Nutritional support teams increase percutaneous endoscopic gastrostomy uptake in motor neuron disease

AIM:To examine factors influencing percutaneous endoscopic gastrostomy(PEG) uptake and outcomes in motor neuron disease(MND) in a tertiary care centre.METHODS:Case notes from all patients with a confirmed diagnosis of MND who had attended the clinic at the Repatriation General Hospital between January 2007 and January 2011 and who had since died,were audited.Data were extracted for demographics(age and gender),disease characteristics(date of onset,bulbar or peripheral predominance,complications),date and nature of discussion of gastrostomy insertion,nutritional status [weight measurements,body mass index(BMI)],date of gastrostomy insertion and subsequent progress(duration of survival) and quality of life(QoL) [Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)].In addition,the type of clinician initiating the discussion regarding gastrostomy was recorded as Nutritional Support Team(involved in providing nutrition input viz Gastroenterologist,Speech Pathologist,Dietitian) and other(involved in non-nutritional aspects of patient care).Factors affecting placement and outcomes including length of survival,change in weight and QoL were determined.RESULTS:Case records were available for all 86 patients(49 men,mean age at diagnosis 66.4 years).Thirty-eight patients had bulbar symptoms and 48 had peripheral disease as their presenting feature.Sixty-six patients reported dysphagia.Thirty-one patients had undergone gastrostomy insertion.The major indications for PEG placement were dysphagia and weight loss.Nine patients required immediate full feeding,whereas 17 patients initially used the gastrostomy to supplement oral intake,4 for medication administration and 1 for hydration.Initially the PEG regime met 73% ± 31% of the estimated total energy requirements,increasing to 87% ± 32% prior to death.There was stabilization of weight in patients undergoing gastrostomy [BMI at 3 mo(22.6 ± 2.2 kg/m 2) and 6 mo(22.5 ± 2.0 kg/m 2) after PEG placement compared to weight at the time of the procedure(22.5 ± 3.0 kg/m 2)].However,weight loss recurred in the terminal stages of the illness.There was a strong trend for longer survival from diagnosis among MND in PEG recipients with limb onset presentation compared to similar patients who did not undergo the procedure(P = 0.063).Initial discussions regarding PEG insertion occurred earlier after diagnosis when seen by nutrition support team(NST) clinicians compared to other clinicians.(5.4 ± 7.0 mo vs 11.9 ± 13.4 mo,P = 0.028).There was a significant increase in PEG uptake(56% vs 24%,P = 0.011) if PEG discussions were initiated by the NST staff compared to other clinicians.There was no change in the ALSFRS-R score in patients who underwent PEG(pre 34.1 ± 8.6 vs post 34.8 ± 7.4),although in non-PEG recipients there was a nonsignificant fall in this score(33.7 ± 7.9 vs 31.6 ± 8.8).Four patients died within one month of the procedure,4 developed bacterial site infection requiring antibiotics and 1 required endoscopic therapy for gastric bleeding.Less serious complications attributed to the procedure included persistent gastrostomy site discomfort,poor appetite,altered bowel function and bloating.CONCLUSION:Initial discussion with NST clinicians increases PEG uptake in MND.Gastrostomy stabilizes patient weight but weight loss recurs with advancing disease.

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

Amyotrophic lateral sclerosis（ALS） and motor neuron diseases（MNDs） are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons（UMNs/LMNs）, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons（MNs）, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Mills’syndrome is a unique entity of upper motor neuron disease with N-shaped progression:Three case reports

BACKGROUND Mills’syndrome is an extremely rare degenerative motor neuron disorder first described by Mills in 1900,but its nosological status is still not clear.We aimed to analyze the clinical features of Mills’syndrome.CASE SUMMARY Herein,we present 3 cases with similar features as those described in Mills’original paper and review the related literature.Our patients showed middle-and older-age onset,with only upper motor neuron symptoms evident throughout the course of the disease.Spastic hemiplegia began in the lower extremity with a unique progressive pattern.CONCLUSION We consider that Mills’syndrome is a unique entity of motor neuron disorder with an N-shaped progression.Clinicians should maintain a high index of suspicion for the diagnosis of Mills’syndrome when the onset involves lower extremity paralysis without evidence of lower motor neuron or sensory involvement.

New trends in treatment of muscle fatigue throughout rehabilitation of elderlies with motor neuron diseases

Muscle fatigue is a problem in rehabilitation,particularly in elderlies and patients with motor neuron diseases.There are high contradictions in the effectiveness of the used methods to decrease muscle fatigue during rehabilitation.They mainly concentrate on increasing rest periods,decreasing training load,or using an ascending intensity of manner of exercise.The training should focus on the newly discovered sensory system of muscle fatigue because of the important role of the sensory system in driving the motor system.Thus,this editorial provides insight on using proprioceptive training to enhance the sensory system of muscle fatigue.

Pathogenesis of motor neuron disease

OBJECTIVE: To summarize and analyze the factors and theories related to the attack of motor neuron disease, and comprehensively investigate the pathogenesis of motor neuron disease. DATA SOURCES: A search of Pubmed database was undertaken to identify articles about motor neuron disease published in English from January 1994 to June 2006 by using the keywords of 'neurodegenerative diseases'. Other literatures were collected by retrieving specific journals and articles. STUDY SELECTION: The data were checked primarily, articles related to the pathogenesis of motor neuron disease were involved, and those obviously irrelated to the articles were excluded. DATA EXTRACTION: Totally 54 articles were collected, 30 of them were involved, and the other 24 were excluded. DATA SYNTHESIS: The pathogenesis of motor neuron disease has multiple factors, and the present related theories included free radical oxidation, excitotoxicity, genetic and immune factors, lack of neurotrophic factor, injury of neurofilament, etc. The studies mainly come from transgenic animal models, cell culture in vitro and patients with familial motor neuron disease, but there are still many restrictions and disadvantages. CONCLUSION: It is necessary to try to find whether there is internal association among different mechanisms, comprehensively investigate the pathogenesis of motor neuron diseases, in order to provide reliable evidence for the clinical treatment.

Treatment of Motor Neuron Disease with Qi-invigorating Herbs——A Report of 31 Cases

The motor neuron disease (MND) refers to a group of progressive diseases with unknown reasons, which attacks the cells of the anterior horn of the spinal cord, the motor nuclei of the brain stem cranial nerves and the pyramidal cells of the cerebral motor cortex. It is characterized in clinic by atrophy of the muscles, myasthenia and even death due to paralysis of the respiratory muscle. Currently, there is still no any effective cure for this illness. 50-70% of the victims will die in 3 to 5 years, and the survival time for those with brain stem injuries is no more than two years.1 Since 1996, the authors have treated 31 cases of motor neuron disease with large dosage of qi-invigorating drugs in accordance with Prof. Liu Mocai's experience, and obtained certain therapeutic effects. A report follows.……

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis （ALS）. The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.

Eiehavioral Symptoms in Motor Neuron Disease and Their Negative Impact on Caregiver Burden

Background： The spectrum of abnormal behaviors in amyotrophic lateral sclerosis/motor neuron disease （ALS/MND） has been described, but its practical meaning, namely its impact on caregiver burden, has not been clearly documented in Chinese population. This study aimed to assess the distribution of abnormal behaviors in Chinese population, and to analyze the relationship between behavior changes and caregivcr burden. Methods： Sixty-five patients with ALS/MND have been consecutively enrolled into registry platform of Peking Union Medical College Hospital. An investigation was performed to these patients and their caregivers using the revised ALS function rating scale, Frontal Behavioral Inventory-ALS version, the Frontal Assessment Battery, and the Caregiver Burden Inventory. Results： Twenty-eight （43.1%） patients displayed abnormal behaviors of varying degrees, with one fulfilling the diagnostic criteria of frontotemporal lobe degeneration. Irritability, logopenia, and inflexibility ranked top 3 of abnormal behavior list. Correlation analysis revealed that the degree of behavioral change and frontal cognitive status were significantly associated with caregiver burden, with more extensive impact from disinhibitive behaviors. Analysis of covariance analysis showed that after associated factors were corrected, caregivers of patients with moderate to severe behavior change reported significantly heavier developmental burden, physical burden, and total burden than those with no behavioral change. Conclusions： Nettrobehavioral symptoms could present in around 40% of Chinese patients with ALS/MND, and the distribution of these behaviors was also unique. Besides, abnormal behaviors were highly related to caregivers＇ burden.

Lower and upper motor neuron involvement and their impact on disease prognosis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting,breathing and swallowing difficulties resulting in patient’s death in two to five years after disease onset.In amyotrophic lateral sclerosis,both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration,accounting for great clinical heterogeneity of the disease.Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis.Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials.Since amyotrophic lateral sclerosis has low incidence rates,conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging.This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods,highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease.We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease.Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups,based on the disease pathophysiology and spatiotemporal pattern.Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups,we provide proof that instrumental studies could provide valuable insights in the disease pathology.

Catheter-related infections caused by Mycobacterium abscessus in a patient with motor neurone disease:A case report

BACKGROUND Mycobacterium abscessus(M.abscessus)is a rapidly growing mycobacterium and ubiquitous in the environment,which infrequently causes disease in humans.However,it can cause cutaneous or respiratory infections among immunocompromised hosts.Due to the resistance to most antibiotics,the pathogen is formidable and difficult-to-treat.CASE SUMMARY Here,we present a case of catheter-related M.abscessus infections in a patient with motor neurone disease.Catheter and peripheral blood cultures of the patient showed positive results during Gram staining and acid-fast staining.The alarm time of catheter blood culture was 10.6 h earlier than that of peripheral blood.After removal of the peripherally inserted central catheter,secretion and catheter blood culture were positive.M.abscessus was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing.CONCLUSION For catheter-related M.abscessus infection,rapid diagnosis and timely and adequate antimicrobial therapy are crucial.

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNASeq screening approach to a standard model of TAR DNA-binding protein-43(TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.

Proximal-distal motor unit number estimationdynamic changes in patients with amyotrophic lateral sclerosis A one-year follow-up

BACKGROUND：Amyotrophic lateral sclerosis （ALS） is the most common of all the motor neuron diseases and the absence of a biologic marker has made both diagnosis and tracking evolution of the disease difficult, Electrodiagnostic tests play a fundamental role in quantifying pathological changes in the motor unit pool.OBJECTIVE：We assessed distal-proximal Motor Unit （MU） loss and changes using the method of motor unit number estimation （MUNE）.DESIGN, TIME AND SETTING：A case-control study was performed at the Department of Neuroscience, Pisa University Medical School, Italy from December 1999 to November 2009. PARTICIPANTS：A total of 50 ALS patients were recruited, 30 males：mean age （59.6 ± 13.3） years; 20 females：mean age （63.9 ± 11.7） years; range （30-82） years; all patients had probable or definite ALS. Thirty healthy volunteers were recruited from department staffs, including 20 males and 10 females; mean age （57.7 ± 13.8） years served as controls.METHODS：MUNE was performed for both the biceps brachii and abductor digiti minimi muscles of the same side. The technique used relayed substantially on manual incremental stimulation of the motor nerve, known as the McComas technique （50 ms sweep duration, a gain of 2 mV/Div for M wave, 0.5 mV/Div for each step; filters 10-20 kHz）.MAIN OUTCOME MEASURES：MUNE results were measured.RESULTS：Functioning MU numbers, measured by MUNE, decreased in the biceps brachii and abductor digiti minimi muscles over the entire one-year follow-up period （one assessment every three months） compared with baseline determination, the rate of MU decrease was similar in both muscles, but steeper distally.CONCLUSION：MUNE is a feasible method for ALS patients both proximally and distally to track changes over time in muscle MUs during the disease＇s evolution.

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1G93A mouse model of ALS. Histone deacetylase 6 （HDAC6） is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.

Considerations on the concept, definition, and diagnosis of amyotrophic lateral sclerosis

The concept, definition, and diagnosis of amyotrophic lateral sclerosis(ALS) currently present some problems. This article systematically reviews the literature on the history, current concepts, definition, and diagnosis of ALS, and discloses the present problems based on the retrieved literature and the authors' clinical experience. The current concepts and definitions of ALS have not yet been unified or standardized in clinical practice, and are sometimes vague or inaccurate, which can cause difficulties for neurologists in the clinical treatment of ALS. The concept and definition of ALS need to be further ascertained, and the current diagnostic criteria for ALS require further development. The identification of effective and objective biomarkers may be a feasible method for the early and accurate diagnosis of ALS. Therefore, future research should focus on the identification of reliable biomarkers—especially neuroimaging biomarkers—through autopsy. Standardizing the concept and definition of ALS and formulating clear diagnostic criteria will largely avoid many uncertainties in the future clinical research and treatment of ALS, which will greatly benefit patients.

Current application of neurofilaments in amyotrophic lateral sclerosis and future perspectives

Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far.Unfortunately,diagnostic and prognostic biomarkers are lacking in clinical practice.Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum.Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis,reflecting the extensive damage of motor neurons and axons.Hence,neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis.The potential usefulness of neurofilaments regards various aspects,including diagnosis,prognosis,patient stratification in clinical trials and evaluation of treatment response.In this review paper,we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis.We also discuss the open issues concerning the use of neurofilaments clinical practice,as no overall guideline exists to date;finally,we address the most recent evidence and future perspectives.

Ultra-early amplitude decrement after repetitive nerve stimulation supports early neuromuscular junction injury in amyotrophic lateral sclerosis:a prospective cross-sectional study

The dying-back hypothesis holds that the damage to neuromuscular junctions and distal axons in amyotrophic lateral sclerosis occurs at the earliest stage of the disease.Previous basic studies have confirmed early damage to neuromuscular junctions,but it is difficult to obtain such evidence directly in clinical practice.In this prospective cross-sectional study,we recruited 22 patients with early amyotrophic lateral sclerosis with disease duration < 12 months and with clinical symptoms limited to the upper limbs.We also recruited 32 healthy controls.Repetitive nerve stimulation was performed,and patients were followed for 12 months.We found a significant change in the response to repetitive nerve stimulation in amyotrophic lateral sclerosis patients without spontaneous electromyographic activity.Patients that were prone to denervation had an increased decrement response of target muscles after repetitive nerve stimulation.These results suggest that changes in response to repetitive nerve stimulation may occur before denervation in amyotrophic lateral sclerosis patients.The damage to lower motor neurons is more obvious in patients with a higher percentage of repetitive never stimulation-related amplitude decrements.This study was approved by the Institutional Ethics Committee of Peking University Third Hospital(approval No.M2017198) on August 24,2017.

Remodeling of astrocyte secretome in amyotrophic lateral sclerosis:uncovering novel targets to combat astrocyte-mediated toxicity

Amyotrophic lateral sclerosis(ALS)is an adult-onset paralytic disease characterized by progressive degeneration of upper and lower motor neurons in the motor cortex,brainstem and spinal cord.Motor neuron degeneration is typically caused by a combination of intrinsic neuronal(cell autonomous)defects as well as extrinsic(non-cell autonomous)factors such as astrocyte-mediated toxicity.Astrocytes are highly plastic cells that react to their microenvironment to mediate relevant responses.In neurodegeneration,astrocytes often turn reactive and in turn secrete a slew of factors to exert pro-inflammatory and neurotoxic effects.Various efforts have been carried out to characterize the diseased astrocyte secretome over the years,revealing that pro-inflammatory chemokines,cytokines and microRNAs are the main players in mediating neuronal death.As metabolomic technologies mature,these studies begin to shed light on neurotoxic metabolites such as secreted lipids.In this focused review,we will discuss changes in the astrocyte secretome during ALS.In particular,we will discuss the components of the reactive astrocyte secretome that contribute to neuronal death in ALS.

Progressive muscle cramps with pain as atypical initial presentations of amyotrophic lateral sclerosis:a case report

Amyotrophic lateral sclerosis(ALS)is the most common form of motor neuron disease and is a progressive and devastating neurodegenerative disease that affects both lower and upper motor neurons.Muscle cramps,which are characterized by a sudden,painful,involuntary contraction of muscles,are not rare in ALS patients.However,muscle cramps do not normally present early in ALS and therefore not used for the initial diagnosis of ALS.In this paper the authors present a case of ALS with initial manifestation of progressive painful muscle cramps in the absence of muscle weakness.This case might help people to recognize atypical foremost presentations of ALS and therefore formulate effective therapies.