical right-to-die organisations such as Exit Deutsche Schweiz and Dignitas offer suicide assistance to members suffering from incurable diseases.Objectives: First, to determine whether differences exist between the members who received assistance in suicide from Exit Deutsche Schweiz and Dignitas. Second, to investigate whether the practices of Exit Deutsche Schweiz have changed since the 1990s.Methods: This study analysed all cases of assisted suicide facilitated by Exit Deutsche Schweiz and Dignitas between 2001 and 2004 and investigated by the University (...) of Zurich’s Institute of Legal Medicine. Furthermore, data from the Exit Deutsche Schweiz study which investigated all cases of assisted suicide during the period 1990–2000 were compared with the data of the present study.Results: More women than men were assisted in both organisations. Dignitas provided more assistance to non-residents, younger persons : D: 64.5 ; E: 76.6 ; p = 0.001), and people suffering from fatal diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Lethal medications were more often taken orally in cases assisted by Dignitas. The number of women and the proportion of older people suffering from non-fatal diseases among suicides assisted by Exit Deutsche Schweiz has increased since the 1990s : 69.3 to 76.9, p = 0.000), non-fatal diseases: 22% to 34%, p = 0.026).Conclusions: Weariness of life rather than a fatal or hopeless medical condition may be a more common reason for older members of Exit Deutsche Schweiz to commit suicide. The strong over-representation of women in both Exit Deutsche Schweiz and Dignitas suicides is an important phenomenon so far largely overlooked and in need of further study. (shrink)

We explored the care experiences and needs of the home caregivers of patients with amyotrophic lateral sclerosis (ALS) to improve their quality of life. We interviewed home caregivers in-depth and analyzed the data using Colaizzi's descriptive phenomenological method. We interviewed 11 home caregivers of patients with ALS with a disease duration between 1.5 and 4 years. Primary caregivers were predominantly female and were the patients' spouses. Daily caregiving time averaged 4–14 h for 0.5–3.5 years. Interview themes included (...) helplessness and adaptation to life changes, hopelessness, compassion for the patient’s prognosis, and expectation for diverse support. The study sample size was limited, as all participants were from a single tertiary hospital, and all patients had severe functional impairment. Caregivers of patients with ALS experience a considerable burden. Patients and their caregivers can benefit from diversified support channels, and assistive communication systems can be applied to home care. Future research will focus on in-home public long-term care services in China. (shrink)

Access to communication is critical for individuals with late-stage amyotrophic lateral sclerosis and minimal volitional movement, but they sometimes present with concomitant visual or ocular motility impairments that affect their performance with eye tracking or visual brain-computer interface systems. In this study, we explored the use of modified eye tracking and steady state visual evoked potential BCI, in combination with the Shuffle Speller typing interface, for this population. Two participants with late-stage ALS, visual impairments, and minimal volitional (...) movement completed a single-case experimental research design comparing copy-spelling performance with three different typing systems: commercially available eye tracking communication software, Shuffle Speller with modified eye tracking, and Shuffle Speller with SSVEP BCI. Participant 1 was unable to type any correct characters with the commercial system, but achieved accuracies of up to 50% with Shuffle Speller eye tracking and 89% with Shuffle Speller BCI. Participant 2 also had higher maximum accuracies with Shuffle Speller, typing with up to 63% accuracy with eye tracking and 100% accuracy with BCI. However, participants’ typing accuracy for both Shuffle Speller conditions was highly variable, particularly in the BCI condition. Both the Shuffle Speller interface and SSVEP BCI input show promise for improving typing performance for people with late-stage ALS. Further development of innovative BCI systems for this population is needed. (shrink)

Terminally ill patients in 10 states plus Washington, D.C. have the right to take prescribed medications to end their lives (medical aid in dying). But otherwise-eligible patients with neuromuscular disabilities (ALS and other illnesses) are excluded if they are physically unable to “self-administer” the medications without assistance. This exclusion is incompatible with disability rights laws that mandate assistance to provide equal access to health care. This contradiction between aid-in-dying laws and disability rights laws can force patients and clinicians into violating (...) one or the other, potentially creating an underclass of patients denied medical care that is available to those with other (less physically disabling) terminal illnesses. The immediacy of this issue is demonstrated by a lawsuit in Federal court filed in August 2021, requesting assistance in self-administration for terminally ill patients with neuromuscular diseases. This paper discusses the background of this conflict, the ethical issues at the heart of the dilemma, and recommends potential remedies. (shrink)

Should first-in-human trials be designed to maximize the prospect of therapeutic benefit for volunteers, prioritize avoidance of unintended harms, or aim for some happy medium between the two? Perennial controversies surrounding initiation and design of early-phase trials hinge on how this question is resolved. In this paper, we build on the premise that the task of early-phase testing is to optimize various components of a potential therapy so that later, confirmatory trials have the maximal probability of informing drug development and (...) clinical care. We then explore three strategies that investigators might use to manage trial risks while optimizing a therapy, using cell therapy for Amyotrophic Lateral Sclerosis (ALS) as an example. We argue that an iterative application of maximin strategies over successive cohorts and trials, which we call the “risk-escalation model,” establishes a moral principle that should guide decision-making in early-phase trials. (shrink)

Clinical neuroethics and neuroskepticism are recent entrants to the vocabulary of neuroethics. Clinical neuroethics has been used to distinguish problems of clinical relevance arising from developments in brain science from problems arising in neuroscience research proper. Neuroskepticism has been proposed as a counterweight to claims about the value and likely implications of developments in neuroscience. These two emergent streams of thought intersect within the practice of neurology. Neurologists face many traditional problems in bioethics, like end of life care in the (...) persistent vegetative state, determination of capacity in progressive dementia, and requests for assisted suicide in cognition-preserving neurodegenerative disease (like amyotrophic lateral sclerosis). Neurologists also look to be at the forefront of downstream clinical applications of neuroscience, like pharmacological enhancement of mental life. At the same time, the practice of neurology, concerned primarily with the structure, function, and treatment of the nervous system, has historically fostered a kind of skeptical attitude toward its own subject matter. Not all problems that appear primarily neurological are primarily neurological. This disciplinary skepticism is generally clinical in orientation and limited in scope. The rise of interest in clinical neuroethics and in neuroskepticsim generally suggests a possible broader application. The clinical skepticism of neurology provides impetus for thinking about the appropriate role for skepticism in clinical areas of neuroethics. After a brief review of neuroskepticism and clinical neuroethics, a taxonomy of clinical neuroskepticism is offered and reasons why a stronger rather than weaker form of clinical neuroskepticism is currently warranted. (shrink)

Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5‐bisphosphate (PI(3,5)P2), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2, and mutations that disrupt complex function and/or (...) formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot‐Marie‐Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases. (shrink)

Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell‐specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult‐onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral (...) sclerosis (ALS). Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1G93A mice—a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF‐dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders. BioEssays 26:943–954, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The transactivation response‐DNA binding protein of 43 kDa (TDP‐43) is an aggregation‐prone nucleic acid‐binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP‐43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP‐43 are altered in the disease state where TDP‐43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by (...) the C‐terminal prion‐like domain. Here, we review three emerging and poorly understood aspects of TDP‐43 biology linked to its aggregation. First, how post‐translational modifications in the proximity of TDP‐43 N‐terminal domain (NTD) promote aggregation. Second, how TDP‐43 engages FG‐nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone. (shrink)

Oregon is the only state in the United States where a physician may legally prescribe a lethal dose of barbiturate for a patient intending suicide. The Oregon Death with Dignity Act was passed by voters in 1994 and came into effect after much legal wrangling in October of 1997. At the same time, a cabinetmaker named Pat Matheny was struggling with progressive weakness from amyotrophic lateral sclerosis, or ALS. I met with Pat and his family for a (...) lengthy interview in October 1998 in Coos Bay, Oregon, for a television news report on his decision to get a lethal prescription. Below is an extract from that interview. On the day this introduction was written, 10 March 1999, Pat took the prescribed lethal overdose of barbiturates and died at home. His illness was taking his voice, he could not move his hands or legs, and breathing was becoming very difficult. His mother told me he knew that was for him. (shrink)

Pushing back on policies favored by dying patients is a challenging endeavor, requiring tact, engagement, openness to bidirectional learning, and willingness to offer alternative solutions. It's easy to make missteps, especially in the age of social media. Holly Fernandez Lynch shares her experience learning with and from the amyotrophic lateral sclerosis (ALS) community, first as a caricature of an ivory tower bioethicist and more recently as a trusted advisor, at least for some. Patient‐engaged bioethics doesn't mean taking (...) the view that patients are always right, but even when disagreement continues, progress is possible if academics and patients recognize the unique expertise each has to offer. (shrink)

In-vivo phenotyping of genetically engineered mouse models for amyotrophic lateral sclerosis is established by combining BT-MRI and CASL G. Vanhoutte1, E. Storkebaum2, P. Carmeliet2, A. Van der Linden1.

Along with political, economic, ethical, rehabilitative and military dimensions, psychopathological sequelae of war and terrorism also deserve our attention. The terrorist attack on the World Trade Centre ( W.T.C.) in 2001 and the Gulf War of 1990-91 gave rise to a number of psychiatric disturbances in the population, both adult and children, mainly in the form of Post-traumatic Stress disorder (PTSD). Nearly 75,000 people suffered psychological problems in South Manhattan alone due to that one terrorist attack on the WTC in (...) New York and the Pentagon in Washington. In Gulf War I, more that 1,00,000 US veterans reported a number of health problems on returning from war, whose claims the concerned government has denied in more than 90% cases. Extensive and comprehensive neurological damage to the brain of Gulf War I veterans has been reported by one study, as has damage to the basal ganglia in another, and Amyotrophic Lateral Sclerosis (ALS) in a third, possibly due to genetic mutations induced by exposure to biological and chemical agents, fumes from burning oil wells, landfills, mustard or other nerve gases. The recent Gulf War will no doubt give rise its own crop of PTSD and related disorders. In a cost-benefit analysis of the post Gulf War II scenario, the psychopathological effects of war and terrorism should become part of the social audit any civilized society engages in. Enlightened public opinion must become aware of the wider ramifications of war and terrorism so that appropriate action plans can be worked out. (shrink)

Neurofilaments are one of the major components of the neuronal cytoskeleton and are responsible for maintaining the calibre of axons. They are modified by post‐translational changes that are regulated in complex fashions including by the interaction with neighbouring glial cells. Neurofilament accumulations are seen in several neurological diseases and neurofilament mutations have now been associated with Charcot‐Marie‐Tooth disease, Parkinson's disease and amyotrophic lateral sclerosis. In this review, we discuss the structure, normal function and molecular pathology of neurofilaments. (...) BioEssays 25:346–355, 2003. © 2003 Wiley Periodicals, Inc. (shrink)