Objectives: To review the outcome of acute ventilatory support in patients presenting acutely with respiratory failure, either with an established diagnosis of motor neurone disease (MND) or with a clinical event where the diagnosis of MND has not yet been established.
Methods: Outcome was reviewed in 24 patients with respiratory failure due to MND who received endotracheal intubation and intermittent positive pressure ventilation either at presentation or as a result of the unexpected development of respiratory failure. Patients presenting to local hospitals with acute respiratory insufficiency and requiring tracheal intubation, ventilatory support, and admission to an intensive therapy unit (ITU) before transfer to a regional respiratory care unit were selected. Clinical features of presentation, management, and outcome were studied.
Results: 24 patients with MND were identified, all being intubated and ventilated acutely within hours of presentation. 17 patients (71%) were admitted in respiratory failure before the diagnosis of MND had been made; the remaining seven patients (29%) were already known to have MND but deteriorated rapidly such that intubation and ventilation were initiated acutely. Seven patients (29%) died on ITU (between seven and 54 days after admission). 17 patients (71%) were discharged from ITU. 16 patients (67%) received long term respiratory support and one patient required no respiratory support following tracheal extubation. The daily duration of support that was required increased gradually with time.
Conclusion: When a patient with MND is ventilated acutely, with or without an established diagnosis, independence from the ventilator is rarely achieved. Almost all of these patients need long term ventilatory support and the degree of respiratory support increases with time as the disease progresses. The aim of management should be weaning the patient to the minimum support compatible with symptomatic relief and comfort. Respiratory failure should be anticipated in patients with MND when the diagnosis has been established.
This article describes noninvasive acute and long-term management of the respiratory muscle paralysis of high spinal cord injury (SCI). This includes full-setting, continuous ventilatory support by noninvasive intermittent positive pressure ventilation (NIV) to support inspiratory muscles and mechanically assisted coughing (MAC) to support inspiratory and expiratory muscles. The NIV and MAC can also be used to extubate or decannulate ‘unweanable’ patients with SCI, to prevent intercurrent respiratory tract infections from developing into pneumonia and acute respiratory failure (ARF), and to eliminate tracheostomy and resort to costly electrophrenic/diaphragm pacing (EPP/DP) for most ventilator users, while permitting glossopharyngeal breathing (GPB) for security in the event of ventilator failure.
Spinal cord injuries; Tetraplegia; Glossopharyngeal breathing; Assisted cough; Mechanical insufflation–exsufflation; Respiratory therapy; Noninvasive mechanical ventilation; Electrophrenic pacing; Diaphragm pacing
Patients with chronic obstructive pulmonary disease and congestive heart failure exacerbations, as well as pneumonia benefit from the use of non-invasive ventilation (NIV), due to increased patient comfort and a reduced incidence of ventilator-associated pneumonia. However, some patients do not tolerate NIV due to anxiety or agitation, and traditionally physicians have withheld sedation from these patients due to concerns of loss of airway protection and respiratory depression. We report our recent experience with a 91-year-old female who received NIV for acute respiratory distress secondary to pneumonia. The duration of NIV was a total time period of 86 h, using the bilevel positive airway pressure mode via a full face mask. The patient was initially agitated with the NIV, but with the addition of the dexmedetomidine, she tolerated it well. The dexmedetomidine was administered without a loading dose, as a continuous infusion ranging from 0.2 to 0.5 mcg/kg/hr, titrated to a Ramsey score of three. This case illustrates the safe use of dexmedetomidine to facilitate NIV, and improve compliance, which may reduce ICU length of stay.
Acute respiratory failure; agitation; critical care; dexmedetomidine; non-invasive ventilation; sedation
► Patients with COPD who are established on long-term home NIV do not display differences in the excitability of the corticospinal pathways to the respiratory muscles compared to patients with COPD who do not require NIV ► The excitability of intracortical facilitatory and inhibitory circuits assessed using paired transcranial magnetic stimulation is strongly correlated with indices of disease severity in patients with COPD, namely inspiratory muscle strength and hypercapnia respectively. ► Finally, although NIV did reduce the excitability of the corticospinal pathway to the diaphragm it did not, in contrast to previous findings in healthy subjects, alter the excitability of intracortical inhibitory or facilitatory circuits.
Chronic obstructive pulmonary disease is associated with altered cortical excitability. The relevance of this to the need for non-invasive ventilation is not known. We assessed the diaphragm response to transcranial magnetic stimulation in terms of motor threshold and latency as well as assessing intracortical excitability using paired stimulation in eight long-term users and six non-users of home ventilation with COPD. Overall, intracortical facilitation was strongly correlated with inspiratory muscle strength (r2 0.72, p < 0.001) whereas intracortical inhibition was correlated with PaCO2 (r2 0.51, p = 0.01). The two groups did not differ in motor evoked potential or latency, nor in the excitability of intracortical inhibitory or facilitatory circuits assessed using paired stimulation. The acute effect of isocapnic non-invasive ventilation was studied in six established ventilator users. Diaphragm motor evoked potential fell but there was no effect on intracortical facilitation or inhibition, implying an effect of neuromechanical feedback at brainstem or spinal level.
Transcranial magnetic stimulation; Diaphragm; Motor cortex; Paired stimulation
Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a neurodegenerative disorder of unknown aetiology. Progressive motor weakness and bulbar dysfunction lead to premature death, usually from respiratory failure. Confirming the diagnosis may initially be difficult until the full clinical features are manifest. For all forms of the disease there is a significant differential diagnosis to consider, including treatable conditions, and therefore specialist neurological opinion should always be sought. Clear genetic inheritance has been demonstrated in a minority of patients with familial ALS but elucidation of the biological basis of genetic subtypes is also providing important information which may lead to treatments for sporadic forms of the disease. In the absence of curative or disease modifying therapy, management is supportive and requires a multidisciplinary approach. If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.
Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative.
The authors’ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported.
The mean (± SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8±3.5 years and 0.90±0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8±3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years).
Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone.
Duchenne; Lung volume recruitment; Neuromuscular; Noninvasive ventilation; Ventilation
Motor neurone disease (MND) is a devastating condition. This preliminary study aims to identify relevant personal factors affecting the experience of living with MND from the perspective of persons with MND (pwMND) in an Australian cohort. A prospective cross-sectional survey of pwMND (n = 44) using an open-ended questionnaire identified personal factors that were categorised thematically. Standardised questionnaires assessed disease severity: depression, anxiety, and stress and coping strategies. Personal factors identified included demographic factors (socioeconomic status), emotional states (depression, anxiety, and fear), coping strategies (problem-based coping and denial), personality, beliefs (religious and personal values), attitudes (of the patient), and others (such as perceived support). An understanding of personal factors by treating clinicians is essential in the provision of optimal care in MND. This study may assist in the development of personal factors within the International Classification of Functioning, Disability, and Health for improved consensus of care and communication amongst treating clinicians.
Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.
Noninvasive ventilation (NIV) has been one of the major advances in respiratory medicine in the last decade. NIV improves quality of life, prolongs survival, and improves gas exchange and sleep quality in restrictive patients, but evidence available now does not allow us to establish clear criteria for prescribing NIV in patients with chronic respiratory failure due to COPD. On the basis of the available studies, NIV should not be used as a treatment of choice for all patients with COPD, even when disease is severe. However, there is more evidence that NIV has an important effect in these patients. In fact, a selected group of patients may well benefit from domiciliary mechanical ventilation, and we need to be able to identify who they are. Moreover, NIV can be a new strategy to improve exercise tolerance in COPD patients.
noninvasive ventilation; COPD
Diaphragm pacing, which entails electrical stimulation to the phrenic nerve, is an effective means of managing patients with ventilatory insufficiency and intact lowermotor-neurone innervation of the diaphragm. The pacing apparatus is used to pace the right and left hemidiaphragms alternately to avoid fatigue, which may damage the muscle irreversibly. Among the important benefits of pacing in quadriplegics with paralysis or respiratory muscles are the social and psychological advantages of not being dependent on a mechanical ventilator.
A 40 year old mother of three with autosomal dominant scapuloperoneal muscular dystrophy presented with severe neurogenic respiratory failure requiring nocturnal non-invasive ventilation (NIV). Because of the development of profound proximal muscular weakness as a consequence of the progressive nature of her neurological disease, she eventually was unable to apply and remove the facial interface to set up her NIV circuit. She therefore became dependent on her children and carers to start and stop NIV during the night. A rocking bed was successfully employed as an alternative to nocturnal NIV. Ventilation was facilitated by the passive movement of the diaphragm as a consequence of the movement of the abdominal contents under the effect of gravity. Benefit was demonstrated objectively by pulse oximetry and subjectively by the improvement in the patient's symptomatology and continued independence at night. The ease of use of a rocking bed should be borne in mind when the necessity for nocturnal ventilatory support in neuromuscular disease results in the potential loss of independence for a patient.
Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles.
We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD).
Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD.
Amyotrophic lateral sclerosis; Motor neuron disease; Orofacial apraxia; Primary lateral sclerosis; Tractography
Amyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE).
Using indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation).
NIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure.
NIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure.
Amyotrophic lateral sclerosis; Noninvasive ventilation; Energy expenditure; Diaphragm; Inspiratory neck muscles
Hypoventilation due to respiratory muscle atrophy is the most common cause of death as a result of amyotrophic lateral sclerosis (ALS). Patients aged over 65 years and presenting bulbar symptoms are likely to have a poorer prognosis. The aim of the study was to assess the possible impact of age and treatment with non-invasive ventilation (NIV) on survival in ALS. Based on evidence from earlier studies, it was hypothesized that NIV increases rates of survival regardless of age.
Eighty-four patients diagnosed with ALS were followed up on from January 2001 to June 2012. These patients were retrospectively divided into two groups according to their age at the time of diagnosis: Group 1 comprised patients aged ≤ 65 years while Group 2 comprised those aged > 65 years. Each group included 42 patients. NIV was tolerated by 23 patients in Group 1 and 18 patients in Group 2. Survival was measured in months from the date of diagnosis.
The median age in Group 1 was 59 years (range 49 – 65) and 76 years in Group 2 (range 66 – 85). Among patients in Group 1 there was no difference in probability of survival between the NIV users and non-users (Hazard Ratio = 0.88, 95% CI 0.44 – 1.77, p = 0.7). NIV users in Group 2 survived longer than those following conventional treatment (Hazard Ratio = 0.25, CI 95% 0.11 – 0.55, p <0.001). ALS patients in Group 2 who did not use NIV had a 4-fold higher risk for death compared with NIV users.
This retrospective study found that NIV use was associated with improved survival outcomes in ALS patients older than 65 years. Further studies in larger patient populations are warranted to determine which factors modify survival outcomes in ALS.
Amyotrophic lateral sclerosis; Survival; Non-invasive ventilation
the frequency and severity of coughing and choking episodes, possible
related factors, and their association with chest infections in
patients with motor neuron disease (MND).
patients with MND and 23 healthy volunteers were studied. Cough was
assessed using a questionnaire and a 3 day diary, and volitional cough
quantified by peak cough flow and sound intensity. Other clinical
symptoms, smoking habit, affective state, oral secretions, bulbar
signs, and quantitative assessments of swallowing and respiratory
function were documented.
MND coughed and choked significantly more often and to a greater degree
than the healthy volunteers (26 of 37patients with MND and 2 of 23 volunteers, p<0.001). Female sex, older age, abnormal speech, reduced
swallowing capacity, and low forced vital capacity (FVC)% predicted
were each significantly associated with excessive coughing and choking
episodes in patients with MND. Smokers had significantly more severe
and prolonged episodes of coughing and choking than non-smokers
(p<0.05). Patients with upper motor neuron bulbar signs had a greater
tendency to severe and prolonged episodes of coughing and choking than
those without (p<0.05). Chest infections were reported only rarely
among the patients who coughed and choked.
and choking episodes are common in patients with MND but infrequently
associated with overt chest infection. Upper motor neuron bulbar signs
may both promote factors (for instance, dysphagia) which trigger cough
and reduce volitional capacity to suppress it.
Hypoventilation due to respiratory insufficiency is the most common cause of death in amyotrophic lateral sclerosis (ALS) and non-invasive ventilation (NIV) can be used as a palliative treatment. The current guidelines recommend performing spirometry, and recording nocturnal oxyhemoglobin saturation and arterial blood gas analysis to assess the severity of the hypoventilation. We examined whether the respiratory rate and thoracic movement were reliable preliminary clinical signs in the development of respiratory insufficiency in patients with ALS.
We measured the respiratory rate and thoracic movement, performed respiratory function tests and blood gas analysis, and recorded subjective hypoventilation symptoms in 42 ALS patients over a 7-year period. We recommended NIV if the patient presented with hypoventilation matching the current guidelines. We divided patients retrospectively into two groups: those to whom NIV was recommended within 6 months of the diagnosis (Group 1) and those to whom NIV was recommended 6 months after the diagnosis (Group 2). We used the Mann Whitney U test for comparisons between the two groups.
The mean partial pressure of arterial carbon dioxide in the morning in Group 1 was 6.3 (95% confidence interval 5.6–6.9) kPa and in Group 2 5.3 (5.0–5.6) kPa (p = 0.007). The mean respiratory rate at the time of diagnosis in Group 1 was 21 (18–24) breaths per minute and 16 (14–18) breaths per minute in Group 2 (p = 0.005). The mean thoracic movement was 2.9 (2.2–3.6) cm in Group 1 and 4.0 (3.4–4.8) cm in Group 2 (p = 0.01). We observed no other differences between the groups.
Patients who received NIV within six months of the diagnosis of ALS had higher respiratory rates and smaller thoracic movement compared with patients who received NIV later. Further studies with larger numbers of patients are needed to establish if these measurements can be used as a marker of hypoventilation in ALS.
Amyotrophic lateral sclerosis; Hypoventilation; Non-invasive ventilation
The objective of this research was to develop a disease-specific measure for fatigue in patients with motor neurone disease (MND) by generating data that would fit the Rasch measurement model. Fatigue was defined as reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest.
Qualitative interviews were undertaken to confirm the suitability of a previously identified set of 52 neurological fatigue items as relevant to patients with MND. Patients were recruited from five U.K. MND clinics. Questionnaires were administered during clinic or by post. A sub-sample of patients completed the questionnaire again after 2-4 weeks to assess test-retest validity. Exploratory factor analyses and Rasch analysis were conducted on the item set.
Qualitative interviews with ten MND patients confirmed the suitability of 52 previously identified neurological fatigue items as relevant to patients with MND. 298 patients consented to completing the initial questionnaire including this item set, with an additional 78 patients completing the questionnaire a second time after 4-6 weeks. Exploratory Factor Analysis identified five potential subscales that could be conceptualised as representing: 'Energy', 'Reversible muscular weakness' (shortened to 'Weakness'), 'Concentration', 'Effects of heat' and 'Rest'. Of the original five factors, two factors 'Energy' and 'Weakness' met the expectations of the Rasch model. A higher order fatigue summary scale, consisting of items from the 'Energy' and 'Weakness' subscales, was found to fit the Rasch model and have acceptable unidimensionality. The two scales and the higher order summary scale were shown to fulfil model expectations, including assumptions of unidimensionality, local independency and an absence of differential item functioning.
The Neurological Fatigue Index for MND (NFI-MND) is a simple, easy-to-administer fatigue scale. It consists of an 8-item fatigue summary scale in addition to separate scales for measuring fatigue experienced as reversible muscular weakness and fatigue expressed as feelings of low energy and whole body tiredness. The underlying two factor structure supports the patient concept of fatigue derived from qualitative interviews in this population. All three scales were shown to be reliable and capable of interval level measurement.
Spinal muscular atrophy (SMA), a motor neuron disease (MND) and one of the most common genetic causes of infant mortality, currently has no cure. Patients with SMA exhibit muscle weakness and hypotonia. Stem cell transplantation is a potential therapeutic strategy for SMA and other MNDs. In this study, we isolated spinal cord neural stem cells (NSCs) from mice expressing green fluorescent protein only in motor neurons and assessed their therapeutic effects on the phenotype of SMA mice. Intrathecally grafted NSCs migrated into the parenchyma and generated a small proportion of motor neurons. Treated SMA mice exhibited improved neuromuscular function, increased life span, and improved motor unit pathology. Global gene expression analysis of laser-capture-microdissected motor neurons from treated mice showed that the major effect of NSC transplantation was modification of the SMA phenotype toward the wild-type pattern, including changes in RNA metabolism proteins, cell cycle proteins, and actin-binding proteins. NSC transplantation positively affected the SMA disease phenotype, indicating that transplantation of NSCs may be a possible treatment for SMA.
This review examines the commonly held premise that, apart from the Western Pacific forms, motor neuron disease (MND), has a uniform worldwide distribution in space and time; the methodological problems in studies of MND incidence; and directions for future epidemiological research. MND is more common in men at all ages. Age-specific incidence rises steeply into the seventh decade but the incidence in the very elderly is uncertain. A rise in mortality from MND over recent decades has been demonstrated wherever this has been examined and may be real rather than due to improved case ascertainment. Comparison of incidence studies in different places is complicated by non-standardised methods of case ascertainment and diagnosis but there appear to be differences between well studied populations. In developed countries in the northern hemisphere there is a weak positive correlation between standardised, age-specific incidence and distance from the equator. There is now strong evidence for an environmental factor as the cause of the Western Pacific forms of MND. A number of clusters of sporadic MND have been reported from developed countries, but no single agent identified as responsible.
One hundred and sixty one patients with motor neurone disease (MND), from the Lothian Region of Scotland, were studied in an attempt to identify factors important in disease aetiology. Onset of the disease was between 1961 and 1981 and the incidence was highest between 1968 and 1975. The probability of developing MND was greatest between the ages of 65 and 69, and a greater proportion of female patients than of males had onset in the bulbar muscles. Some 5% of patients had a positive family history of MND. There was no evidence that infective agents were important in the aetiology of the disease. There was a suggestion that the patient group contained a greater number of electrical workers, food, drink and tobacco workers, and rubber workers than would have been expected. However, a larger series of patients would be needed to confirm an increased susceptibility to MND in individuals engaged in these occupations.
The mechanisms leading to patient/ventilator asynchrony has never been systematically assessed. We studied the possible association between asynchrony and respiratory mechanics in patients ready to be enrolled for a home non-invasive ventilatory program. Secondarily, we looked for possible differences in the amount of asynchronies between obstructive and restrictive patients and a possible role of asynchrony in influencing the tolerance of non-invasive ventilation (NIV).
The respiratory pattern and mechanics of 69 consecutive patients with chronic respiratory failure were recorded during spontaneous breathing. After that patients underwent non-invasive ventilation for 60 minutes with a "dedicated" NIV platform in a pressure support mode during the day. In the last 15 minutes of this period, asynchrony events were detected and classified as ineffective effort (IE), double triggering (DT) and auto-triggering (AT).
The overall number of asynchronies was not influenced by any variable of respiratory mechanics or by the underlying pathologies (that is, obstructive vs restrictive patients). There was a high prevalence of asynchrony events (58% of patients). IEs were the most frequent asynchronous events (45% of patients) and were associated with a higher level of pressure support. A high incidence of asynchrony events and IE were associated with a poor tolerance of NIV.
Our study suggests that in non-invasively ventilated patients for a chronic respiratory failure, the incidence of patient-ventilator asynchronies was relatively high, but did not correlate with any parameters of respiratory mechanics or underlying disease.
Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by selective death of motor neurons leading to spasticity, muscle wasting and paralysis. Human VAMP-associated protein B (hVAPB) is the causative gene of a clinically diverse group of MNDs including amyotrophic lateral sclerosis (ALS), atypical ALS and late-onset spinal muscular atrophy. The pathogenic mutation is inherited in a dominant manner. Drosophila VAMP-associated protein of 33 kDa A (DVAP-33A) is the structural homologue of hVAPB and regulates synaptic remodeling by affecting the size and number of boutons at neuromuscular junctions. Associated with these structural alterations are compensatory changes in the physiology and ultrastructure of synapses, which maintain evoked responses within normal boundaries. DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human diseases including locomotion defects, neuronal death and aggregate formation. Aggregate accumulation is accompanied by a depletion of the endogenous protein from its normal localization. These findings pinpoint to a possible role of hVAPB in synaptic homeostasis and emphasize the relevance of our fly model in elucidating the pathophysiology underlying motor neuron degeneration in humans.
The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls.
Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals.
Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.
Motor neuron disease; Amyotrophic lateral sclerosis; Toxicant; Heavy metal; Neurotoxin; Locus ceruleus; Motor neurons; Autometallography; Mercury; Sporadic ALS; Familial ALS
Ninety four neurologists in the United Kingdom, China, and West Germany responded to two structured questionnaires. The first assessed the diagnostic weighting assigned to a number of symptoms, signs, and clinical investigations ascertained from classical descriptions and case notes of patients with motor neuron disease (MND). The second tested the likelihood and consistency of diagnosis in a series of case summaries representing the clinical data of 10 patients with clinically and pathologically documented motor neuron disease. There was a wide measure of agreement concerning the common clinical features of the disease, especially regarding fasciculation of the tongue, fasciculation associated with weakness seen in more than one limb, and dysphagia. In the case summaries, however, there was clear variation in the ranked likelihood of the diagnosis of MND and in the consistency of diagnostic behaviour in the different groups of neurologists. These findings support the need for internationally agreed criteria in the diagnosis of MND. Any such criteria will need to be tested against a standardised data set to establish their validity.
Non-invasive ventilation (NIV) can increase exercise tolerance, reduce exercise induced desaturation and improve the outcome of pulmonary rehabilitation in patients with chronic respiratory disease. It is not known whether it can be applied to increase exercise capacity in patients admitted with non-hypercapnic acute exacerbations of COPD (AECOPD). We investigated the acceptability and feasibility of using NIV for this purpose.
On a single occasion, patients admitted with an acute exacerbation of chronic respiratory disease who were unable to cycle for five minutes at 20 watts attempted to cycle using NIV and their endurance time (Tlim) was recorded. To determine feasibility of this approach in clinical practice patients admitted with AECOPD were screened for participation in a trial of regular NIV assisted rehabilitation during their hospital admission.
In 12 patients tested on a single occasion NIV increased Tlim from 184(65) seconds to 331(229) seconds (p = 0.04) and patients desaturated less (median difference = 3.5%, p = 0.029). In the second study, 60 patients were admitted to hospital during a three month period of whom only 18(30)% were eligible to participate and of these patients, only four (7%) consented to participate.
NIV improves exercise tolerance in patients with acute exacerbations of chronic respiratory disease but the applicability of this approach in routine clinical practice may be limited.