End of life decision making when home mechanical ventilation is used to sustain breathing in Motor Neurone Disease: patient and family perspectives.

BACKGROUND: Motor Neurone Disease (MND) leads to muscle weakening, affecting movement, speech, and breathing. Home mechanical ventilation, particularly non-invasive ventilation (NIV), is used to alleviate symptoms and support breathing in people living with MND. While home mechanical ventilation can alleviate symptoms and improve survival, it does not slow the progression of MND. This study addresses gaps in understanding end-of-life decision-making in those dependent on home mechanical ventilation, considering the perspectives of patients, family members, and bereaved families. METHODS: A UK-wide qualitative study using flexible interviews to explore the experiences of people living with MND (n = 16), their family members (n = 10), and bereaved family members (n = 36) about the use of home mechanical ventilation at the end of life. RESULTS: Some participants expressed a reluctance to discuss end-of-life decisions, often framed as a desire to "live for the day" due to the considerable uncertainty faced by those with MND. Participants who avoided end-of-life discussions often engaged in 'selective decision-making' related to personal planning, involving practical and emotional preparations. Many faced challenges in hypothesising about future decisions given the unpredictability of the disease, opting to make 'timely decisions' as and when needed. For those who became dependent on ventilation and did not want to discuss end of life, decisions were often 'defaulted' to others, especially once capacity was lost. 'Proactive decisions', including advance care planning and withdrawal of treatment, were found to empower some patients, providing a sense of control over the timing of their death. A significant proportion lacked a clear understanding of the dying process and available options. CONCLUSIONS: The study highlights the complexity and evolution of decision-making, often influenced by the dynamic and uncertain nature of MND. The study emphasises the need for a nuanced understanding of decision-making in the context of MND.

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Optimizing breathlessness management in amyotrophic lateral sclerosis: insights from a comprehensive systematic review.

BACKGROUND: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies. METHODS: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials. RESULTS: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients. CONCLUSION: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted.

Thalamic Alterations in Motor Neuron Diseases: A Systematic Review of MRI Findings.

BACKGROUND: Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by motor impairment and non-motor symptoms. The involvement of the thalamus in MNDs, especially in conditions such as amyotrophic lateral sclerosis (ALS), and its interaction with frontotemporal dementia (FTD), has garnered increasing research interest. This systematic review analyzed magnetic resonance imaging (MRI) studies that focused on thalamic alterations in MNDs to understand the significance of these changes and their correlation with clinical outcomes. METHODS: Following PRISMA 2020 guidelines, the PubMed and Scopus databases were searched from inception to June 2023 for studies related to MRI findings in the thalamus of patients with MNDs. Eligible studies included adult patients diagnosed with ALS or other forms of MND who underwent brain MRI, with outcomes related to thalamic alterations. Studies were evaluated for risk of bias using the Newcastle-Ottawa scale. RESULTS: A total of 52 studies (including 3009 MND patients and 2181 healthy controls) used various MRI techniques, including volumetric analysis, diffusion tensor imaging, and functional MRI, to measure thalamic volume, connectivity, and other alterations. This review confirmed significant thalamic changes in MNDs, such as atrophy and microstructural degradation, which are associated with disease severity, progression, and functional disability. Thalamic involvement varies across different MND subtypes and is influenced by the presence of cognitive impairment and mutations in genes including chromosome 9 open reading frame 72 (C9orf72). The synthesis of findings across studies indicates that thalamic pathology is a prevalent early biomarker of MNDs that contributes to motor and cognitive deficits. The thalamus is a promising target for monitoring as its dysfunction underpins a variety of clinical symptoms in MNDs. CONCLUSIONS: Thalamic alterations provide valuable insights into the pathophysiology and progression of MNDs. Multimodal MRI techniques are potent tools for detecting dynamic thalamic changes, indicating structural integrity, connectivity disruption, and metabolic activity.

New knowledge on anti-IgLON5 disease.

PURPOSE OF REVIEW: Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported. RECENT FINDINGS: Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects. SUMMARY: Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.

Concentric needle jitter analysis of the genioglossus muscle in patients with motor neuron disease.

OBJECTIVES: Difficulty relaxing the genioglossus muscle makes the evaluation of spontaneous activity problematic in patients with motor neuron disease (MND). We performed jitter analysis using conventional disposable concentric needle electrodes (CNEs) of the voluntarily activated genioglossus muscle in patients with and without MND to detect the denervation-reinnervation process. METHODS: CNE jitter analysis was performed at the genioglossus muscle in 21 MND(+) patients and 22 MND(-) subjects. The jitter analysis was considered abnormal if the jitter values exceeded these limits for the mean consecutive difference (MCD) or the individual MCD in more than 10% of readings. RESULTS: Seventeen MND(+) patients (81%) had at least three abnormal individual jitter values whereas denervation findings were obtained in eleven of them during the needle electromyographic examination at genioglossus muscle. None of the MND(-) subjects showed CNE jitter abnormality. CONCLUSION: CNE jitter analysis of genioglossus muscle may provide an useful information that may be suggestive of a diagnosis of MND/ALS.

An introduction to neuropalliative care: A growing need.

Palliative care (PC) defined as 'an approach improving the quality of life of patients and their families facing problems associated with life-limiting illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual' aims to enhance the improve the remaining time that patients have, emphasising choice for patients and families.1 Patients with neurological disease such as Parkinson's (PD) and motor neurone disease (MND) benefit from PC earlier in disease with increasing emphasis over time. Understanding and communicating uncertain trajectories, honest prognostic communication when patients are ready and careful symptom control has been shown to enhance quality of life in patients and caregivers, giving greater autonomy to these patients when supported in decision-making by a palliative approach. Although obstacles to palliative care are frequent, there are strategies which can help overcome them.

Eutanasia y suicidio asistido en enfermedades neurológicas: una revisión sistemática / Euthanasia and assisted suicide in neurological diseases: a systematic review

Objetivo Identificar las enfermedades neurológicas por las que con mayor frecuencia se solicita la eutanasia y el suicidio asistido en los países donde están legalizados, las particularidades de la eutanasia en algunas de ellas y mostrar la evolución de sus cifras. Métodos Revisión bibliográfica sistemática. Resultados Las demencias, enfermedad de motoneurona, esclerosis múltiple y enfermedad de Parkinson son las enfermedades neurológicas que más frecuentemente motivan la petición de eutanasia o suicidio asistido. Las solicitudes por demencia son las más numerosas, están creciendo y plantean problemas éticos y legales adicionales al disminuir la capacidad de decisión. En algunos países la proporción de solicitudes respecto al total de casos de esclerosis múltiple, enfermedad de motoneurona o enfermedad de Huntington es mayor que en cualquier otra enfermedad. Conclusiones Después del cáncer las enfermedades neurológicas son el motivo más frecuente de pedir la eutanasia y el suicidio asistido. (AU)

Objective To identify the neurological diseases for which euthanasia and assisted suicide are most frequently requested in the countries where these medical procedures are legal and the specific characteristics of euthanasia in some of these diseases, and to show the evolution of euthanasia figures. Methods We conducted a systematic literature review. Results Dementia, motor neuron disease, multiple sclerosis, and Parkinson's disease are the neurological diseases that most frequently motivate requests for euthanasia or assisted suicide. Claims related to dementia constitute the largest group, are growing, and raise additional ethical and legal issues due to these patients’ diminished decision-making capacity. In some countries, the ratios of euthanasia requests to all cases of multiple sclerosis, motor neuron disease, or Huntington disease are higher than for any other disease. Conclusions After cancer, neurological diseases are the most frequent reason for requesting euthanasia or assisted suicide. (AU)

FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.

Fluctuating salience in those living with genetic risk of motor neuron disease: A qualitative interview study.

BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision. CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website. PATIENT OR PUBLIC CONTRIBUTION: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.

Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy.

Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387His variant and the distal Trp375* (W375X) chinese variant, both located at the end of the low complexity C-terminal region and proximal to the termination codon, retain their catalytic activity on some substrates, and mechanistically their functional impairment is different. The L200P variant, as well as most VRK1 pathogenic variants, impairs the phosphorylation of BAF and histone H4K16 acetylation, which are required for DNA attachment to the nuclear envelope and chromatin accessibility to DNA repair mechanisms, respectively. The R387H variant impairs phosphorylation of H2AX, an early step in different types of DNA damage responses. The functional variability of VRK1 protein variants and their different combinations are a likely contributor to the clinical phenotypic heterogeneity of motor neuron and neurological diseases associated with rare VRK1 pathogenic variants. KEY MESSAGES: VRK1 variants implicated in motor neuron diseases are functionally different. The L200P variant is kinase inactive, and the R387H variant is partially active. VRK1 variants alter H4K16 acetylation and loss of coilin and BAF phosphorylation. VRK1 variants alter Cajal bodies and DNA damage responses. VRK1 variant combination determines the neurological phenotype heterogeneity.

Clinical prognostic factors predicting survival of motor neuron disease patients with gastrostomy: A retrospective analysis.

INTRODUCTION/AIMS: Enteral feeding via gastrostomy is a key intervention to prevent significant weight loss in Motor Neuron Disease (MND). The aim of this study was to explore demographic, clinical, and nutritional factors associated with survival time in MND patients with gastrostomy. METHODS: The retrospective study analyzed 94 MND patients (n = 58 bulbar-onset and n = 36 limb-onset) who underwent gastrostomy between 2015 and 2021. The primary outcome was the survival time from gastrostomy insertion to death. Independent variables of interest explored were: age at gastrostomy insertion, disease onset type, known genetic cause, use of riluzole, non-invasive ventilation (NIV) use, forced vital capacity prior to gastrostomy, weight loss from diagnosis to gastrostomy insertion, and body mass index (BMI) at the time of gastrostomy insertion. RESULTS: The median survival time from gastrostomy to death was 357 days (± 29.3, 95%CI: 299.5, 414.5). Kaplan-Meier method and log-rank test revealed patients with lower body mass index <18.5 kg/m2 at the time of gastrostomy insertion (p = .023) had shorter survival. Cox proportional hazards model with multivariable adjustment revealed that older age (p = .008), and greater weight loss from diagnosis to gastrostomy (p = .003) were associated with shorter survival time post gastrostomy. Limb onset (p = .023), NIV use not being required (p = .008) and daily NIV use when required and tolerated (p = .033) were associated with longer survival. DISCUSSION: Preventing or minimizing weight loss from MND diagnosis and encouraging NIV use when clinically indicated are modifiable factors that may prolong the survival of MND patients with gastrostomy.

Electrochemical detection of the neurotransmitter glutamate and the effect of the psychotropic drug riluzole on its oxidation response.

Glutamate is the main excitatory neurotransmitter in the brain and plays a leading role in degenerative diseases, such as motor neuron diseases. Riluzole is a glutamate regulator and a therapeutic drug for motor neuron diseases. In this work, the interaction between glutamate and riluzole was studied using cyclic voltammetry and square-wave voltammetry at a glassy carbon electrode (GCE). It was shown that glutamate underwent a two-electron transfer reaction on the GCE surface, and the electrochemical detection limits of glutamate and riluzole were 483 µmol/L and 11.47 µmol/L, respectively. The results confirm that riluzole can promote the redox reaction of glutamate. This work highlights the significance of electrochemical technology in the sensing detection of the interaction between glutamate and related psychotropic drugs.

Supporting people with Motor Neuron Disease (MND) to make decisions about gastrostomy feeding tube placement: a survey of UK healthcare professionals' practice and beliefs.

OBJECTIVE: Understand the practice and beliefs of healthcare professionals (HCPs) supporting the decision-making of people with MND (pwMND) about gastrostomy placement, including identifying differences between professions. METHODS: An online cross-sectional survey disseminated to HCPs who support the decision-making of pwMND about gastrostomy placement. RESULTS: A total of 139 participants completed the survey including representation from a range of healthcare professions. A third (36/101, 36%) initiated discussions about gastrostomy later in practice than they believed was ideal. In relation to the outcome of declining compared to accepting gastrostomy, participants were more likely to discuss aspiration (80% vs. 68%), choking (76% vs. 58%) and prognosis (36% vs. 22%). Participants believed gastrostomies should be placed after a mean 8.1% weight loss since symptom-onset. More participants favored gastrostomy placement before pwMND presented with respiratory symptoms (45%) compared to onset of dysphagia (11%). Half believed pwMND placed gastrostomies too late. Participants were more likely to 'often'/'always' recommend pwMND to have a gastrostomy (23%) than continue without (7%) or decline (4%) gastrostomy, when believing these were the best option for pwMND. Nurses and dietitians discussed the broadest range of information, while doctors were more likely to discuss mortality risk and prognosis. CONCLUSION: There is variation in HCPs practice and beliefs about initiating discussions, the sharing of information and recommendations, and timing, about gastrostomy placement. The information shared varies by profession and there is evidence of sub-optimal communication between HCPs. Further research is required to understand how these findings may impact on the decision-making of pwMND about gastrostomy.

Assessment of diagnostic criteria for multifocal motor neuropathy in patients included in the Italian database.

BACKGROUND AND PURPOSE: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real-life data in multifocal motor neuropathy (MMN) patients. METHODS: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty-six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria. RESULTS: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied. AUTHOR: When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti-GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%-83% of the patients. Anti-GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations. CONCLUSIONS: This study provides insights into the real-world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria.