Introduction

Respiratory muscle weakness occurs in a broad variety of muscle disorders, typically in the context of severe and diffuse muscle weakness, and manifests itself relatively late in the disease course. The clinical presentation of early neuromuscular chronic respiratory failure (ERF, i.e. chronic-onset respiratory muscle weakness whilst the patient is still ambulant) is rare, but represents a distinct diagnostic category requiring a different approach and differential diagnosis. In this clinical situation, the conditions which should be considered first include amyotrophic lateral sclerosis and myasthenia gravis, and these are the most common non-muscle diseases with this presentation. If these conditions are excluded in a patient, there remains a challenging differential diagnosis of several muscle conditions. This review will focus on a clinical approach to the diagnosis of chronic muscle diseases that present with ERF.

Mechanisms of chronic neuromuscular respiratory failure

ERF may occur in muscle disease due to the following mechanisms. Weakness of respiratory muscles (including diaphragm and/or intercostal muscles, or accessory respiratory muscles) can directly result in respiratory insufficiency due to respiratory pump failure. Weakness begins insidiously but becomes more severe, and hypoventilation ensues with rise in arterial carbon dioxide and consequent proportional fall in arterial oxygen. However, additional factors which may coexist in particular muscle diseases, such as kyphoscoliosis, and chest wall deformity which are associated with restrictive changes in pulmonary physiology or weakness of pharyngeal and laryngeal muscles which may additionally compromise airway clearance and predispose to aspiration and pneumonia. Muscle contractures or muscle fibrosis may also occur in respiratory muscles and limit chest movement, thus increasing the work required for adequate respiratory function. Some muscle diseases also have a contribution of abnormal central respiratory control (for example myotonic dystrophy type 1). Furthermore the innervation of respiratory muscles can be compromised, as in certain motor neuropathies (most commonly amyotrophic lateral sclerosis), or via abnormal neurotransmission (as in myasthenia gravis). Finally, all of the above can contribute to susceptibility to atelectasis or respiratory tract infection causing a disproportionate reduction in arterial partial pressure of oxygen (PaO2).

Clinical presentation of early respiratory failure

Patients with ERF due to chronic muscle diseases will typically be referred to out-patient clinics in neurology or respiratory medicine for assessment of unexplained dyspnoea, orthopnoea, or sleepiness (Box 1). Typical sleep symptoms resemble those of obstructive sleep apnoea, and include sleep disruption, morning headache, and hypersomnolence [1]. These symptoms may result from fragmented sleep, nocturnal hypoventilation with consequent hypercapnia, or both. The nocturnal hypoventilation is most pronounced during REM sleep as muscle weakness is further aggravated by REM muscle atonia. In response individuals may become REM avoidant and less restorative, and stage 1 sleep will be increased [2]. Respiratory complaints may also predominate with symptoms due to diaphragmatic weakness such as orthopnoea, dyspnoea on bending forward, or dyspnoea on immersion into a pool. Dyspnoea on exertion is a variable finding which will depend on the level of exertion of an individual. First presentation with recurrent chest infections or choking episodes may point to laryngeal dysfunction or other impairment in airway clearance. The former can precipitate acute physiological decompensation, sometimes resulting in admission to intensive care. Physical signs of respiratory failure (RF) include tachypnoea, slow speech, use of accessory respiratory muscles at rest, and loss of chest-abdomen respiratory synchronisation/abdominal paradox where the abdomen moves out of phase with the rib cage [3]. An audibly ineffectual cough may also be present [4]. These symptoms are often very subtle and progress insidiously over months or years. The RF may be frequently misdiagnosed as obstructive sleep apnoea, asthma, or chronic obstructive lung disease (COPD). As a result, RF due to neuromuscular disease can go unrecognised for prolonged periods until it becomes advanced and presents acutely due to an exacerbating increase in respiratory demand such as an infection or pulmonary embolism. Eventually, chronic RF can result in severe disability, susceptibility to pulmonary and other medical complications, and death.

Diagnostic evaluation

In patients with the above symptoms, various diagnostic tests can confirm the presence of RF.

Sleep testing

Sleep testing may reveal sleep apnoea or nocturnal hypoventilation. Most causes of neuromuscular weakness will be associated with nocturnal hypoventilation once the vital capacity has fallen to 60 %. Obstructive sleep apnoea (OSA) may be evident if obesity is more prominent or if muscles of the upper airway are involved. Central sleep apnoea (CSA) will rarely be seen due to derangements in the control of ventilation more prominent in sleep than wakefulness, this is the case in myotonic dystrophy. In considering specific testing, overnight oximetry is often readily available and convenient for patients. It is likely to show prolonged periods of hypoxaemia if nocturnal hypoventilation is present or intermittent hypoxia if OSA or CSA is present. A pattern of periodic desaturation may suggest REM-related OSA or hypoventilation. The addition of transcutaneous PCO2 monitoring, if available, will show a rise in CO2 corresponding to the period of hypoventilation, but is not essential to diagnose ERF. A rise of 10 mmHg in the CO2 or above a peak of 55 mmHg for 10 min is consistent with nocturnal hypoventilation. Home cardiorespiratory monitors will provide further details of the respiratory flow contour to differentiate between central and obstructive events but are not validated for use in diagnosis of neuromuscular disorders. These monitors may include respiratory effort bands which may reveal abdominal paradox, and also contribute to differentiating central from obstructive apnoea. Full polysomnography (PSG) should be considered in patients with report of significant sleep disruption/insomnia or who are likely to fail home monitoring due to poor co-ordination related to muscle weakness. PSG provides additional information on sleep duration and sleep state allowing greater certainty of the diagnosis. PSG can also be used as a setting for initiation/titration of ventilator therapies [5]. Daytime arterial blood gas measurement will confirm decreased PaO2 and elevated PaCO2 in advanced disease. The pH will be low or normal, depending on the duration of hypercapnia. The latter may have gone unrecognised for some time, and occasionally, chronic hypercapnia may be suggested in retrospect by finding a previously elevated venous bicarbonate concentration [6].

Pulmonary function testing

Pulmonary function in respiratory muscle weakness characteristically shows a restrictive ventilatory defect, with a reduced vital capacity (VC) and normal ratio with the forced expiratory volume in 1 s (FEV1 to FVC >0.7). Due to the direct effect of expiratory weakness, peak expiratory flows are typically reduced, but the finding is nonspecific and any abnormal result should be followed by spirometry. Similarly reserve volume will be found to be increased due to weakness in expiratory muscles. Spirometry may have an egg-shaped appearance due to the lack of a sharp rise in expiratory flow and an abrupt end to the effort. Hypercapnic respiratory failure is particularly likely with a VC of less than 15 ml/kg, an absolute value of 1 l, 50 % of predicted and/or a decrease in VC of greater than 20–30 % whilst recumbent compared with the standing position [4, 7]. The latter is a characteristic of severe bilateral diaphragmatic weakness or paralysis and reflects the difficulty in displacing the abdominal contents without the aid of gravity when in the supine posture. Respiratory muscle function can be assessed directly by measuring maximum respiratory pressures during forceful voluntary manoeuvres with airway occlusion, with measurements made either statically at the mouth or in the nostril during a forceful sniff with the other nostril occluded. Levels suggestive of inspiratory muscle weakness are maximal inspiratory pressure less than −30 cmH2O, maximal expiratory pressure of <40 cmH2O, or a nasal sniff pressure of less than 32 % of predicted [1] whilst values greater than 80 cmH2O for men, or 70 cmH2O for women and sniff nasal inspiratory pressure greater than 70 cmH2O for men, or 60 cmH2O for women exclude neuromuscular weakness [8]. Further testing is required for patients in the indeterminate zone between these cut-offs. It should be noted that maximum pressures are, by definition, strictly effort dependent and therefore are not “fail safe”; it is essential to ensure maximal cooperation and effort, and several practice attempts may be required before achieving reproducible and valid results. Bulbar weakness preventing proper mouth seal can also falsely lower results. Maximum pressure measurements are generally more sensitive than VC to milder degrees of respiratory muscle weakness, but by the time hypercapnia develops, VC would be expected to be severely reduced to below 50 % of predicted. Recurrent infection or other evidence of a poor cough should prompt measurement of the peak cough flow (PCF). A peak cough flow of less than 270 l/min is suggestive that cough assist techniques should be implemented whilst at less than 160 l/min the aforementioned complications are likely. [4] Chest physiotherapy by techniques including cyclical breathing, huffing, or percussion may aid in secretion mobilisation but alone is likely to prove ineffective [4].

Pulmonary imaging

Chest radiography or CT scanning may demonstrate coexistent scoliosis which may contribute to RF, and may also be helpful to exclude coexistent pulmonary parenchymal disease. Dynamic imaging by ultrasound or fluoroscopy can be used to assess diaphragmatic motion and confirm diaphragmatic weakness [1, 7].

Finally, other causes of RF should also be ruled out as appropriate to the clinical situation and may entail further respiratory, cardiovascular, neurological, and toxicological investigations (Fig. 1).

Fig. 1
figure 1

Algorithm for diagnosis and treatment of chronic muscle disease presenting with early respiratory failure. CK creatine kinase, GAA acid α-glucosidase, PM polymyositis, DM dermatomyositis, RRF ragged red fibres, COX cytochrome c oxidase, PCR polymerase chain reaction, mtDNA mitochondrial DNA, LGMD limb-girdle muscular dystrophy, HIV human immunodeficiency virus, SPEP serum protein electrophoresis

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Differential diagnosis of muscle diseases

Numerous neuromuscular diseases include RF as a component, although this is most frequent towards the end of the disease course, and a discussion of these is beyond the scope of this review. Of these, chronic neuromuscular disorders presenting with ERF are a distinct entity and the differential diagnosis for this group is summarised in Table 1. Of these, the most important conditions that are not primary muscle diseases are amyotrophic lateral sclerosis and myasthenia gravis. For both of these conditions, ERF as an initial presentation of the disorder is common (about 3 % of patients with ALS [9], and 14 % of patients with myasthenia gravis [10]). Because this work focuses on muscle diseases these conditions will not be reviewed in detail. It should also be noted that some of these conditions (namely myasthenia gravis) can also present with acute respiratory failure, and that any of these conditions may present acutely in combination with another illness (such as respiratory infection or drug toxicity).

Table 1 Chronic neuromuscular disorders which present with early respiratory failure
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Table 2 summarises those conditions which are muscle diseases, which will be the focus of this article, and for purposes of this review the conditions will be discussed in these broad aetiological categories. It is important to emphasise that for some of these conditions, ERF is a typical presentation of the disease, and we distinguish diseases that have ERF as a typical versus uncommon presentation, in Table 2. Although some of the conditions have only few reported cases with this clinical presentation, some of these have management implications and should still be considered in the initial differential diagnosis, and these have also been indicated in Table 2.

Table 2 Categories of muscle disease which may present with early respiratory failure
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Conditions which we have not included are disorders presenting with acute neuromuscular respiratory failure (which have been reviewed in detail elsewhere), as well as muscle diseases that have respiratory muscle weakness late in the clinical presentation (e.g. several years after onset of the condition, or in patients who are no longer ambulant due to diffuse severe muscle weakness, or when muscle weakness does not predominate at any point in the clinical phenotype).

Hereditary muscle diseases causing early respiratory failure

Metabolic myopathies

Late-onset Pompe disease

Also known as glycogen storage disease type II, this lysosomal storage disorder is caused by deficiency of acid α-glucosidase (GAA) and may present from infancy to late adulthood [11].

Late-onset Pompe disease (PD) is the prototype muscle disease which presents with ERF. The presentation of chronic respiratory muscle weakness in ambulant patients is one of the typical clinical presentations for PD [12], and respiratory failure is the most common cause of death [13]. Because this disease is potentially treatable with enzyme replacement therapy, reaching the diagnosis of PD is important. Unfortunately diagnosis is often delayed by several years on account of the rarity and phenotypic variability of this disease [14]. Recently, diagnostic guidelines for this condition were published [15]. To summarise, PD should be considered in patients with adult-onset proximal myopathy and/or respiratory muscle weakness. Testing for GAA enzyme activity is quickly and accurately achieved with dried blood spot testing and should be performed amongst the initial diagnostic tests [16]. The muscle biopsy classically demonstrates vacuolar glycogen accumulation, but can occasionally be normal [17]. Muscle tissue can also be used for GAA enzyme testing. When muscle pathology and enzyme activity are difficult to interpret, the diagnosis can be confirmed with GAA sequencing.

Treatment with alglucosidase alpha was evaluated in a placebo-controlled trial in adult-onset disease, significantly stabilising walking distance and pulmonary function [18]. The treatment was also demonstrated to be safe and effective in a 3-year observational study [19]. Since PD is progressive, treatment should be considered, though evidence for this treatment is recent, and long-term outcomes are unknown. Furthermore, patients may develop antibodies to the infusion [20], which leads to infusion-related reactions, and potentially decreased treatment efficacy [21], which requires further study in adult patients.

Other treatment options include nutrition and exercise programs designed to increase fatty acid utilisation by muscle, which may slow deterioration in this condition [22]. Prognosis in this condition is difficult to predict, since enzyme activity levels do not correlate with phenotype in late-onset PD. It has been suggested that respiratory dysfunction and low BMI are predictive of poor prognosis [23], although the latter claim has been disputed, suggesting that low BMI actually portended better response to treatment and thus better prognosis [24]. Another prognostic factor includes the presence of homozygous deletion polymorphism at intron 16 of the angiotensin converting enzyme gene (rs1799752), which is associated with poorer phenotype and prognosis [25]. It is likely that numerous genetic factors interact to produce the phenotype in individual patients, and as more of these are identified genomic medicine may identify individuals at higher risk for deterioration, and thus closer follow-up and intervention.

Mitochondrial myopathy

Mitochondrial myopathies are caused by primary dysfunction of the mitochondrial respiratory chain, and typically produce multisystem disease, on account of the fact that mitochondria are distributed throughout the body and required for energy production. Dysfunction is most likely to occur in tissues/organs with high energy requirements, therefore explaining that MM most often affects muscles (particularly extraocular muscle), and the nervous, cardiac, and endocrine systems. A detailed description of all mitochondrial myopathies, and their clinical characteristics, prognosis, diagnosis, and treatment is beyond the scope of this review, although this topic was recently reviewed in detail [26].

Clinically apparent respiratory dysfunction in mitochondrial myopathies appears to be an unusual finding: in recent series, respiratory dysfunction has similar prevalence to controls in patients with the m.3243A>G mutation [27], and was present in only one of 40 patients in a recent PEO series [28]. However, a recent study of 23 patients suggests that respiratory muscle weakness is common in PEO and is more likely to appear in patients with limb-girdle muscle weakness (although abnormalities of pulmonary function do not correspond to respiratory symptoms) [29]. In another study of 331 patients with unexplained dyspnoea, 28 (8.5 %) of these were diagnosed with respiratory muscle weakness due to mitochondrial myopathy [30]. This suggests that respiratory muscle weakness due to mitochondrial myopathy may be more common than that has been recognised. However, this study is limited due to the absence of genetic studies; therefore, misdiagnosis could have occurred depending on interpretation of the muscle pathology, which can be nonspecific. Referral bias may also have played a role.

Numerous case studies also report mitochondrial myopathy presenting initially with respiratory failure. Reports have identified families in which multiple individuals presented with respiratory failure, suggesting specificity of certain mutations for respiratory muscles. These families have mutations of tRNA genes at mitochondrial DNA (mtDNA) positions 3302 [31] and 3288 [32]. The other individual cases which have been genetically characterised are also due to tRNA gene mutations [33–35], and it is unclear why other types of mutations, or deletions, have not been described.

Other reports discuss patients who had presented with acute respiratory failure requiring ventilator support. In retrospect, they had experienced chronic respiratory symptoms which had been unrecognised, or had not come to medical attention [35–38]. In some instances, background respiratory dysfunction was worsened in the context of an acute illness or other metabolic stressors. As it is characteristic for metabolic stressors to expose subclinical metabolic diseases [39], mitochondrial myopathy should be considered in the differential diagnosis in these contexts.

It is important to mention that mitochondrial disorders also affect respiratory function via central mechanisms [40–43], that may be frequently symptomatic, or mimic the clinical presentation of respiratory muscle weakness (i.e. nocturnal symptoms of obstructive sleep apnoea [44, 45]).

Other causes

Individual cases of myophosphorylase deficiency [46] and debrancher enzyme deficiency [47] have been reported with respiratory failure as an initial presenting feature.

Inherited muscle diseases

Muscular dystrophies

Myotonic dystrophy type 1: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy and is a multisystem disorder caused by a noncoding CTG repeat expansion in the DMPK gene resulting in RNA hyperaggregation. The condition has autosomal dominant inheritance with high penetrance and variable expressivity, and maternal anticipation. Clinical features include frontal balding, atrophic facial muscles, distal myopathy with myotonia, and frequent involvement of the central nervous, ocular, endocrine, and cardiac systems.

The severity and likelihood of developing RF in DM1 correlate well with the severity of the phenotype [48]. Respiratory muscle weakness was demonstrated in one-third of 106 patients in one series, including some with only distal muscle weakness [48]. Uncommonly, DM1 patients develop overt RF whilst still ambulant, as the case for 3 patients (who had dyspnoea at rest) in one series [49]. Hypersomnolence is extremely common in DM1, affecting 69.8 % of patients in one recent series [50]; in some cases hypercapnia or sleep apnoea may contribute, but most evidence favours a neurological origin as the main cause in DM1 [51–53]. Sleep disorders are increasingly recognised in DM1 [51, 54]. Obstructive sleep apnoea, presumed due to weakness and hypotonia of upper airway muscles, is frequently found [50], particularly amongst those who are overweight and even without hypersomnolence [55].

Treatment for patients with symptomatic hypercapnia may include nocturnal non-invasive ventilation (NIV), although patients with DM1 tend to adapt less well to this form of therapy than those with respiratory failure due to other neuromuscular conditions [56]. There is insufficient evidence to recommend symptomatic treatment with stimulants for DM1 patients on the basis of randomised placebo-controlled data [57, 58].

Limb-girdle muscular dystrophy: Respiratory muscle involvement occurs in several muscular dystrophies, although as a rule this tends to occur late in the disease course, when there is generalised and severe muscle weakness. In limb-girdle muscular dystrophies (LGMD), respiratory failure is relatively uncommon for the majority of cases, and RF tends not to present even in advanced disease. The exceptions include LGMD2I (due to FKRP mutation) and LGMD 2C-F (sarcoglycanopathies) which commonly involve respiratory failure as a component of their disease course, and also may present with ERF in the context of limited limb muscle symptoms.

Mutations in the FKRP gene cause a broad disease spectrum which includes congenital myopathy (MDC1C), or proximal myopathy in childhood or adulthood (LGMD2I) [59]. Respiratory muscle weakness is a common complication in LGMD2I, affecting 10 of 16 patients in one series [60]. Respiratory failure may occur in patients whilst they are still ambulant, but, typically, this is after several years’ disease duration [61, 62]. In another series, five patients requiring nocturnal ventilatory support were still ambulant [63]. Furthermore, results of this series suggested that respiratory muscle weakness was more likely to be a prominent feature in individuals with later-onset disease [63].

LGMD2C-F are due to mutations in the sarcoglycans, which are proteins demonstrated to be integral to the function of diaphragmatic muscle [64]. For the sarcoglycanopathies, the usual clinical presentation involves childhood onset with severe proximal and eventually distal muscle weakness, with a clinical course resembling Duchenne muscular dystrophy. All patients with sarcoglycanopathies (LGMD2C-F) are likely to have some degree of respiratory failure, though this would appear to be most significant with LGMD2C and 2D [65]. Of these, LGMD2D (due to α-sarcoglycan mutations) has been reported to present with respiratory failure [66].

Inherited myopathies with myofibrillar pathology

Myofibrillar myopathies: Myofibrillar myopathies (MFM) are muscular dystrophies characterised by the pathological findings of Z-disc disorganisation and the abnormal accumulation of myofibrillar elements [67]. Respiratory muscle weakness is a common feature during the disease course of most MFM, including those caused by filamin [68], desmin [69], α B-crystallin [70], BAG3 [71], and a minority caused by myotilin mutations [72]. Of these, there are cases reported of patients presenting with respiratory failure in MFM due to mutations in desmin [69], α B-crystallin [70], and BAG3 [71]. The predilection for most of the MFM to affect the respiratory muscles (MFM caused by ZASP mutation has not been associated with respiratory muscle weakness) is not understood, although desmin has elevated expression in the diaphragm and may have a conformation particularly important to the function of this muscle [73].

Hereditary myopathy with early respiratory failure (HMERF): HMERF (OMIM #603689) is caused by mutations in the 119th fibronectin 3 domain of the giant sarcomeric gene titin (TTN) [74–76] and meets diagnostic criteria for MFM on muscle pathology [75, 76], as well as having similarities with other subtypes of MFM in clinical presentation and MRI abnormalities [77, 78]. The condition is common compared with other subtypes of MFM in the United Kingdom, probably owing to a founder effect [75], although another study of MFM patients in the United States found a similar prevalence [79], suggesting that the disease is internationally distributed and likely to be common in other populations as well. The original mutation associated with this condition is in the kinase domain of TTN [80] but appears to have also been associated with another mutation in the 119th fibronectin 3 domain [81], and further study will need to determine whether the kinase variant is pathogenic (it has also been found in normal controls and is listed as a low-frequency polymorphism in dbSNP: rs140319117). The condition typically presents with distal leg weakness and respiratory muscle weakness in mid-life, although broad phenotypic variability exists [77].

Inherited myopathies with other pathology

TPM3 myopathy: The tropomyosin-3 (TPM3) gene encodes a muscle protein required for actin binding. Myopathy caused by TPM3 mutations can be associated with a variety of disease phenotypes and muscle pathologies. Clinically, this disorder may present at any age from congenitally up into late adulthood. The phenotype includes hypotonia, muscle atrophy, and contractures in early-onset presentations [82, 83], and in adulthood, proximal myopathy often with respiratory failure [83]. Scoliosis and/or lumbar lordosis are commonly associated features, and can contribute to respiratory failure. This disease may show muscle pathology of congenital fibre-type disproportion myopathy [83], nemaline myopathy [84], or cap myopathy [85]. Inheritance may be autosomal recessive or dominant (potentially due to a dominant negative effect [86]). Respiratory failure as an early component of the disease, whilst patients are still ambulant, appears to be a typical presentation of this rare disease [83, 87]. TPM3 myopathy should be considered in the differential diagnosis when any of the above nonspecific muscle pathology findings are present, but particularly for congenital fibre-type disproportion [88].

FHL1-related syndromes: There is a very broad spectrum of muscle disease phenotypes caused by mutations in FHL1. Amongst these are early-onset muscle diseases such as reducing body myopathy, or rigid spine syndrome, as well as adult-onset muscle diseases such as X-linked myopathy with postural muscle atrophy (XMPMA), a scapuloperoneal syndrome, or an Emery–Dreifuss muscular dystrophy phenotype [89]. Interestingly, there is also phenotypic variability between individuals sharing the same mutation and founder haplotype [90]. FHL1 mutations can also present with the clinical and pathological features of MFM [91]. Amongst these phenotypes, XMPMA has been reported to have respiratory failure in ambulant patients [92, 93] and should be considered in adult-onset muscle disease having atrophy of postural muscles and hypertrophy of muscles with predominance of type II muscle fibres [93].

Oculopharyngodistal myopathy: This myopathy is characterised by ophthalmoparesis and ptosis, with pharyngeal and distal muscle weakness. Pathological changes include the presence of rimmed vacuoles, and inheritance pattern may be autosomal dominant [94] or recessive [95]. The genetic basis of this condition has not yet been discovered. In a recent study, 21 patients were studied with spirometry testing (18 of whom were still ambulant), and 13 had evidence of respiratory muscle involvement (8 of whom had daytime hypercapnia and 3 requiring nocturnal ventilatory support) [96]. The resemblance of this condition to PEO might present diagnostic confusion with mitochondrial myopathy, although distal muscle weakness is uncommon for mitochondrial disease, and muscle pathology markedly different.

Acquired myopathies presenting with early respiratory failure

Inflammatory myopathy

This category of disease includes polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). All these diseases are associated with subclinical respiratory muscle dysfunction, with DM patients more frequently affected [97]. In one study of 156 PM/DM patients, 21.8 % had respiratory muscle weakness, although it was not specified how this was ascertained [98]; although in general the impression is that respiratory muscle weakness rarely causes respiratory failure in these disorders [99]. Cases have been reported of PM presenting with respiratory failure: one in which respiratory failure was the first and predominant feature that progressed over three months [100]. In another case, the patient was admitted to intensive care and in retrospect probably had longstanding respiratory muscle weakness [101]. One case of antisynthetase syndrome had isolated respiratory muscle weakness [102] (although it should be emphasised that the more common cause of respiratory failure in these patients is interstitial lung disease). Other reports exist of patients having been admitted to the ICU for respiratory muscle weakness due to PM [103] or DM [104], (although it should be noted many of these presented acutely to hospital rather than with chronic ERF to ambulatory clinics); in the DM patients most of these were early in the course of their disease and the authors emphasise the high mortality for these patients [104]. There is also a case report of a patient with respiratory muscle weakness occurring 5 years after onset of limb symptoms in a patient with IBM [105]. All of these cases have in common that the consequences of respiratory muscle weakness in these conditions can be severe, and fortunately for PM and DM, treatment is available.

Sporadic adult-onset nemaline myopathy

Nemaline myopathy (NM) is a congenital myopathy which rarely presents in adulthood (6 out of 143 cases in the largest study of this disorder) [106]. It is defined by the presence of nemaline structures within muscle fibres on Gomori trichrome histochemistry and/or electron microscopy, within the context of a characteristic clinical picture.

Adult-onset nemaline myopathy (AONM) features several differences with the typical congenital form which presents neonatally or in early childhood. AONM is distinguished by late age of onset, and milder phenotype, which includes proximal myopathy, often with dysphagia, and respiratory muscle weakness [107]. Although numerous genetic causes exist for typical NM, and a family history is frequently present, the reported cases of AONM are most frequently sporadic, without genetic aetiology identified [106]. In these cases, the disorder may relate to other causes: AONM has been associated with HIV infection [108] as well as monoclonal gammopathy [107]. Furthermore, nemaline pathology is not a specific finding and has also been described in other inherited, endocrine, and inflammatory disorders [83, 109, 110].

Several cases of AONM presenting with respiratory failure have been reported [111–113], and respiratory failure is a recognised component of the disease course [107, 114]. Given the possibility of responsivity to immunomodulation [115], ruling out this diagnosis with muscle biopsy is important. Furthermore, identification of patients with nemaline pathology on muscle biopsy should prompt additional investigation with serum protein electrophoresis and HIV serology.

Other causes

Individual cases of sarcoid myopathy [116] and colchicine myopathy [117] have been reported and should be considered because of their management implications.

Management of chronic respiratory failure due to muscle diseases

In the absence of specific therapy to reverse or stabilise progressive muscle weakness, therapy is focussed on management of the respiratory complications. Sleep disordered breathing can be stabilised with introduction of non-invasive ventilation. Unloading of the respiratory system during the night improves ventilatory mechanics and can delay progression of respiratory impairment and ventilatory failure. Early involvement of pulmonary medicine specialists is recommended to plan for the introduction of NIV once vital capacity has fallen to ~50 % of predicted, or earlier if low mouth pressures, symptoms of sleep disordered breathing, orthopnoea, or daytime hypercapnoea as described above is present. The goal of NIV is to completely take over the work of respiration during sleep [118]. The evidence to support the use of NIV in this context was generated in observational trials followed by randomised trials in ALS populations [119] which showed improvement in survival and quality of life. Comparison of historical cohorts of DMD patients has also shown that NIV has likely contributed to the substantial improvement in longevity in these diseases. Whilst longevity is likely only to be impacted if the disease is rapidly progressive, improvement in quality of life justifies the effort of introduction of NIV where bulbar function is preserved.

Poor peak cough flow, recurrent respiratory infection, or the presence of significant atelectasis should prompt the introduction of manual or mechanical cough assist. Use of manual cough assist should be considered for individuals with persistent glottis function and good hand strength. It involves the use of a bag valve mask to deliver stacked breaths to expand the lung closer to total lung capacity. The patient will then use an abdominal thrust to increase intra-abdominal pressure and forcefully exhale. For patients unable to co-ordinate their breathing mechanical in-exsufflation can be considered. These devices deliver a positive pressure breath followed by negative pressure to suck out mobilised secretions. In addition to improving the efficiency of cough these techniques may improve lung compliance and decrease atelectasis [4]. Chest physiotherapy with percussion or other techniques to mobilise secretions may be considered if secretions are tenacious or purulent but alone are insufficient in this population [4].

Conclusion

Chronic muscle diseases presenting with ERF represent an uncommon clinical presentation. Recognising ERF and identifying the underlying condition can have important implications for patient care, particularly with the increasingly widespread availability of long-term domiciliary NIV, which is a highly effective form of treatment for many patients with symptomatic hypercapnic respiratory failure due to respiratory muscle weakness. These conditions have in common that they are mainly inherited metabolic diseases or muscular dystrophies. It is thus far unclear why these conditions involve the respiratory muscles at an early stage. As the molecular mechanism is discovered for more of these diseases, such as oculopharyngodistal muscular dystrophy, we may gain further insight on the differentiating features of respiratory muscle function compared with other skeletal muscles, and eventually design treatments targeted to respiratory muscle. These would have implications for the diseases listed above and potentially also for more common muscle diseases (such as Duchenne muscular dystrophy) which cause respiratory failure at other time-points in the disease course. This would be an important development in the treatment of muscle disease, since respiratory failure is one of the most important contributors to patient morbidity and mortality. The identification of the diseases discussed in this review are therefore important from a research point of view, to identify novel therapeutic targets which could be valuable for both rare and common muscle diseases with respiratory failure.