Motor neurone disease (MND) is a relatively uncommon neurodegenerative illness, resulting in progressive weakness of all muscle groups, with death most frequently as a result of respiratory complications [1▪]. The lifetime risk of MND is 1 in 1000, and the incidence of MND is 5–7 per 100 000 population [1▪], with a slight male predominance of 1.7 : 1. There is no cure for this relentless progressive disease. Riluzole has been shown to prolong survival by 3–4 months. The median survival of patients ranges between 27 and 64 months. Scotton et al.[2▪] have attempted to classify MND patients into prognostic categories using six variables: age of onset, diagnostic delay, El Escorial category, riluzole, sex and site of onset [1▪].
In the majority of patients, there is a combination of both upper motor neuron (UMN) and lower motor neuron (LMN) involvement, the so-called ‘typical MND’ (Amyotrophic Lateral Sclerosis). There is now evidence that MND is not restricted only to the motor system. The clinical spectrum includes often subtle behavioural changes, including dysexecutive impairment, altered behaviour and frontotemporal dementia [2▪]. The majority of patients presents with limb weakness (60%) or bulbar (swallow, speech disturbance; 30%) involvement [3▪]. Rarely (3–5%), MND presents only with respiratory symptoms . In this small group of patients, there are common findings of male predominance, camptocormia (head drop), widespread fasciculations, initially preserved limb function and significant weight loss. A younger age at onset is associated with a poorer prognosis.
Most patients with MND have sporadic disease. A genetic basis for MND has been considered to account for only 5% of all MND diagnoses; however, the expanding genetic understanding is changing this landscape. Clinicians involved in MND clinics have observed that patients with MND have a tendency to greater overall cardiovascular fitness and lower BMI [5▪].
There is published evidence of improved survival by the involvement of patients with MND in a specialized multidisciplinary clinic . Clinicians who have infrequent contact with MND patients may feel overwhelmed with the complexity of care required and ‘may not recognize the significance of progressive symptoms, or over-interpret relatively benign symptoms’ [7▪].
This review will focus on the respiratory issues that patients, families and clinicians face in the progression of MND. Unlike other areas of medicine and research, there is a paucity of evidence-based medicine to help guide clinicians caring for patients with MND. Miller  highlights these gaps in the 2009 ‘Practice Parameters Update for the care of MND’. Guidelines for care are often based on the ‘clinical experience, expert opinion and observational research’.
BREATHLESSNESS: THE CONCEPT
Breathlessness (dyspnoea) is a complex symptom that can evoke significant distress. There are many descriptions for breathlessness, most of which have explored the language that patients with chronic obstructive pulmonary disease (COPD) use to describe the symptoms. These include tired, air hunger, tightness, suffocation, panic and fatigue. A patient with asthma may describe tightness of the chest, but patients with MND will not [9▪]. Our understanding of the pathophysiology of dyspnoea is poor. The emotional response to dyspnoea can result in panic, which may initiate a vicious circle increasing the work of breathing leading to escalation of panic and worsening of symptoms. This ultimately may result in an emergency admission to a hospital.
Simon [10▪] in semi-structured interviews examined the differences in the sensation of breathlessness in patients with either MND, COPD, lung cancer or cardiac failure. Nine of the fifty-one patients had MND. In this group of patients, seven out of nine described dyspnoea which was triggered as a predictable response to effort, such as activities of daily living. Patients not only reported that activities may be deliberately avoided or curtailed to minimize symptoms, but also appreciated that these episodes of breathlessness which were triggered by an activity were alleviated when rest was allowed. This is in stark contrast to the unpredictable episodes of dyspnoea which can quickly escalate into panic. Patients with MND may experience a variety of respiratory symptoms, including hypoventilation, dyspnoea with exertion, orthopnoea and, ultimately, ventilatory failure .
Many patients with MND will have normal pulmonary parenchyma. It is the wasting of the diaphragm, intercostal muscles and accessory muscles which results in the sensation of dyspnoea.
MND involves a continual series of losses, with consequences for employment, independence, future, relationships and intimacy . Breathlessness is just one of the many symptoms that patients with MND suffer from, and its management requires collaboration by treating health professionals. It requires integrated care to provide education, support and symptom management. The palliative care teams are ideally suited to help provide this.
Unfortunately, despite considerable work to date, our understanding of the physiology of dyspnoea is rudimentary and our management strategies are yet to provide complete relief from this very distressing symptom.
OPIOIDS AND BREATHLESSNESS
Opioids have been used for over a decade for refractory dyspnoea [13,14], with demonstrated safety and efficacy, resulting in clinical and statistical improved dyspnoea scores using 0–100 mm Visual Analogue Scales (VAS). There are many myths surrounding the use of opioids for dyspnoea, including the concerns that respiratory failure will ensue with their use. Several studies have now demonstrated safety utilizing transcutaneous CO2 (tcpaCO2) or end-tidal CO2 measurements (ETCO2) [11,15], and long-term use and safety is demonstrated in a phase II incremental dose and pharmacovigilance study . In this study, participants with refractory breathlessness were commenced on 10 mg of slow-release oral morphine daily and further dose increases were allowed if a 10% improvement in breathless was not achieved, up to a maximum dose of 30 mg daily. Seventy percent of participants improved at 10 mg per 24 h. For every 16 people commenced on the medication, 1 person responded. For every 46 people commenced on the medication, one person withdrew because of side-effects. The improvement in breathlessness was maintained at 3 months in one-third of all participants who commenced the study. Constipation was the most common side-effect. There were no admissions to hospital as a result of the use of morphine and no episodes of respiratory depression.
Although there has been considerable progress in the understanding of dyspnoea and the role of opioids for refractory breathlessness, there are considerable gaps in our knowledge. Johnson [17▪] highlights these issues, which include ‘is there a class effect of opioids?’, ‘which sub-groups of patients may derive most benefit?’, route of administration, and is there synergism of benzodiazepines and opioids in the relief of breathlessness? The majority of the work to date has been undertaken in patients with COPD. Regarding MND, there is an urgent need to complement the work being undertaken with noninvasive ventilation (NIV), with increasing the knowledge surrounding the role of opioids for breathlessness in this group of patients. Are the results for patients with COPD and refractory breathlessness similar in MND patients? What are the side-effects? What is the optimal dose regime? What is the most effective and tolerable delivery device [18▪], especially given the presence of bulbar symptoms in many patients with MND. In the Practice Parameter Update , there is no mention of the use of opioids in the respiratory section. In a study of neurologists and the care of MND patients [19▪], over half are using opioids in the palliative care setting for breathlessness. The evidence base to inform this practice is lacking.
NONINVASIVE VENTILATION IN MOTOR NEURONE DISEASE
Ultimately, the majority of patients with MND will have respiratory symptoms, culminating in respiratory failure. A number of these patients will derive significant benefit from the use of NIV. There has been increasing use of NIV in patients with MND over the last decade [19▪], but in the Cochrane review ‘Update in mechanical ventilation in MND’ published in 2013 [20▪], there were no new randomized trials found to add to the original review. The Bourke study published in 2006  stands as the only randomized controlled trial of NIV in MND. Forty-one patients were randomized to NIV or standard care. For those on NIV, there was both a survival advantage of 48 days and an improvement in the quality of life (QoL), with this benefit most apparent in those patients with normal or only moderate bulbar dysfunction. The median survival in this group was 205 days, and QoL (SF36) was maintained for most of this period. In those patients with severe bulbar involvement, there was a slight improvement in the sleep quality and an improvement in dyspnoea, but no survival benefit was apparent with NIV.
Sleep disturbance in MND is multifactorial, with respiratory factors, sialorrhoea and pain potentially contributing. A pilot study of 12 patients with MND [22▪] examined paired baseline sleep studies and sleep studies with NIV. Overall oxygen saturation improved with the use of NIV; however, there were no improvements noted in sleep efficiency, arousals or the frequency of respiratory events when using NIV. This pilot study was too small to enable analysis of those with bulbar symptoms, orthopnoea or hypercapnia. Further larger studies are required. Importantly, these sleep studies were conducted using ambulatory devices in the patient's home environment, a technique which now has a strong evidence base in sleep medicine [23▪].
The predefined criteria for entry into the Bourke study was orthopnoea with a maximum inspiratory pressure (PIMax) less than 60% predicted and symptomatic hypercapnia. There are a number of investigations used to assess respiratory function and the need for NIV. Symptoms including morning headache, daytime drowsiness and orthopnoea are important to assess at each clinic visit. Investigations that are useful include arterial blood gas, forced vital capacity (erect and supine), inspiratory and expiratory maximal pressures and sniff nasal inspiratory pressure (SNIP). As facial musculature weakens, these test become less reliable. They are also dependent on patient effort, which may prove difficult in a patient who is fatigued. Clinically, the most useful parameters appear to be symptoms and an arterial blood gas. The National Institute for Clinical Excellence (NICE) Guidelines  recommend the use of FVC less than 50%, or less than 80% with symptoms, orthopnoea, and SNIP or maximal inspiratory pressure less than 40 or 65 cm, respectively, with symptoms.
The use of noninvasive assessment of gas exchange is gaining an evidence base. Using a transcutaneous carbon dioxide (PtcCO2) monitor (TOSCA 500) [25▪], in a prospective observational cohort sample of clinic patients with MND, PtcCO2 was compared to an arterialized capillary blood gas from the ear lobe. The Pearson's correlation coefficient of 0.808 was highly statistically significant (P < 0.0001), providing evidence that the TOSCA is reasonably accurate for assessing PtcCO2. Patients preferred the noninvasive method over the pin prick associated with a capillary blood gas. The hope is that with experience, more noninvasive methods of assessment may be included in guidelines in the future.
Diaphragm pacing for MND is a current topic of interest, and many patients enquire regarding its use. At this point in time, the evidence supporting its use is limited and remains under the Humanitarian Device Exemption (HDE) with the United States Food and Drug Administration (FDA) [26▪]. The authors in their summary state the ‘clinical effectiveness and long term safety concerns remain to be addressed’.
WITHDRAWAL FROM VENTILATION
There is considerable concern with the use of NIV that ultimately with the progression of MND, the ability of the equipment to maintain adequate gas exchange is finite, and this raises the clinical conundrum of ‘withdrawal from ventilation’ [27▪]. In qualitative interviews of carers following the death of the patient with MND, the key themes that emerged included ‘unexpected speed of deterioration’, hospitalization versus dying at home, resuscitation attempts, decision making regarding withdrawal from NIV (particularly professional healthcarers) and positive impacts of NIV use. Participants reported that the death had been peaceful, and ‘choking to death’ had not been a reality. This study not only highlights the importance of planning, but also provides warning to patients and family that clinical deterioration can occur suddenly. Emphasis is placed on ongoing discussion at clinical consultations of end-of-life plans, particularly to avoid unnecessary intervention such as clinically futile resuscitation attempts. The dissemination of advanced care plans is essential to enable patient's wishes to be carried out.
In a prospective study to assess the impact of education for both patients and carers regarding the use and role of NIV in MND [28▪], uncertainty about ventilator decisions was reduced from 75 to 4% and 65 to 24% for patients and carers, respectively. Critically, there was a close correlation (76%) between decisions made at time 1 after education and at time 4 (when faced with commencing NIV), often despite a considerable time lapse between T1 and T4, underscoring the importance of an education programme to confirm or establish informed decisions. Patients uniformly felt the education programme had reduced their anxiety about ventilation.
It is well established that involvement in a multidisciplinary setting improves the management and care of patients and families with MND [7▪]. There is an increasing understanding of breathlessness, its language, meaning and impact on the QoL, and emerging evidence regarding its management, particularly with opioids and NIV. Proactive education appears to reduce patient knowledge and anxiety, and aids decision making. There are many unanswered questions and further research is required into the aspects of overall QoL , impact of NIV, quality of sleep, when to initiate NIV and what investigations to base this decision on [30▪]. What is the role of cough augmentation in patients with MND and NIV? What are the optimal pharmacological strategies to provide comfort when NIV is no longer effective or when a patient decides to withdraw from ventilator support?
Conflicts of interest
Declaration of interest: The author reports no conflicts of interest. The author alone was responsible for the content and writing of this article.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1▪. Rafiq MK, Proctor AR, McDermott CJ, Shaw PJ. Respiratory management of motor neurone disease
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This review provides an excellent overview of respiratory physiology and ventilator failure. It has tips for symptom assessment, the use and initiation of NIV, and includes practical aspects of care of the ventilated patient. Importantly a section on withdrawal of ventilation and palliative care strategies is included
2▪. Scotton WJ, Scott KM, Moore DH, et al. Prognostic categories for amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012; 13:503–508.
This paper highlights six clinical variables which are easily collected which may help in this difficult area.
3▪. Baumer D, Talbot K, Turner MR. Advances in motor neurone disease
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This review has a good overview of the clinical features of MND. The section summarising emerging genetic knowledge, pathogenesis and biomarkers simplifies a complicated area of knowledge.
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This paper summarises the observations that patients with MND tend to have fewer co-morbid illnesses. Large health databases from hospital admissions are utilised for this comparison.
6. Traynor BJ, Alexander M, Corr B, et al. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996–2000. J Neurol Neurosurg Psychiatry 2003; 74:1258–1261.
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This editorial highlights the complexity of care of MND patients and the importance of a multi-disciplinary approach to care.
8. Miller RG, Jackson CE, Kasarskis EJ. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug nutritional and respiratory therapies (an evidence-based review). Neurology 2009; 73:1218–1226.
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Our knowledge of the mechanisms of dyspnoea is rudimentary, and the mechanism of symptom relief with opioids primitive. Hallenback explores the pathophysiology of dyspnoea and the pharmacology of opioids, and acknowledges our understanding is far from complete. He invites us to “expand, refine or refute this understanding”.
10▪. Simon ST, Higginson IJ, Benalia H, et al. Episodes of breathlessness
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This qualitative study examines the sensation and experience of breathlessness in 51 patients with either MND (9/51), heart failure, lung cancer or COPD. They hope that understanding different patterns of breathlessness may help to tailor treatment strategies. Further work is required prior to clinical recommendations being adopted.
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17▪. Johnson MJ, Abernethy AP, Currow DC. Gaps in the evidence base of opioids for refractory breathlessness
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Johnson provides an overview of the current understanding of the role of opioids for breathlessness, and highlights the marked areas of uncertainty and guides us with potential future study designs to help answer these complex questions.
18▪. Simon ST, Niemand AM, Benalia H, et al. Acceptability and preferences of six different routes of drug application for acute breathlessness
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In order to improve compliance with medications, the mechanism of delivery is important, especially with bulbar symptoms in MND patients. Inhaled and sub-lingual were deemed most acceptable to MND patients, although prior experience may have influenced this. Effectiveness of the drug delivery must be considered, especially with weak bulbar and respiratory muscles.
19▪. O’Neill CL, Williams TL, Peel ET, et al. Non-invasive ventilation in motor neuron disease: an update of current UK practice. J Neurol Neurosurg Psychiatry 2012; 83:371–376.
This paper highlights the increased use of NIV in patients with MND over the last decade. The responses from the participating neurologists in this study emphasises the lack of consistency in assessing MND patients for possible NIV use.
20▪. Radunovic A, Annane D, Rafiq MK, Mustfa N. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Collaboration 2013; 3:
This updated review of NIV in MND failed to find any new randomised controlled trials of NIV since the original paper by Bourke (2006).
21. Bourke SC, Tomlinson M, Williams TL, et al. Effects of noninvasive ventilation
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22▪. Katzberg HD, Selegiman A, Guion L, et al. Effects of noninvasive ventilation
on sleep outcomes in amyotrophic lateral sclerosis. J Clin Sleep Med 2013; 9:345–351.
This paper explores the effects of NIV in MND patients sleep. The study only has 12 patients and focussed on physiological parameters. Mention is made of the utility of home monitoring and assessment of sleep. Given the nature of this illness, a focus on symptoms relief would have been more helpful.
23▪. Chai-Coetzer CL, Antic NA, Rowland LS, et al. Primary versus specialist sleep centre management of obstructive sleep apnoea and daytime sleepiness and quality of life: a randomised trial. JAMA 2013; 309:997–1004.
This paper emphasises the utility and success of ambulatory sleep assessment and management of obstructive sleep apnoea by family practitioners.
24. National Institute for Health and Clinical Excellence. 2010 Motor Neurone Disease
. The use of non-invasive ventilation in the management of motor neurone disease
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25▪. Rafiq MK, Bradburn M, Proctor AR, et al. Using transcutaneous carbon dioxide monitor (TOSCA 500) to detect respiratory failure in patients with amyotrophic lateral sclerosis: a validation study. Amyotroph Lateral Scler 2012; 13:528–532.
The collection of an arterial blood gas can be a painful experience. Rafiq and colleagues have demonstrated that the non-invasive assessment of respiratory failure with trans-cutaneous carbon dioxide measurement is acceptable and reproducible. Further work to refine this technique in MND patients is required.
26▪. Amirjani N, Kiernan MC, McKenzie DK, et al. Is there a case for diaphragm pacing for amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler 2012; 13:521–527.
This review article highlights the many unknowns with regards to diaphragm pacing in MND, and cautions it is still too early for open access to this procedure as clinical effectiveness and long term safety remain to be addressed.
27▪. Baxter SK, Baird WO, Thompson S, et al. The use of noninvasive ventilation
at the end of life in patients with motor neurone disease
: a qualitative exploration of family carer and health professional experiences. Palliat Med 2013; 27:516–523.
This qualitative paper asks family cares and professionals to reflect on the use of NIV at the end of life in patients with MND. Most considered it beneficial. There was uncertainty around care plans at the end of life. This highlights the importance of having a documented advanced care plan to help direct the care of the patient.
28▪. McKim DA, King J, Walker K, et al. Formal ventilation patient education for ALS predicts real-life choices. Amyotroph Lateral Scler 2012; 13:59–65.
This prospective study demonstrated the effectiveness of an education programme on NIV in MND. It enabled decision making for patients regarding the acceptability and use of NIV.
29. Zamietra K, Lehman EB, Felgoise SH, et al. Noninvasive ventilation
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30▪. Vrijsen B, Testelmans D, Belge C, et al. Noninvasive ventilation
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